Stevens-Johnson syndrome (SJS) is a rare but life-threatening skin reaction disease and carbamazepine is one of its most common causes. We report a case of SJS secondary to carbamazepine in a patient with previous pruritus due to carbamazepine which was given for treatment of trigeminal neuralgia. We would like to caution all providers that carbamazepine readministration should be avoided in the patient with a previous history of SJS or adverse skin reaction. In addition, we strongly recommend gradual titration when initiating treatment with carbamazepine.

Vertebral compression fractures (VCFs), the most common fragility fractures, account for approximately 700,000 injuries per year. Since open surgery involves morbidity and implant failure in the osteoporotic patient population, new minimally invasive biological solution to vertebral bone repair is needed. Previously, we showed that adipose-derived stem cells (ASCs) overexpressing a BMP gene are capable of inducing spinal fusion in vivo. We hypothesized that a direct injection of ASCs, designed to transiently overexpress rhBMP6, into a vertebral bone void defect would accelerate bone regeneration. Porcine ASCs were isolated and labeled with lentiviral vectors that encode for the reporter gene luciferase (Luc) under constitutive (ubiquitin) or inductive (osteocalcin) promoters. The ASCs were first labeled with reporter genes and then nucleofected with an rhBMP6-encoding plasmid. Twenty-four hours later, bone void defects were created in the coccygeal vertebrae of nude rats. The ASC-BMP6 cells were suspended in fibrin gel (FG) and injected into the bone void. A control group was injected with FG alone. The regenerative process was monitored in vivo using microCT, and cell survival and differentiation were monitored using tissue specific reporter genes and bioluminescence imaging (BLI). The surgically treated vertebrae were harvested after 12 weeks and subjected to histological and immunohistochemical (against porcine vimentin) analyses. In vivo BLI detected Luc-expressing cells at the implantation site over a 12-week period. Beginning 2 weeks postoperatively, considerable defect repair was observed in the group treated with ASC-BMP6 cells. The rate of bone formation in the stem cell–treated group was two times faster than that in the FG–treated group, and bone volume at the endpoint was twofold compared to the control group. Twelve weeks after cell injection the bone volume within the void reached the volume measured in native vertebrae. Immunostaining against porcine vimentin indicated that the ASC-BMP6 cells contributed to new bone formation. Here we show the potential of injections of BMP-modified ASCs to repair vertebral bone defects in a rat model. Our results could pave the way to a novel approach for the biological treatment of traumatic and osteoporosis-related vertebral bone injuries.

The putative tumor suppressor, DBC1 (deleted in breast cancer-1), was recently found to negatively regulate SIRT1 in vitro and in vivo, but the mechanism whereby DBC1 regulates SIRT1 in liver cancer remains to be elucidated. In this study, it was found that although the expression of DBC1 and SIRT1 was not aberrantly regulated in a large cohort of human hepatocellular carcinoma (HCC) patients, these proteins were highly overexpressed in a subset of HCC tissues compared with surrounding non-cancer tissues. In liver cancer, DBC1 and SIRT1 were found to be positively correlated. Inactivation of DBC1 or SIRT1 reduced SNU-182 (a liver cancer cell line) proliferation as determined by MTT viability assays. Notably, although DBC1 functions as a negative regulator of SIRT1 in A549 lung cancer cells since it suppresses the deacetylase activity of the p53 protein, it did not affect the p53 deacetylase activity of SIRT1 in SNU-182 cells. Taken together, we conclude that DBC1 is associated with SIRT1 in HCC, but that it does not inhibit SIRT1.

Antiphospholipid syndrome (APS) is defined as an autoimmune disorder characterized by recurrent thrombosis or obstetrical morbidity. A 29-year-old woman who was diagnosed with APS underwent emergency cesarean delivery at 23 weeks' gestation. She had a seizure attack and her laboratory findings were: AST/ALT 1459/1108 IU/L, LDH 1424 IU/L, 30% hematocrit, a platelet count of 43 × 103/ml and urine protein (4+). We describe the anesthetic experience of catastrophic HELLP syndrome with antiphospholipid syndrome and we review the relevant literature.

