Sex differences in the susceptibility to valproic acid-associated liver injury in epileptic patients.

BACKGROUND: Valproic acid has been widely used as an antiepileptic drug for several decades. Long-term valproic acid treatment is usually accompanied by liver injury. Although both men and women are susceptible to valproic acid-associated liver injury, hepatotoxicity differs between the sexes. However, the mechanisms underlying sex differences in valproic acid-associated liver injury remain unclear. METHODS: To explore potential risk factors for the susceptibility to valproic acid-associated liver injury, 231 pediatric patients with epilepsy (119 males, 112 females) were enrolled for laboratory and genetic analysis. RESULTS: Heterozygous genotype of catalase C-262T (P = 0.045) and the concentrations of glutathione (P = 0.002) and thiobarbituric acid-reactive substances (P = 0.011) were associated with the sex-specific susceptibility to valproic acid-associated liver injury. Meanwhile, logistic regression analysis revealed that carriers of heterozygous genotype of catalase C-262T (P = 0.010, odds ratio: 4.163; 95 percent confidence interval 1.400 - 7.378), glutathione concentration (P = 0.001, odds ratio: 2.421; 95 percent confidence interval 2.262 - 2.591) and male patients (P = 0.005, odds ratio: 1.344; 95% confidence interval 0.782 - 2.309) had a higher risk for valproic acid-associated liver injury. DISCUSSION: The mechanism underlying valproic acid-induced hepatotoxicity remains unclear. Additionally, factors that may contribute to the observed differences in the incidence of hepatotoxicity between males and females have yet to be defined. This study identifies several genetic factors that may predispose patients to valproic acid-associated hepatotoxicity. LIMITATIONS: This relatively small sample size of children with one ethnicity some of whom were taking other antiepileptics that are potentially hepatotoxic. CONCLUSION: Catalase C-262T genotype, glutathione concentration and gender (male) are potential risk factors for the susceptibility to valproic acid-associated liver injury.

Associations between one-carbon metabolism and valproic acid-induced liver dysfunction in epileptic patients.

Valproic acid (VPA) has been widely used as an antiepileptic drug for decades. Although VPA is effective and well-tolerated, long-term VPA treatment is usually associated with hepatotoxicity. However, the underlying mechanisms of VPA-caused hepatotoxicity remain unclear. In this study, a total of 157 pediatric patients with epilepsy were recruited and divided into normal liver function (NLF, 112 subjects) group and abnormal liver function (ABLF, 45 subjects) group. We observed that MTHFR A1298C and MTHFR C677T variants may be linked to VPA-induced liver dysfunction (p = 0.001; p = 0.023, respectively). We also found that the MTHFR A1298C polymorphism was associated with a higher serum Hcy level (p = 0.001) and a lower FA level (p = 0.001). Moreover, the serum Hcy levels was strongly correlated with the GSH and TBARS concentrations (r = -0.6065, P < 0.001; r = 0.6564, P < 0.001, respectively). Furthermore, logistic analysis indicated that MTHFR A1298C/C677T polymorphisms and increased Hcy concentrations may be risk factors for VPA-induced liver dysfunction. These results suggested that individual susceptibility to VPA-induced liver dysfunction may result from MTHFR A1298C/C677T polymorphisms and increased Hcy levels. This study may be helpful for the prevention and guidance of VPA-induced liver dysfunction.

Diagnosis and treatment of post-cholecystectomy diarrhoea.

The incidence of cholecystitis is relatively high in developed countries and may usually be attributed to gallstones, the treatment for which involves complete surgical removal of the gallbladder (cholecystectomy). Bile acids produced following cholecystectomy continue to flow into the duodenum but are poorly absorbed by the colon. Excessive bile acids in the colon stimulate mucosal secretion of water and electrolytes leading, in severe cases, to diarrhoea. Bile acid diarrhoea (BAD) is difficult to diagnose, requiring a comprehensive medical history and physical examination in combination with laboratory evaluation. The current work reviews the diagnosis and treatment of BAD following cholecystectomy.

Effects of Sheep Bone Collagen Peptide on Liver Lipid Deposition in Ovariectomized Rats.

