Native mitral valve fungal endocarditis caused by Aspergillus fumigatus: A case report.

INTRODUCTION: Aspergillus endocarditis is a rare fungal infection associated with a poor prognosis. Most cases of Aspergillus endocarditis involve prosthetic valves, with native valve involvement being rarely reported. CASE PRESENTATION: A 53-year-old asian female patient presented with fever, chills, dyspnea, generalized fatigue, and significant weight loss one month after undergoing left lower lobectomy for a pulmonary abscess. Echocardiogram showed a large mobile vegetation with a broad base on the anterior leaflet of the mitral valve, resembling atrial myxoma. Despite negative blood cultures, circulating DNA of Aspergillus fumigatus was detected by metagenome Next Generation Sequencing, prompting the initiation of empiric antifungal therapy with voriconazole. Emergency surgery, involving thorough debridement and mitral valve replacement, was successfully performed. Indefinite fungal suppression therapy with oral voriconazole is continued to mitigate the risk of recurrence. The patient survived with no signs of Aspergillus disease recurrence for four years. CLINICAL DISCUSSION: Diagnosis of Aspergillus endocarditis requires a high index of suspicion and is often delayed due to consistently negative results from blood cultures. Non-culture-based methods, particularly metagenome Next-Generation Sequencing, play a crucial role in early diagnosis and therapeutic decision-making. Surgical debridement and valve replacement are imperative for survival in cases of Aspergillus endocarditis. Voriconazole should be considered the primary fungicidal agent for its treatment. Moreover, lifelong fungal suppression therapy is strongly recommended for all survivors to ensure long-term survival and minimize the risk of recurrence. CONCLUSION: Despite grim prognosis associated with Aspergillus endocarditis, patients can attain long-term survival through meticulous surgical debridement and lifelong antifungal therapy.

Ganglioside-focused Glycan Array Reveals Abnormal Anti-GD1b Auto-antibody in Plasma of Preclinical Huntington's Disease.

Huntington's disease (HD) is a progressive and devastating neurodegenerative disease marked by inheritable CAG nucleotide expansion. For offspring of HD patients carrying abnormal CAG expansion, biomarkers that predict disease onset are crucially important but still lacking. Alteration of brain ganglioside patterns has been observed in the pathology of patients carrying HD. Here, by using a novel and sensitive ganglioside-focused glycan array, we examined the potential of anti-glycan auto-antibodies for HD. In this study, we collected plasma from 97 participants including 42 control (NC), 16 pre-manifest HD (pre-HD), and 39 HD cases and measured the anti-glycan auto-antibodies by a novel ganglioside-focused glycan array. The association between plasma anti-glycan auto-antibodies and disease progression was analyzed using univariate and multivariate logistic regression. The disease-predictive capacity of anti-glycan auto-antibodies was further investigated by receiver operating characteristic (ROC) analysis. We found that anti-glycan auto-antibodies were generally higher in the pre-HD group when compared to the NC and HD groups. Specifically, anti-GD1b auto-antibody demonstrated the potential for distinguishing between pre-HD and control groups. Moreover, in combination with age and the number of CAG repeat, the level of anti-GD1b antibody showed excellent predictability with an area under the ROC curve (AUC) of 0.95 to discriminate between pre-HD carriers and HD patients. With glycan array technology, this study demonstrated abnormal auto-antibody responses that showed temporal changes from pre-HD to HD.

Signal peptide stabilizes folding and inhibits misfolding of serum amyloid A.