Histone deacetylases (HDACs) are known to play a central role in the regulation of several cellular properties interlinked with the development and progression of cancer. Recently, HDAC1 has been reported to be overexpressed in hepatocellular carcinoma (HCC), but its biological roles in hepatocarcinogenesis remain to be elucidated. In this study, we demonstrated overexpression of HDAC1 in a subset of human HCCs and liver cancer cell lines. HDAC1 inactivation resulted in regression of tumor cell growth and activation of caspase-independent autophagic cell death, via LC3B-II activation pathway in Hep3B cells. In cell cycle regulation, HDAC1 inactivation selectively induced both p21WAF1/Cip1 and p27Kip1 expressions, and simultaneously suppressed the expression of cyclin D1 and CDK2. Consequently, HDAC1 inactivation led to the hypophosphorylation of pRb in G1/S transition, and thereby inactivated E2F/DP1 transcription activity. In addition, we demonstrated that HDAC1 suppresses p21WAF1/Cip1 transcriptional activity through Sp1-binding sites in the p21WAF1/Cip1 promoter. Furthermore, sustained suppression of HDAC1 attenuated in vitro colony formation and in vivo tumor growth in a mouse xenograft model. Taken together, we suggest the aberrant regulation of HDAC1 in HCC and its epigenetic regulation of gene transcription of autophagy and cell cycle components. Overexpression of HDAC1 may play a pivotal role through the systemic regulation of mitotic effectors in the development of HCC, providing a particularly relevant potential target in cancer therapy.

Most spine fusion procedures involve the use of prosthetic fixation devices combined with autologous bone grafts rather than biological treatment. We had shown that spine fusion could be achieved by injection of bone morphogenetic protein-2 (BMP-2)-expressing mesenchymal stem cells (MSCs) into the paraspinal muscle. In this study, we hypothesized that posterior spinal fusion achieved using genetically modified MSCs would be mechanically comparable to that realized using a mechanical fixation. BMP-2-expressing MSCs were injected bilaterally into paravertebral muscles of the mouse lumbar spine. In one control group BMP-2 expression was inhibited. Microcomputed tomography and histological analyses were used to evaluate bone formation. For comparison, a group of mouse spines were bilaterally fused with stainless steel pins. The harvested spines were later tested using a custom four-point bending apparatus and structural bending stiffness was estimated. To assess the degree to which MSC vertebral fusion was targeted and to quantify the effects of fusion on adjacent spinal segments, images of the loaded spine curvature were analyzed to extract rigidity of the individual spinal segments. Bone bridging of the targeted vertebrae was observed in the BMP-2-expressing MSC group, whereas no bone formation was noted in any control group. The biomechanical tests showed that MSC-mediated spinal fusion was as effective as stainless steel pin-based fusion and significantly more rigid than the control groups. Local analysis showed that the distribution of stiffness in the MSC-based fusion group was similar to that in the steel pin fusion group, with the majority of spinal stiffness contributed by the targeted fusion at L3–L5. Our findings demonstrate that MSC-induced spinal fusion can convey biomechanical rigidity to a targeted segment that is comparable to that achieved using an instrumental fixation.

Histone deacetylase 2 (HDAC2) is crucial for embryonic development, affects cytokine signaling relevant for immune responses and is often significantly overexpressed in solid tumors; but little is known about its role in human hepatocellular carcinoma (HCC). In this study, we showed that targeted-disruption of HDAC2 resulted in reduction of both tumor cell growth and de novo DNA synthesis in Hep3B cells. We then demonstrated that HDAC2 regulated cell cycle and that disruption of HDAC2 caused G1/S arrest in cell cycle. In G1/S transition, targeted-disruption of HDAC2 selectively induced the expression of p16INK4A and p21WAF1/Cip1, and simultaneously suppressed the expression of cyclin D1, CDK4 and CDK2. Consequently, HDAC2 inhibition led to the down-regulation of E2F/DP1 target genes through a reduction in phosphorylation status of pRb protein. In addition, sustained suppression of HDAC2 attenuated in vitro colony formation and in vivo tumor growth in a mouse xenograft model. Further, we found that HDAC2 suppresses p21WAF1/Cip1 transcriptional activity via Sp1-binding site enriched proximal region of p21WAF1/Cip1 promoter. In conclusion, we suggest that the aberrant regulation of HDAC2 may play a pivotal role in the development of HCC through its regulation of cell cycle components at the transcription level providing HDAC2 as a relevant target in liver cancer therapy.