Liver can be directly involved in the synthesis and decomposition of fatty acids. Liver lipid deposition is one of the most common chronic liver diseases. Estrogen deficiency can cause lipid deposition and energy metabolism disorders in the liver. Sheep bone collagen peptide (SBCP) has been shown to have estrogen-like effects in previous studies. And SBCP has high bioavailability, safety and non-toxic side effects. This study aimed to investigate the effect of SBCP on liver lipid deposition (LLD) caused by estrogen deficiency. Female Wistar rats were treated as follows (n=10): sham group: underwent peri-ovary fat removal operations, ovariectomized rats (model group), ovariectomized rats receiving SBCP treatments: SBCP high dose group (SBCP-H), SBCP medium dose group (SBCP-M) and SBCP low dose group (SBCP-L). After 8 wk, the model group demonstrated severe LLD and liver pathological changes, with increased malondialdehyde (MDA) and free fatty acid (FFA) levels (p<0.05). Additionally, the total superoxide dismutase (T-SOD) activity (p<0.05), serum albumin-to-globulin (A/G) ratio (p<0.05), amount of butyric acid-producing bacteria and short-chain fatty acids (SCFAs) content decreased. SBCP intervention could inhibit the occurrence of LLD and alleviate the liver histopathological damage induced by estrogen deficiency by relieving oxidative stress, preventing the loss of butyric acid-producing bacteria, and decreasing the abundance of Lactobacillus reuteri in the gut. The results suggested that SBCP could improve the LLD indecued by estrogen deficiency.

Involvement of CYP2E1-ROS-CD36/DGAT2 axis in the pathogenesis of VPA-induced hepatic steatosis in vivo and in vitro.

Valproic acid (VPA) is a widely prescribed antiepileptic drug, which may cause steatosis in the liver. Oxidative stress is associated with the progression of VPA-induced hepatic steatosis. However, the potential mechanisms are not fully understood. In this study, we demonstrated the involvement of CYP2E1-ROS-CD36/DGAT2 axis in the pathogenesis of VPA-induced hepatic steatosis in vitro and in vivo. First, VPA treatment (500 mg/kg in mice, 5 mM in LO2 cells) induced hepatic steatosis and enhanced reactive oxidative stress (ROS) level, and ROS scavenger, N-acetyl-L-cysteine (NAC, 200 mg/kg in mice, 1 mM in LO2 cells) reversed the changes. Next, we observed the enhanced expression and enzymatic activity of cytochrome P450 2E1 (CYP2E1) in VPA-treated mice and LO2 cells. Importantly, VPA-induced ROS accumulation and hepatic steatosis were attenuated when CYP2E1 was inhibited using CYP2E1 inhibitor, diallyl sulfide (DAS, 100 mg/kg in mice, 1 mM in LO2 cells) or in CYP2E1-knockdown cell line, suggesting that CYP2E1 plays a potential role in ROS production following hepatic steatosis. Furthermore, gene expression analysis showed that the mRNA levels of cluster of differentiation 36 (CD36), a fatty acid translocase protein and distinct diacylglycerol acyltransferase 2 (DGAT2) were significantly upregulated in mice and LO2 cells after VPA treatment, while the change was alleviated by NAC and DAS. Meanwhile, time course experiments demonstrated that the increase of CYP2E1 level occurred earlier than that of ROS, CD36 and DGAT2, and ROS generation preceded the onset of hepatic steatosis. Taken together, VPA treatment enhances the expression and enzymatic activity of CYP2E1, which promotes ROS production and then causes CD36 and DGAT2 overproduction and hepatic steatosis in mice and LO2 cells, which provides a novel insight into VPA-induced hepatic steatosis.

Sub-10-nm multicolored gold nanoparticles for colorimetric determination of antibiotics via formation of interlocking rings.

A general approach is presented for synthesis of multicolored gold nanoparticles (GNPs) by Au(I)-mediated generation of interlocking rings in proteins and antibiotics. The Au(I) ions are shuttled from proteins to antibiotics, and this causes the formation of interlocking rings. The multicolored GNPs of different sizes were synthesized in the rings by using the rapid nucleation method. To take the unique colors of GNPs, a functional array was designed for the colorimetric determination and discrimination of antibiotics, specifically of amoxicillin, chlortetracycline, erythromycin, spiramycin, neomycin, thiamphenicol, gentamycin and lincomycin. The method is based on the "three color" (RGB) principle. The color response patterns are characteristic for each antibiotic and can be quantitatively differentiated by statistical techniques. The limits of detection (LOD, at S/N = 3) for spiramycin (Sp) have been calculated to be 0.18 µM and 0.10 µM in water and milk, respectively. The good linear range (from 0.3 to 3.5 µM) has been used for the quantitative assay of Sp in a certified reference material. Graphical abstractSchematic presentation of gold nanoparticles (GNPs) synthesis via formation of interlocking rings in protein and antibiotics. The Au(I) ions mediate protein and antibiotics to be interlocking rings, which are quickly fixed via microwave reaction. The GNPs are synthesized and assembled in the rings.

Catalase C-262T Polymorphism Is a Risk Factor for Valproic Acid-Induced Abnormal Liver Function in Chinese Patients With Epilepsy.