Signal peptide (SP) plays an important role in membrane targeting for insertion of secretory and membrane proteins during translocation processes in prokaryotes and eukaryotes. Beside the targeting functions, SP has also been found to affect the stability and folding of several proteins. Serum amyloid A (SAA) proteins are apolipoproteins responding to acute-phase inflammation. The fibrillization of SAA results in a protein misfolding disease named amyloid A (AA) amyloidosis. The main disease-associated isoform of human SAA, SAA1.1, is expressed as a precursor protein with an N-terminal signal peptide composed of 18 residues. The cleavage of the SP generates mature SAA1.1. To investigate whether the SP affects properties of SAA1.1, we systematically examined the structure, protein stability, and fibrillization propensity of pre-SAA1.1, which possesses the SP, and Ser-SAA1.1 without the SP but containing with an additional N-terminal serine residue. We found that the presence of the SP did not significantly affect the predominant helical structure but changed the tertiary conformation as evidenced by intrinsic fluorescence and exposed hydrophobic surfaces. Pre-SAA1.1 and Ser-SAA1.1 formed distinct oligomeric assemblies in which pre-SAA1.1 populated as tetramer and octamer, whereas Ser-SAA1.1 existed as a predominant hexamer. Pre-SAA1.1 was found significantly more stable than Ser-SAA1.1 upon thermal and chemical unfolding. Ser-SAA1.1, but not pre-SAA1.1, is capable of forming amyloid fibrils in protein misfolding study, indicating a protective role of the SP. Altogether, our results demonstrated a novel role of the SP in SAA folding and misfolding and provided a novel direction for therapeutic development of AA amyloidosis.

Acute-phase serum amyloid A for early detection of hepatocellular carcinoma in cirrhotic patients with low AFP level.

Regular hepatocellular carcinoma (HCC) surveillance by ultrasonography in combination with the α-fetoprotein (AFP) examination is unsatisfactory in diagnostic sensitivity for early-stage HCC especially in cirrhotic patients. We conducted a prospective study in a tertiary medical center in Taiwan and consecutively collected serum samples from patients with chronic hepatitis, liver cirrhosis (LC), or HCC for new biomarker discovery. Overall, 166 patients were enrolled, including 40 hepatitis, 30 LC, and 96 HCC. Four acute-phase serum amyloid A (A-SAA) derived biomarkers including total A-SAA, A-SAA monomer and oligomer, and protein misfolding cyclic amplification (PMCA) signal were measured and compared between patients with and without HCC. A-SAA biomarkers significantly increased in the HCC group when compared to the hepatitis and LC groups, and generally increased in more advanced tumor stages. Among A-SAA biomarkers, the area under the receiver operator characteristic curves (AUROCs) for PMCA signal in discrimination of all-stage and early-stage HCC were 0.86 and 0.9 in cirrhotic patients, which is comparable to AFP. For cirrhotic patients with low AFP (< 7 ng/mL), PMCA signal maintained good capacity in prediction of early-stage HCC (AUROC: 0.94). Serum A-SAA and its prion-like property showed a potential to complement AFP in detection of early-stage HCC.

A Modified Technique for Valve Regurgitation After Partial Atrioventricular Septal Defect Repair.

Given its complex pathologic anatomy, recurrent left atrioventricular valve regurgitation after partial atrioventricular septal defect repair remains a challenge for surgical correction. Here, we introduce a modified bridging technique by shortening the anteroposterior leaflet distance in selected patients with inadequate coaptation to compensate for the short leaflet height, specifically that of the anterior leaflet.

The phytochemistry, pharmacology and applications of Melicope pteleifolia: A review.

