Emergence of ehrlichiosis by a new tick-borne Ehrlichia species in China.

OBJECTIVES: From March to June 2021, the reported number of clinically diagnosed endemic typhus in Anhui and Hubei provinces of China nearly increased four-fold compared with the monthly average numbers in last 5 years. An etiological and epidemiological investigation was initiated. METHODS: The clinical specimens from the reported patients and the potential vector ticks were collected for molecular and serological detection, as well as cell culturing assay to identify the potential pathogen. RESULTS: Polymerase chain reaction and sequence analysis of rrs and groEL showed that the pathogen from these patients was Ehrlichia sp., isolated from Haemaphysalis longicornis attached to these patients. The phylogenetic analysis based on 39 Ehrlichia genomes suggested that it should be taxonomically classified as a novel species, tentatively named "Candidatus Ehrlichia erythraense". A total of 19 of 106 cases were confirmed as Candidatus Ehrlichia erythraense infections by polymerase chain reaction, sequencing, and/or serological tests. The most frequent symptoms were fever (100%), rashes (100%), asthenia (100%), anorexia (100%), and myalgia (79%). CONCLUSION: The occurrence of the disease presenting with fever and rashes in Anhui and Hubei provinces was caused by a novel species of the genus Ehrlichia; physicians need to be aware of this newly-discovered pathogen to ensure appropriate testing, treatment, and regional surveillance.

The first reported outbreak of an undetermined species of human infection with spotted fever group Rickettsia in Lu'an, China.

OBJECTIVE: On May 2, 2017, an outbreak of unexplained fever with rashes was reported in Lu'an, China. In this study, we aimed to identify the possible pathogens, epidemiological characteristics, and risk factors of this outbreak. METHODS: We conducted descriptive field epidemiological studies. Blood samples were tested using an indirect immunofluorescence assay for Rickettsia rickettsii antibody, and nested polymerase chain reaction and gene sequencing assays were performed. RESULTS: We recruited 39 cases who had symptomatic onset from April 20 to June 8, 2017. Among these, 9 were suspected cases, 18 were probable cases, and 12 were confirmed cases. No one died. The main clinical manifestations were fever (100%), rash (100%), fatigue (97.3%), myalgia (83.8%), and anorexia (83.8%). None of the patients died. Thirty-seven patients who were treated with antibiotics during hospitalization showed significant improvement. The cases were distributed across 14 townships in 2 counties. The median age was 59 (43.0-81.0) years, of which 93.3% had a history of tea picking (28/30), and 77.3% (17/22) had a history of tick bites. The mean incubation period was 5.0 days (2.0-13.0 days). Serum IgG titers were higher in convalescent patients than in the general population (p = 0.016). Phylogenetic analysis revealed that the ompA sequences of Rickettsia sp. Lu'an-2018 had an 86.8%-99.0% sequence identity with the 23 strains of Rickettsia found worldwide. CONCLUSIONS: This was the first reported outbreak of an undetermined species of a human infection with the spotted fever group of Rickettsia in China, which might be caused by ticks biting local residents when picking tea.

High glucose alters tendon homeostasis through downregulation of the AMPK/Egr1 pathway.

Diabetes mellitus (DM) is associated with higher risk of tendinopathy, which reduces tolerance to exercise and functional activities and affects lifestyle and glycemic control. Expression of tendon-related genes and matrix metabolism in tenocytes are essential for maintaining physiological functions of tendon. However, the molecular mechanisms involved in diabetic tendinopathy remain unclear. We hypothesized that high glucose (HG) alters the characteristics of tenocyte. Using in vitro 2-week culture of tenocytes, we found that expression of tendon-related genes, including Egr1, Mkx, TGF-ß1, Col1a2, and Bgn, was significantly decreased in HG culture and that higher glucose consumption occurred. Down-regulation of Egr1 by siRNA decreased Scx, Mkx, TGF-ß1, Col1a1, Col1a2, and Bgn expression. Blocking AMPK activation with Compound C reduced the expression of Egr1, Scx, TGF-ß1, Col1a1, Col1a2, and Bgn in the low glucose condition. In addition, histological examination of tendons from diabetic mice displayed larger interfibrillar space and uneven glycoprotein deposition. Thus, we concluded that high glucose alters tendon homeostasis through downregulation of the AMPK/Egr1 pathway and the expression of downstream tendon-related genes in tenocytes. The findings render a molecular basis of the mechanism of diabetic tendinopathy and may help develop preventive and therapeutic strategies for the pathology.