BACKGROUND: Individual susceptibility to valproic acid (VPA)-caused hepatotoxicity might result from genetic deficiencies in the detoxification and antioxidant enzymes including glutathione S-transferases (GSTs), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx). This study aimed to investigate the relationships between GST mu 1 (GSTM1), GST theta 1 (GSTT1), CAT C-262T, GPx1 Pro200Leu, and SOD2 Val16Ala polymorphisms and the risk of abnormal liver function in Chinese epileptic patients treated with VPA monotherapy. METHODS: According to the levels of liver function indicators, a total of 267 epileptic patients between 1 and 65 years of age were divided into normal liver function group and abnormal liver function group. GSTM1 and GSTT1 polymorphisms were determined using polymerase chain reaction (PCR) amplification based on the absence of a PCR amplification product. CAT, GPx1, and SOD2 polymorphisms were identified using PCR-restriction fragment length polymorphism or direct automated DNA sequencing. RESULTS: Carriers of CAT had an increased risk of developing abnormal liver function compared with noncarriers in VPA-treated patients (odds ratio 3.968, P = 0.003). Logistic regression analyses indicated that the CAT genotype was a significant genetic risk factor for VPA-induced liver dysfunction. It suggests that individual susceptibility to VPA-induced liver dysfunction may at least partially result from genetic deficiencies in CAT C-262T.

Simple, rapid, sensitive, selective and label-free lincomycin detection by using HAuCl4 and NaOH.

A simple, rapid, sensitive, selective and label-free method is presented for the colorimetric determination of lincomycin (Lin) by using HAuCl4 and NaOH. Upon the addition of Lin, the mixture of HAuCl4 and NaOH shows a color change from colorless to blue (or dark blue). The limit of colorimetric detection is as low as 1 µM, observed both in Milli-Q water and real samples. The selectivity of Lin detection is excellent compared with 9 other common antibiotics. On the basis of the "three-color" principle of Thomas Young, we extracted the red, green and blue (RGB) alterations of the sensor in the absence and presence of different concentrations of Lin. The color changes are quantitatively illustrated by the total Euclidean distances (EDs = [ΔR2 + ΔG2 + ΔB2]1/2). The good linear relationship between the EDs and Lin concentration is used for the quantitative assay of Lin. The developed method demonstrates great potential for the detection of Lin in environmental water and milk.

CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation.

Inhibition of checkpoint kinase 1 (CHK1) is a promising therapeutic strategy to increase the effectiveness of DNA-damaging drugs in pancreatic cancer. However, owing to the multiple roles of CHK1 in the DNA damage response (DDR) pathway, the molecular mechanism of chemosensitization by CHK1 inhibitors is not definitive. In the present study, we explored the antitumor mechanism of LY2603618, a specific CHK1 inhibitor, alone or in combination with gemcitabine in 5 pancreatic cancer cell lines. LY2603618 treatment of the pancreatic cancer cell lines resulted in growth inhibition, with IC50 values ranging from 0.89 to 2.75 µM, but limited cell death. Importantly, treatment of pancreatic cancer cell lines with LY2603618 reduced the levels of pCDC25C, pCDK1, and pCDK2, accompanied by DNA damage and RRM1/2 downregulation. Furthermore, LY2603618 synergized with gemcitabine treatment to induce growth inhibition and apoptosis in pancreatic cancer cells. Mechanistic investigations showed that gemcitabine sensitization by CHK1 inhibition was associated with CDK­dependent RRM1/2 downregulation and DNA damage enhancement. These findings provide a basis for further development of combining CHK1 inhibitors and gemcitabine to treat pancreatic cancer.

Cucurbitacin B and SCH772984 exhibit synergistic anti-pancreatic cancer activities by suppressing EGFR, PI3K/Akt/mTOR, STAT3 and ERK signaling.

Cucurbitacin B (CuB) is a natural tetracyclic triterpene product and displays antitumor activity across a wide array of cancers. In this study, we explored the anti-pancreatic cancer activity of CuB alone and in combination with SCH772984, an ERK inhibitor, in vitro and in vivo. CuB inhibited proliferation of pancreatic cancer cells by arresting them in the G2/M cell cycle phase. This was associated with inhibition of EGFR expression and activity and downstream signaling, including PI3K/Akt/mTOR and STAT3. Interestingly, ERK activity was markedly enhanced by activating AMPK signaling after 12 h of CuB treatment. SCH772984 potentiates the cytotoxic effect of CuB on pancreatic cancer cells through complementary inhibition of EGFR, PI3K/Akt/mTOR, STAT3 and ERK signaling, followed by an increase in the pro-apoptotic protein Bim and a decrease in the anti-apoptotic proteins Mcl-1, Bcl-2, Bcl-xl and survivin. Furthermore, combined therapy with CuB and SCH772984 resulted in highly significant growth inhibition of pancreatic cancer xenografts. These results may provide a basis for further development of combining CuB and ERK inhibitors to treat pancreatic cancer.

Minimally invasive video-assisted double-valve replacement through right anterolateral Minithoracotomy.