ETHNOPHARMACOLOGY RELEVANCE: The leaves, stems and roots of Melicope pteleifolia (Champ. ex Benth.) T.Hartley (MP; Rutaceae, called sanyaku in Chinese; syn.: Euodia lepta), have been used traditionally for the treatment of sore throat, rheumatism, eczema, dermatitis, bruises, and insect, rat, snake bites based on traditional Chinese medicine concepts. AIM OF THIS STUDY: This paper aims to provide a comprehensive and critical analysis of studies on MP and focusing on potential relationships between traditional uses and pharmacological effects, assessing the therapeutic potential as a medicine. MATERIALS AND METHODS: Relevant data on MP were retrieved using the keywords "Melicope pteleifolia", "pharmacology", "toxicity" and "applications" in databases including "Pubmed", "SciFinder", "Springer", "Elsevier", "Wiley", "Web of Science", "Google Scholar", "China Knowledge Resource Integrated databases (CNKI)", "PhD" and "MSc dissertations", and a hand-search. RESULTS AND DISCUSSION: The heat-clearing, dampness-removing and gallbladder-normalizing actions of MP have been linked to biomedical concepts like anti-inflammatory, antioxidant and hepatoprotective activities. The latter is potentially based on the presence of furaquinoline alkaloids, phenylpropanoids and flavonoids. Analgesic, antimicrobial and anti-tumor effects have also been reported. Currently limited evidence is available relating to potential toxicological risks especially of aqueous extracts with so far no reports signalling specific risks. Although some studies on the pharmacodynamics of MP have been reported, studies on action mechanisms of MP are still rare. CONCLUSIONS: In the future and prior to initiating clinical trials, the safety, in vitro and in vivo pharmacology, and mechanism of action of MP needs to be assessed, including a focus on the link between traditional uses and modern applications. In addition, phytochemical and biological studies need to conduct on flowers and fruits of MP. Furthermore, strict quality control measures are needed in the studies investigating any aspect of the pharmacology, chemistry and biology of MP.

Morphological features of the thoracic aorta and supra-aortic branches in patients with acute Type A aortic dissection in China.

OBJECTIVES: This study aimed to investigate the morphological characteristics of the dissected thoracic aorta and brachiocephalic arteries within the Chinese population. METHODS: A retrospective analysis of computed tomography scans of 387 patients with acute Type A aortic dissection was carried out. The dimensions of the thoracic aorta at multiple levels and other imaging characteristics were studied. RESULTS: The patients with a maximum diameter ≥55 mm accounted for less than one-third of the population. Among those without Marfan syndrome (MFS) (n = 349), only 114 (32.8%) patients had a maximal aortic diameter ≥ 55 mm, whereas among those with MFS (n = 38), 20 (78.9%) had a maximal aortic diameter ≥ 45 mm. The predicted maximum aortic diameter is 88.46 - 0.81 × height (cm) + 63.02 × body surface area (m2) + 5.50 × (if diabetes, 1, if not, 0) - 6.63 × (if hypertension, 1, if not, 0). A positive correlation was established between a circular false lumen and the probability that brachiocephalic arteries were involved by dissection. The size ratio of false lumen to true lumen was greater in the circumferential group when compared with the crescent group. The independent predictors for the circumferential false lumen were age, atherosclerosis and smoking. CONCLUSIONS: Herein, the morphological characteristics of the thoracic aorta among Chinese patients with acute Type A aortic dissection were described. The currently recommended criteria for prophylactic aorta surgery were applied to most patients with MFS but not to those without MFS within the Chinese population. Furthermore, the shape of the false lumen was identified as a putative risk factor that might affect the prognosis of the patients.

Effect of Histone Deacetylase Inhibition on the Expression of Multidrug Resistance-associated Protein 2 in a Human Placental Trophoblast Cell Line.