Background

Clinicians often experience extrahepatic metastases associated with hepatocellular carcinoma (HCC), even if no evidence of intrahepatic recurrence after treatment is observed. We investigated the pretreatment predictors of extrahepatic metastases in HCC patients.

Methods

Patients diagnosed with HCC without evidence of extrahepatic metastases were prospectively enrolled. We evaluated the correlation between extrahepatic metastases and pretreatment clinical variables, including serum tumor markers.

Results

A total of 354 patients were included. Seventy-six patients (21%) had extrahepatic metastases during the observation period (median, 25.3 months; range, 0.6-51.3 months). Cox regression multivariate analysis showed that serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) production levels, the intrahepatic tumor stage, platelet count, and portal vein thrombosis were independent risk factors for extrahepatic metastases. Patients with a PIVKA-II production ≥ 300 mAU/mL had a 2.7-fold (95% confidence interval; 1.5-4.8; P < 0.001) and 3.7-fold (95% confidence interval; 2.0-6.6; P < 0.001) increased risk for extrahepatic metastases after adjustment for stage, platelet count, alpha-fetoprotein ≥ 400 ng/mL, and portal vein thrombosis according to the AJCC and BCLC staging systems, respectively.

Conclusion

PIVKA-II production levels might be a good candidate predictive marker for extrahepatic HCC metastases, especially in patients with smaller and/or fewer tumors in the liver with in stages regardless of serum alpha-fetoprotein.

Background

Polyglutamine (polyQ)-induced protein aggregation is the hallmark of a group of neurodegenerative diseases, including Huntington's disease. We hypothesized that a protease that could cleave polyQ stretches would intervene in the initial events leading to pathogenesis in these diseases. To prove this concept, we aimed to generate a protease possessing substrate specificity for polyQ stretches.

Methodology/Principal Findings

Hepatitis A virus (HAV) 3C protease (3CP) was subjected to engineering using a yeast-based method known as the Genetic Assay for Site-specific Proteolysis (GASP). Analysis of the substrate specificity revealed that 3CP can cleave substrates containing glutamine at positions P5, P4, P3, P1, P2′, or P3′, but not substrates containing glutamine at the P2 or P1′ positions. To accommodate glutamine at P2 and P1′, key residues comprising the active sites of the S2 or S1′ pockets were separately randomized and screened. The resulting sets of variants were combined by shuffling and further subjected to two rounds of randomization and screening using a substrate containing glutamines from positions P5 through P3′. One of the selected variants (Var26) reduced the expression level and aggregation of a huntingtin exon1-GFP fusion protein containing a pathogenic polyQ stretch (HttEx1(97Q)-GFP) in the neuroblastoma cell line SH-SY5Y. Var26 also prevented cell death and caspase 3 activation induced by HttEx1(97Q)-GFP. These protective effects of Var26 were proteolytic activity-dependent.

Conclusions/Significance

These data provide a proof-of-concept that proteolytic cleavage of polyQ stretches could be an effective modality for the treatment of polyQ diseases.

Tumor immune escape is a major obstacle in cancer immunotherapy but the mechanisms involved remain poorly understood. We have previously developed an immune evasion tumor model using an in vivo immune selection strategy and revealed Akt-mediated immune resistance to anti-tumor immunity induced by various cancer immunotherapeutic agents. In the current study, we employed microarray gene analysis to identify an Akt-activating candidate molecule overexpressed in immune resistant tumors compared to parental tumors. X-linked lymphocyte-regulated protein pM1 (XLR) gene was the most upregulated in immune-resistant tumors compared to parental tumor cells. Furthermore, the retroviral transduction of XLR in parental tumor cells led to activation of Akt, resulting in upregulation of anti-apoptotic proteins and the induction of immune resistance phenotype in parental tumor cells. In addition, we found that transduction of parental tumor cells with other homologous genes from the mouse XLR family, such as synaptonemal complex protein 3 (SCP3) and XLR-related, meiosis regulated protein (XMR) and its human counterpart of SCP3 (hSCP3) also led to activation of Akt, resulting in the upregulation of anti-apoptotic proteins and induction of immune resistance phenotype. Importantly, characterization of a panel of human cervical cancers revealed relatively higher expression levels of hSCP3 in human cervical cancer tissue compared to normal cervical tissue. Thus, our data indicate that ectopic expression of XLR and its homologs in tumor cells represents a potentially important mechanism for tumor immune evasion and serves as a promising molecular target for cancer immunotherapy.