Seroprevalence and risk factors of severe fever with thrombocytopenia syndrome virus infection in endemic areas.

BACKGROUND: To determine the seroprevalence, latent infection rate and risk factors for severe fever with thrombocytopenia syndrome virus (SFTSV) infection, a cross-sectional study was conducted in the general population of the Western region of Anhui Province of China from 1 September to 31 December 2014. METHODS: Twelve villages with the highest rates of endemic SFTS infection were selected from six towns in two counties in the western region of Anhui Province. Blood samples were collected and tested for the presence of SFTSV-IgG antibodies by ELISA. Each participant was interviewed using a structured questionnaire before blood collection. Participants with seropositive specimens were further investigated using another structured questionnaire. RESULTS: Of 2126 blood specimens collected, 99 (4.66%) were seropositive for SFTSV. None of the participants had been diagnosed with SFTS before the blood collection or were accompanied by fever, thrombocytopenia and leukocytopenia after blood collection. Multivariate logistic regression model analysis revealed living in areas of uncontrolled vegetation growth, long-term residents of the locality and tick bites as high risk factors for SFTSV infection. CONCLUSIONS: The overall seroprevalence of SFTSV is higher in the western region of Anhui, possibly due to latent infection, with the main risk factors being living in areas of uncontrolled vegetation growth, long-term residents of the locality and tick bites. Further investigations are warranted to clarify the modes of SFTS virus transmission, while vector management, education on tick bite prevention and personal hygiene management should be implemented for high risk groups in endemic areas.

Role of D2 dopamine receptor in adrenal cortical cell proliferation and aldosterone-producing adenoma tumorigenesis.

Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia are the two characteristic types of primary aldosteronism. Dysregulation of adrenal cortical cell proliferation contributes to both diseases. We previously demonstrated that APA expressed less dopamine D2 receptor than the respective non-tumor tissue and might contribute to the overproduction of aldosterone. As activation of D2 receptor inhibits the proliferation of various cells, downregulation of D2 receptor in APA may play a role in the tumorigenesis of APA. In this study, we demonstrate that D2 receptor plays a role in angiotensin II (AII)-stimulated adrenal cortical cell proliferation. The D2 receptor agonist, bromocriptine, inhibited AII-stimulated cell proliferation in primary cultures of the normal human adrenal cortex and APA through attenuating AII-induced phosphorylation of PK-stimulated cyclin D1 protein expression and cell proliferation. D2 receptor also inhibited AII-induced ERK1/2 phosphorylation. Our results demonstrate that, in addition to inhibiting aldosterone synthesis/production, D2 receptor exerts an anti-proliferative effect in adrenal cortical and APA cells by attenuating PKCµ and ERK phosphorylation. The lower level of expression of D2 receptor in APA may augment cell proliferation and plays a crucial role in the tumorigenesis of APA. Our novel finding suggests a new therapeutic target for primary aldosteronism.

In rat renal fibroblasts, mycophenolic acid inhibits proliferation and production of the chemokine CCL2, stimulated by tumour necrosis factor-alpha.

BACKGROUND AND PURPOSE: Renal fibroblasts play a pivotal role in the development of tubulointerstitial fibrosis, a condition highly predictive of progression towards end-stage renal disease. The present study investigated the anti-mitogenic and anti-inflammatory effects of an inhibitor of inosine monophosphate dehydrogenase, mycophenolic acid (MPA) and the mechanisms underlying its action in normal rat kidney fibroblasts (49F cells). EXPERIMENTAL APPROACH: Proliferation of 49F cells was studied by tetrazole 3-(4, 5-dimethylthiazol-2-yl-)-2,5-diphenyltetrazolium bromide (MTT) test, bromodeoxyuridine incorporation and flow cytometry. The cyclins, tumour suppressor genes and phospho-mitogen-activated protein kinases (MAPKs) were semiquantified by immunoblotting. Apoptosis was measured by quantifying the fragmented DNA and the activity of caspase 3. The monocyte chemokine CCL2 was measured by ELISA. The mRNA expression of CCL2 was measured by real-time PCR. KEY RESULTS: Mycophenolic acid dose-dependently inhibited steady-state proliferation of 49F cells by up-regulation of p21, p27 and p53, in association with a decrease in cyclins D2 and E. Treatment with MPA also triggered apoptosis of 49F cells by activating the caspase 3 cascade. Furthermore, MPA attenuated tumour necrosis factor-alpha-induced CCL2 expression through down-regulation of p38 MAPK, but not that of ERK1/2 or JNK. CONCLUSIONS AND IMPLICATIONS: The anti-mitogenic and anti-inflammatory effects of MPA were mediated by up-regulation of cell cycle inhibitors and pro-apoptotic signals, and by suppression of p38 MAPK pathway respectively. This dual effect of MPA may form the rationale for animal or clinical trials for the treatment of fibrotic renal diseases.