BACKGROUND: Placental multidrug resistance-associated protein 2 (MRP2), encoded by ABCC2 gene in human, plays a significant role in regulating drugs' transplacental transfer rates. Studies on placental MRP2 regulation could provide more therapeutic targets for individualized and safe pharmacotherapy during pregnancy. Currently, the roles of epigenetic mechanisms in regulating placental drug transporters are still unclear. This study aimed to investigate the effect of histone deacetylases (HDACs) inhibition on MRP2 expression in the placental trophoblast cell line and to explore whether HDAC1/2/3 are preliminarily involved in this process. METHODS: The human choriocarcinoma-derived trophoblast cell line (Bewo cells) was treated with the HDAC inhibitors-trichostatin A (TSA) at different concentration gradients of 0.5, 1.0, 3.0, and 5.0 µmol/L. Cells were harvested after 24 and 48 h treatment. Small interfering RNA (siRNA) specific for HDAC1/HDAC2/HDAC3 or control siRNA was transfected into cells. Total HDAC activity was detected by colorimetric assay kits. HDAC1/2/3/ABCC2 messenger RNA (mRNA) and protein expressions were determined by real-time quantitative polymerase chain reaction and Western-blot analysis, respectively. Immunofluorescence for MRP2 protein expression was visualized and assessed using an immunofluorescence microscopy and ImageJ software, respectively. RESULTS: TSA could inhibit total HDAC activity and HDAC1/2/3 expression in company with increase of MRP2 expression in Bewo cells. Reduction of HDAC1 protein level was noted after 24 h of TSA incubation at 1.0, 3.0, and 5.0 µmol/L (vs. vehicle group, all P < 0.001), accompanied with dose-dependent induction of MRP2 expression (P = 0.045 for 1.0 µmol/L, P = 0.001 for 3.0 µmol/L, and P < 0.001 for 5.0 µmol/L), whereas no significant differences in MRP2 expression were noted after HDAC2/3 silencing. Fluorescent micrograph images of MRP2 protein were expressed on the cell membrane. The fluorescent intensities of MRP2 in the control, HDAC2, and HDAC3 siRNA-transfected cells were week, and no significant differences were noticed among these three groups (all P > 0.05). However, MRP2 expression was remarkably elevated in HDAC1 siRNA-transfected cells, which displayed an almost 3.19-fold changes in comparison with the control siRNA-transfected cells (P < 0.001). CONCLUSIONS: HDACs inhibition could up-regulate placental MRP2 expression in vitro, and HDAC1 was probably to be involved in this process.

[Role of c-Jun N-terminal kinase-mediated FOXO3a nuclear translocation in neuronal apoptosis in neonatal rats with hypoxic-ischemic brain damage].

OBJECTIVE: To explore the mechanisms of neuroprotective effects of c-Jun N-terminal kinase (JNK)/FOXO3a transcription factor signaling pathway inhibition on hypoxic-ischemic neuronal apoptosis in neonatal rats with hypoxic-ischemic brain damage (HIBD). METHODS: Sixty-four 7-day-old Sprague-Dawley rats were divided into four groups: hypoxia-ischemia (HI), sham-operated, JNK specific inhibitor AS601245-treated, and DMSO vehicle. Rats' cerebral cortexes were collected at 24 hours after HI. Western blot was used to detect the protein expression of JNK, p-JNK, FOXO3a, nuclear and cytoplasmic FOXO3a, Bim, and CC3. TUNEL staining was used to detect the apoptotic cells. RESULTS: Compared with the sham-operated group, p-JNK protein increased (P<0.01), nuclear protein of FOXO3a increased (P<0.01), cytoplasmic protein decreased (P<0.01), and pro-apoptotic proteins Bim and CC3 increased 24 hours after HI (P<0.01). Compared with the HI and DMSO vehicle groups, p-JNK protein was reduced (P<0.01), nuclear protein of FOXO3a was also reduced (P<0.01), cytoplasmic protein increased (P<0.01), and Bim and CC3 proteins decreased (P<0.01) in the AS601245-treated group 24 hours after HI. TUNEL positive cells were reduced in the AS601245-treated rats compared with the HI and DMSO vehicle groups 24 hours after HI (P<0.01). CONCLUSIONS: JNK activity increases in the neonatal rat brain with HI damage. JNK activity inhibition can inhibit FOXO3a translocation from cytoplasm to nucleus and downregulate the levels of pro-apoptotic proteins Bim and CC3, leading to the reduction of neuronal apoptosis.

[Investigation of pharmacokinetics and pharmacodynamics of different doses of aminophylline in very low birth weight infants].