OBJECTIVE: This study aimed to investigate feasibility and safety of minimally invasive video-assisted surgery for double-valve (mitral and aortic) replacement through right anterolateral minithoracotomy. METHODS: Between February 2011 and April 2013, 60 patients with combined valvular disease underwent double valve replacement, 26 of them by minimally invasive video-assisted surgery through right anterolateral minithoracotomy (study group) and 34 by median sternotomy (control group). Peripheral cardiopulmonary bypass (CPB) was established through right femoral artery and vein. The incision was made around the right breast approximately 5 cm in length. Pericardiotomy, bicaval occlusion, atriotomy and aortotomy, and double valve replacement were performed with thoracoscope. RESULTS: In the study group, times of CPB and aortic cross-clamp were 146.5 ± 40.5 min and 91.5 ± 23.4 min, respectively, which were significantly different from those in the control group, 115.4 ± 26.5 min and 75.4 ± 16.5 min (P<0.05). Thoracic drainage in the study group was significantly lower than the control group, 587 ± 245 ml (study group) versus 756 ± 267 ml (control group) (P<0.05). Length of ICU and postoperative hospital stay were shorter in the study group, 1.9 ± 0.8 and 8.7 ± 4.5 days versus 2.8 ± 1.3 and 11.2 ± 5.6 days in the control group (P<0.05), respectively. There was no statistical difference in the postoperative results of TTE (transthoracic echocardiography) (P>0.05). All patients recovered smoothly with follow-up of six months to two years, with no severe complications. CONCLUSIONS: Minimally invasive video-assisted procedure through right anterolateral minithoracotomy is a new promising approach for double valve replacement. Our study suggested that this approach was feasible, safe and had cosmetic effects.

[An analysis of RHD zygosity of Rh(D)-positive Chinese Han population].

OBJECTIVE: To investigate the RHD zygosity of Rh(D)-positive Chinese Hans in order to study the mother-fetus Rh isoimmunization prophylaxis. METHODS: Rh(D) blood group of 31 115 donors were serotyped, and the RHD zygosities were analyzed, or determined through a PCR method for 3628 donors of Rh(D)-positive individuals. RESULTS: Among the 31 115 donors, 99 were tested Rh(D)-negative by indirect antiglobulin test (IAT) (0.318%). The d frequency was 0.056 41, D was 0.943 59, and Dd heterozygosity was 0.106 45 (10.6%). However the rate was 0.090 32 (about 9.0%) after excluding DEL (IAT-negative). For the 3628 PCR tested donors, 3383 were DD (93.2%), 245 were Dd (6.8%). After excluding nonfunctional RHD alleles, 7.4% of the donors were carrying one functional RHD. It showed that an Rh(D)-negative Chinese Han woman gives an Rh(D)-negative child at a rate of 3.7%-4.5% when her husband is Rh(D)-positive. CONCLUSION: Fetus Rh(D) genotyping may be unnecessary for Chinese Hans if invasive operation was needed for prenatal diagnosis. The Rh prophylaxis could be chosen assuming an Rh(D)-positive fetus.

[18F-FDG uptake of lymphoma lesions of various histological subtypes].

BACKGROUND AND OBJECTIVE: Malignant lymphoma has high 2-fluorine-18-fluoro-2-deoxy-D-glucose (18F-FDG) uptake. This study was to analyze 18F-FDG uptake of lymphoma lesions of various histological subtypes. METHODS: FDG PET/CT images of 102 naive lymphoma patients were analyzed. The maximal standardized uptake value (SUVmax) of every single lesion and the SUVmax of mediastinal blood pool were measured and used to calculate the mean T/MB value (tumor SUVmax /mediastinal SUVmax) of every patient. The mean T/MB value of the patients with the same subtype of lymphoma was calculated. The differences in T/MB value between Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL) patients, between HL and indolent NHL, invasive NHL patients, between B-cell NHL and NK/T-cell NHL patients, and between diffuse large B-cell lymphoma (DLBCL) patients of different stages were analyzed. The expression of Ki-67 in lymph nodes from four patients with relative low T/MB value was detected. RESULTS: The T/MB values were 4.50+/-1.54 in HL patients and 5.21+/-2.86 in NHL patients (P=0.154). The T/MB value was significantly higher in invasive NHL patients than in HL and indolent NHL patients (P<0.001). The T/MB values were 5.29+/-3.00 in B-cell NHL patients and 4.91+/-2.30 in NK/T-cell NHL patients (P=0.57). There was also no significant difference between DLBCL patients of different stages. The positive rate of Ki-67 was lower in the four patients with relative low T/MB value than in positive control group. CONCLUSIONS: 18F-FDG uptake of lymphoma lesions is related to lymphoma invasion, but not related to cell origin and clinical stage. The low 18F-FDG uptake in four patients may be related to low expression of Ki-67.