Impact of spiritual and religious activity on quality of sleep in hemodialysis patients.

BACKGROUND: Sleep disorders are common in hemodialysis (HD) patients. This study examined the relationship between quality of sleep (QoS) and religious/spiritual activity in HD patients. METHODS: The study subjects were 861 HD patients from 14 dialysis clinics in Taiwan. QoS and religious/spiritual activity were evaluated by the Pittsburgh Sleep Quality Index (PSQI) questionnaire and the Royal Free Questionnaire respectively. RESULTS: There was no difference in clinical parameters between the good and poor sleepers. Although total scores of religious and spiritual activity did not correlate with global PSQI score, patients who held strong 'spiritual' beliefs reported more problems in 'sleep disturbances', while those who exercised religious beliefs more strongly reported less trouble in 'daytime dysfunction'. CONCLUSION: There is no significant correlation between QoS and religious/spiritual activity globally. However, the spiritual and religious activity did associate with different components of QoS.

D4 dopamine receptor enhances angiotensin II-stimulated aldosterone secretion through PKC-epsilon and calcium signaling.

Aldosterone secretion is subjected to dopaminergic regulation. Our previous study showed that both human D2 and D4 dopamine receptors (D2R and D4R) modulate aldosterone secretion, but in opposing directions. The inhibitory effect of D2R is mediated by attenuating protein kinase C-micro (PKC-micro) and calcium-dependent signaling. The mechanism of D4R effect on angiotensin II (AII)-stimulated aldosterone secretion is explored in this study. Experiments were done with primary human adrenal cortical cells and human adrenocarcinoma (NCI-H295R) cells. Activation of different PKC isoforms was detected by specific phospho-PKC antibodies and PKC translocation. The role of calcium-dependent signaling was examined by measuring the cytoplasmic inositol 1,4,5-triphosphate (IP(3)) and calcium ([Ca(2+)](i)). The D4R agonist PD-168,077 enhanced AII-stimulated aldosterone synthesis and secretion as early as 30 min following exposure independently of the modulation of aldosterone synthase (CYP11B2) transcription. CYP11B2 mRNA level elevated by AII was augmented by D4R in the later period. These effects were reversed by the D4R antagonist L-745,870. AII activated PKC-alpha/betaII, -epsilon, and -micro but not PKC-delta, -theta, or -zeta/lambda of H295R cells. The D4R agonist selectively enhanced AII-stimulated PKC-epsilon phosphorylation and its translocation to the cell membrane. Furthermore, the D4R agonist enhanced the AII-stimulated elevation of intracellular IP(3) and [Ca(2+)](i). Inhibition of PKC-epsilon translocation by the PKC-epsilon-specific inhibitory peptide attenuated AII-stimulated aldosterone secretion, CYP11B2 mRNA expression, and elevation of intracellular IP(3) and [Ca(2+)](i). We conclude that D4R augmented aldosterone synthesis/secretion induced by AII. The mechanisms responsible for this augmentation are mediated through enhancing PKC-epsilon phosphorylation and [Ca(2+)](i) elevation.

Risk factors of early redialysis after weaning from postoperative acute renal replacement therapy.