OBJECTIVE: To study the pharmacokinetic and pharmacodynamic features of different doses of aminophylline in very low birth weight (VLBW) infants with different postmenstrual ages, weights, and ages (in days). METHODS: A total of 40 VLBW infants with apnea were enrolled. After an intravenous loading dose of 5 mg/kg aminophylline, they were randomized into two groups with different maintenance doses of aminophylline (1 mg/kg and 2 mg/kg, once every 8 hours). Blood concentrations of aminophylline and liver and renal functions were monitored at 8 hours, 3 days, and 7 days after the loading dose. Attacks of apnea were documented. Pharmacokinetic data of aminophylline were compared between the two groups. RESULTS: The steady-state plasma concentration of aminophylline and plasma clearance in the 2 mg/kg group were significantly higher than those in the 1 mg/kg group (P<0.05). However, the elimination half life was shorter in the 2 mg/kg group (P<0.05). Days of apnea attacks within 7 days after birth in the 2 mg/kg group were significantly fewer than in the 1 mg/kg group (P<0.05). Aminophylline plasma clearance was positively correlated with age (in days) after birth and postmenstrual age in both groups. CONCLUSIONS: In VLBW infants, pharmacokinetics and pharmacodynamics are different when different maintenance doses of aminophylline are given. The maintenance dose of 2 mg/kg is associated with a better effect in the treatment of apnea. Postmenstrual age and age (in days) should be considered during the adjustment of dose, and routine blood concentration monitoring should be performed.

[Clinical efficacy of preferred use of high-frequency oscillatory ventilation in treatment of neonatal pulmonary hemorrhage].

OBJECTIVE: To investigate the clinical efficacy and safety of preferred use of high-frequency oscillatory ventilation (HFOV) in the treatment of neonatal pulmonary hemorrhage. METHODS: The clinical efficacy of preferred use of HFOV (preferred use group) and rescue use of HFOV after conventional mechanical ventilation proved ineffective (rescue use group) in the treatment of 26 cases of neonatal pulmonary hemorrhage was retrospectively analyzed. The oxygenation index (OI), pulmonary hemorrhage time, hospitalization time, ventilation time, oxygen therapy time, complications, and outcome of the two groups were compared. RESULTS: Compared with the rescue use group, the preferred use group had significantly lower IO values at 1, 6, 12, 24, 48, and 72 hours after treatment (P<0.05). Compared with the rescue use group, the preferred use group had a significantly lower incidence of ventilator associated pneumonia (VAP) (P<0.05) and a significantly higher cure rate (P<0.05). There were no statistically significant differences in the incidences of pneumothorax, intracranial hemorrhage, and digestive tract hemorrhage between the two groups (P>0.05). Compared with those in the rescue use group, children who survived in the preferred use group had significantly shorter pulmonary hemorrhage time, hospitalization time, ventilation time, and oxygen therapy time (P<0.05). CONCLUSIONS: Compared with the rescue use of HFOV, preferred use of HFOV can better improve oxygenation function, reduce the incidence of VAP, shorten the course of disease, and increase cure rate while not increasing the incidence of adverse effects.

[A co-word analysis of current research on neonatal jaundice].

OBJECTIVE: To investigate the research on neonatal jaundice in recent years by co-word analysis and to summarize the hot spots and trend of research in this field in China. METHODS: The CNKI was searched with "neonate" and "jaundice" as the key words to identify the papers published from January 2009 to July 2013 that were in accordance with strict inclusion and exclusion criteria. To reveal the relationship between different high-frequency key words, Microsoft Office Excel 2013 was used for statistical analysis of key words, and Ucinet 6.0 and Netdraw were used for co-occurrence analysis. RESULTS: A total of 2 054 papers were included, and 44 high-frequency key words were extracted. The current hotspots of research on neonatal jaundice in China were displayed, and the relationship between different high-frequency key words was presented. CONCLUSIONS: There has been in-depth research on clinical manifestations and diagnosis of neonatal jaundice in China, but further research is needed to investigate the etiology, mechanism, and treatment of neonatal jaundice.

[Influence of different antibiotic strategies on outcomes of hospitalized neonates].

OBJECTIVE: To observe the outcomes of hospitalized neonates who were managed with two different antibiotics strategies, namely, the risk factor based antibiotic strategy and the combination antibiotic strategy that is based on risk factors, infection screening and monitoring. METHODS: A cohort study was performed on a control group of 4 406 cases of neonates hospitalized between January 2010 and May 2011 and an observed group of 4 476 neonates hospitalized between July 2011 and October 2012. The control group adopted the risk factor based antibiotic strategy and the observed group received a combination antibiotic strategy based on risk factors, infection screening and monitoring. The rate of antibiotic use, average length of stay, readmission rate and mortality rate were compared between the two groups. RESULTS: With the change from the risk factor based antibiotic strategy to the combination antibiotic strategy, the total rate of antibiotic use decreased from 79.6% to 50.5% (P<0.01). There were no differences in the average length of stay, readmission rate, and mortality rate between the two groups. CONCLUSIONS: The combination antibiotic strategy based on risk factors, infection screening and monitoring can reduce antibiotic use substantially and has no adverse effects on treatment outcomes in hospitalized neonates.

[Clinical application of inhaled nitric oxide in hypoxic respiratory failure of preterm infants].

Inhaled NO (iNO) has been shown to have beneficial effects on decreasing pulmonary inflammation, increasing function of surfactant and improving lung growth in prematurely born animal models. iNO has been gradually applied in the neonatal intensive care unit since its first use for persistent pulmonary hypertension (PPHN) in the early 1990's. Although many research findings have shown the benefits of iNO for hypoxic respiratory failure (HRF) of preterm infants, there is no certain evidence to support the routine use of iNO in premature infants. According to recent literature, the mechanism of iNO therapy, treatment scheme, iNO effectiveness and safety in premature infants were reviewed in this article, so as to provide bases for the clinical use of this treatment.

[Investigation on pharmacokinetics of aminophylline in very low birth weight infants].

OBJECTIVE: To investigate the pharmacokinetics of aminophylline in very low birth weight infant. METHODS: This study investigated 104 very low birth weight infants using aminophylline 5 mg/kg treating apnea who were hospitalized in our department during 2011-2012. The blood concentration of aminophylline was measured in 30 min before, 8 h and 5 d after first time loading dose, and was counterchecked every week before aminophylline withdrawal. The pharmacokinetic parameters of aminophylline were calculated and population pharmacokinetic model was established by MW/Pharm3.6 statistical analysis. RESULTS: The average birth weight of these 104 very low birth weight infants was (1.15 +/- 0.23) kg, average gestational age was (31.19 +/- 2.50) weeks. The results of aminophylline pharmacokinetics showed: the plasma clearance was (17.88 +/- 5.61) mL/(kg x h), the apparent volume of distribution was (0.93 +/- 0.18) L/kg, the half life time was (28.6 +/- 7.59) h. The aminophylline plasma clearance was related to creatinine clearance, gestational age and days of age after birth (related coefficient was 0.68, 0.62, 0.56 respectively, P < 0.05),the apparent volume of distribution was related to birth weight (related coefficient was 0.82, P < 0.05). The population pharmacokinetics model established can predict the concentration-time curve of the patients. CONCLUSION: The pharmacokinetics of aminophylline in very low birth weight infant was quite different from adult, which suggest blood concentration monitoring and dose adjustment for the clinical use of aminophylline in low birth weight infants.

[Neonatal hypophosphatasia].

Hypophosphatasia is a rare inborn disease of metabolism. This paper reviewed its pathogenesis, forms, clinical manifestations, differential diagnosis,treatment and prognosis. Here a case of neonatal hypophosphatasia is reported. This baby was female (30 minutes old). Prenatal ultrasound showed disproportionate biparietal diameter and long bones of limbs in the baby. After birth, she presented with obvious craniomalacia, respiratory distress and cyanosis. Serum alkaline phosphatase level was significantly reduced. Both X-ray and autopsy showed extremely insufficient skeletal mineralization. Four days later she died of respiratory failure.