OBJECTIVE: The aim of this study was to identify risk factors for redialysis in postoperative patients with acute renal failure (ARF) who had previously been weaned from acute dialysis. Although recovery of renal function is anticipated in patients with ARF, no data have been reported on successful weaning from acute dialysis. DESIGN AND SETTING: Retrospective observational case-control study in a 64-bed surgical ICU. PATIENTS AND METHODS: Success in discontinuing dialysis was defined as cessation from dialysis for at least 30 days. A total of 304 postoperative patients who underwent acute renal replacement therapy in a surgical ICU between July 2002 and April 2005 were included. SOFA score biochemical data and renal function parameters were assessed on the day after the last session of renal replacement therapy, designated as day 0 (D0). RESULTS: We could wean 94 patients (30.9%) from acute dialysis for more than 5 days, and 64 of these (21.1%) were successfully weaned for at least 30days. The independent predictors for resuming dialysis within 30 days were: (a) longer duration of dialysis (OR 1.06), (b) higher SOFA score on D0 (OR 1.44), (c) oliguria (urine output <100cc/8h; OR 4.17) on D1, and (d) age over 65 years (OR 6.35). The area under the ROC curve was 0.880. Two-way analysis of variance with repeated measurements over time showed a larger decline in SOFA score and an increase in urine output in patients with successful cessation of dialysis. Kaplan-Meier analysis showed a significant difference in early resumption of dialysis between patients with or without oliguria at D0. CONCLUSIONS: More than two-thirds of patients weaned from postoperative acute dialysis for more than 5 days were free of dialysis for at least 30 days. Less urine output, longer duration of dialysis, age over 65 years, and higher disease severity score are predictive of a patient's redialysis after initial weaning from acute dialysis.

Early renal replacement therapy in patients with postoperative acute liver failure associated with acute renal failure: effect on postoperative outcomes.

BACKGROUND: Acute liver failure after major surgical procedures is associated with a high risk of multiple organ failure, including acute renal failure. The optimal time to initiate renal replacement therapy for acute renal failure is controversial because of the poor overall clinical outcomes. STUDY DESIGN: From July 2002 to January 2005, all patients who had no history of liver disease, but developed acute liver failure and subsequent renal failure requiring renal replacement therapy after major surgery, at a surgical intensive care unit, were retrospectively analyzed. Patients were divided into early or late dialysis groups based on an arbitrary blood urea nitrogen cut-off level of 80 mg/dL before renal replacement therapy. RESULTS: Eighty consecutive patients (21 women), with a mean age of 57.8+/-17.0 (SD) years, comprised the study group. The late dialysis group (n=26) had a higher ICU mortality rate (p=0.02) and a lower renal function recovery rate (p=0.02) than the early dialysis group (n=54). Fifty-three (66.3%) patients died during their ICU stay. Independent risk factors for ICU mortality were renal replacement therapy modality (intermittent hemodialysis versus continuous venous-venous hemofiltration; odds ratio [OR]=4.32, 95% CI 1.26 to 14.79; p=0.02), predialysis APACHE II score> 20 (OR=6.52, 95% CI 1.61 to 26.36; p < 0.01), and late dialysis (OR=4.01, 95% CI 1.05 to 15.27; p=0.04). CONCLUSIONS: The mortality rate in postoperative patients with acute liver failure-associated acute renal failure was very high. Earlier initiation of renal replacement therapy, based on the predialysis blood urea nitrogen level, with continuous venous-venous hemofiltration might provide a better ICU survival rate.

Impact of near-death experiences on dialysis patients: a multicenter collaborative study.

BACKGROUND: People who have come close to death may report an unusual experience known as a near-death experience (NDE). This study aims to investigate NDEs and their aftereffects in dialysis patients. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 710 dialysis patients at 7 centers in Taipei, Taiwan. PREDICTOR: Demographic characteristics, life-threatening experience, depression, and religiosity. OUTCOMES: NDE and self-perceived changes in attitudes or behaviors. MEASUREMENTS: Greyson's NDE scale, Royal Free Questionnaire, 10-Question Survey, Ring's Weighted Core Experience Index, and Beck Depression Inventory. RESULTS: 45 patients had 51 NDEs. Mean NDE score was 11.9 (95% confidence interval, 11.0 to 12.9). Out-of-body experience was found in 51.0% of NDEs. Purported precognitive visions, awareness of being dead, and "tunnel experience" were uncommon (<10%). Compared with the no-NDE group, subjects in the NDE group were more likely to be women and younger at life-threatening events. Both frequency of participation in religious ceremonies and pious religious activity correlated significantly with NDE score in patients with NDEs (P < 0.01 and P = 0.01, respectively). The NDE group reported being kinder to others (P = 0.04) and more motivated (P = 0.02) after their life-threatening events than the no-NDE group. LIMITATIONS: Determining the incidence of NDEs is dependent on self-reporting. Many NDEs occurred before the patient began long-term dialysis therapy. Causality between NDE and aftereffects cannot be inferred. CONCLUSIONS: NDE is not uncommon in the dialysis population and is associated with positive aftereffects. Nephrology care providers should be aware of the occurrence and aftereffects of NDEs. The high occurrence of life-threatening events, availability of medical records, and accessibility and cooperativeness of patients make the dialysis population very suitable for NDE research.

Down-regulation of D2 dopamine receptor and increased protein kinase Cmu phosphorylation in aldosterone-producing adenoma play roles in aldosterone overproduction.

CONTEXT: The mechanism associated with the overproduction of aldosterone by aldosterone-producing adenomas (APA) is unknown. OBJECTIVE: The objective of the study was to explore the role of the D2 dopamine receptor (D2R) on aldosterone synthesis and secretion and clarify the clinical importance of this role on aldosterone overproduction in APA. RESULTS: D2R expression in APA was examined in 24 patients and was much less than that in the nontumorous adrenal cortex. D2R mRNA levels in APA were inversely correlated with CYP11B2 mRNA levels and the patient's plasma aldosterone concentration. Angiotensin II (AII)-stimulated aldosterone secretion and CYP11B2 mRNA expression in human adenocarcinoma cells (H295R) was attenuated by the D2 agonist, bromocriptine (BMC). BMC selectively attenuated AII-induced protein kinase C (PKC)-mu phosphorylation and its translocation to the cell membrane. PKCmu-specific short-hairpin RNA significantly decreased AII-induced CYP11B2 mRNA expression and aldosterone secretion. BMC also attenuated the AII-induced increase in cytoplasmic calcium, partially through an inhibition of cytoplasmic inositol 1,4,5 triphosphate production. Despite similar total PKCmu levels in APA and the nontumorous adrenal cortex, expression of phosphorylated PKCmu in APA was much higher. CONCLUSION: This is the first study to demonstrate that the D2R modulated aldosterone secretion and synthesis through a specific attenuation of PKCmu activity, as well as the intracellular calcium level. Down-regulation of the D2R in APA, in turn, increased PKCmu activity and led to overproduction of aldosterone in affected patients. The D2R may thus serve as a potential treatment target for primary aldosteronism.

Renal hypouricemia is an ominous sign in patients with severe acute respiratory syndrome.

BACKGROUND: The purpose of this study is to determine the incidence and significance of hypouricemia in patients with severe acute respiratory syndrome (SARS). Pulmonary lesions in patients with SARS are thought to result from proinflammatory cytokine dysregulation. Acute renal failure has been reported in patients with SARS, but whether cytokines can injure renal tubules is unknown. METHODS: Sixty patients diagnosed with SARS in Taiwan in April 2003 were studied. Patients were identified as hypouricemic when their serum uric acid (UA) level was less than 2.5 mg/dL (<149 micromol/L) within 15 days after fever onset. Urine UA and creatinine levels were available for 43 patients; the serum cytokines interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-alpha) were measured in 16 patients. RESULTS: Sixteen patients (26.7%) had hypouricemia (UA, 1.68 +/- 0.52 mg/dL [100 +/- 31 micromol/L]). No differences in age, sex, symptoms, vital signs, hemogram, or other biochemistry data existed between the hypouricemic and normouricemic groups. Fractional excretion (FE) of UA (FE UA) in 12 hypouricemic patients was 39.6% +/- 23.4%, significantly greater than that of 31 normouricemic patients (16.4% +/- 11.4%; P < 0.0001). After adjustments for age and sex, high FE UA was significantly associated with the lowest blood oxygenation (P = 0.001; r = -0.624). The number of catastrophic outcomes (endotracheal intubation and/or death) adjusted for older age and sex showed that hypouremic patients had an odds ratio of 10.57 (confidence interval, 2.33 to 47.98; P = 0.002). Kaplan-Meier curves for catastrophic outcome-free results showed significant differences between patients with normouricemia or hypouricemia (P = 0.01). Serum IL-8 levels correlated significantly with FE UA (P < 0.001; r = 0.785) and inversely with serum UA level (P = 0.044; r = -0.509); neither IL-6 nor TNF-alpha level showed such correlations. CONCLUSION: One fourth of patients with SARS developed hypouricemia, which might result from a defect in renal UA handling and was associated with a high serum IL-8 level. Renal hypouricemia is an ominous sign in patients with SARS.