The purpose of this study was to investigate how advanced maternal age influences lifestyle, nutrient intake, iron status, and pregnancy outcomes in pregnant women. The subjects of this study were 112 pregnant women who were receiving prenatal care at gynecologists located in Seoul. The subjects were divided into two groups according to their ages: those over age 35 were the advanced age group of pregnant women (AP) and those under age 35 were the young age group of pregnant women (YP). General factors, nutrient intakes, iron status, and pregnancy outcomes of the two groups were then compared. It was found that 72.5% of the YP group and 51.2% of the AP group had pre-pregnancy alcohol drinking experience; indicating that the YP group had more pre-pregnancy alcohol consumption than the AP group (P < 0.05). The only difference found in nutrient intake between the two groups was their niacin intakes which were 16.83 ± 8.20 mg/day and 13.76 ± 5.28 mg/day, respectively. When gestational age was shorter than 38.7 weeks, the average infant birth weight was 2.95 ± 0.08 kg, and when gestational age was longer than 40 weeks, it averaged at about 3.42 ± 0.08 kg. In other words, as gestational age increased, infant birth weight increased (P < 0.0001), and when maternal weight increased more than 15 kg, the infant birth weight increased significantly (P < 0.05). In conclusion, in order to secure healthy human resources, with respect to advanced aged women, it is necessary to intervene by promoting daily habits that consist of strategic increases in folate and calcium intake along with appropriate amounts of exercise.

Background

The nuclear inclusion a (NIa) protease of turnip mosaic virus (TuMV) is responsible for the processing of the viral polyprotein into functional proteins. NIa was previously shown to possess a relatively strict substrate specificity with a preference for Val-Xaa-His-Gln↓, with the scissile bond located after Gln. The presence of the same consensus sequence, Val12-His-His-Gln15, near the presumptive α-secretase cleavage site of the amyloid-β (Aβ) peptide led us to hypothesize that NIa could possess activity against Aβ.

Methodology/Principal Findings

Western blotting results showed that oligomeric as well as monomeric forms of Aβ can be degraded by NIa in vitro. The specific cleavage of Aβ was further confirmed by mass spectrometry analysis. NIa was shown to exist predominantly in the cytoplasm as observed by immunofluorescence microscopy. The overexpression of NIa in B103 neuroblastoma cells resulted in a significant reduction in cell death caused by both intracellularly generated and exogenously added Aβ. Moreover, lentiviral-mediated expression of NIa in APPsw/PS1 transgenic mice significantly reduced the levels of Aβ and plaques in the brain.

Conclusions/Significance

These results indicate that the degradation of Aβ in the cytoplasm could be a novel strategy to control the levels of Aβ, plaque formation, and the associated cell death.

We investigated potential therapeutic effects of sphingosine-1-phosphate (S1P) receptor modulators FTY720 (fingolimod) and selective S1P1 agonist SEW2871 on a spontaneous autoimmune polyneuropathy (SAP) when given orally at 7 mo (anticipated disease onset) for 4 weeks. Clinical severity, electrophysiologic and histological findings were ameliorated in mice treated with 1 mg/kg of FTY720. Subsequent studies showed that SEW2871 was also effective in halting the progression of SAP, which was accompanied by decreased proliferative and cytokine responses to myelin protein zero (P0), and an increase in regulatory T cells. We conclude that S1P receptor modulators may play a therapeutic role in autoimmune neuropathies.

The aim of this study was to analyse effects that the degree of depression have on the life style variables, nutrient intake, iron indices and pregnancy outcome. Subjects were 114 pregnant women who were receiving prenatal care at a hospital in Seoul. We collected data for general characteristics and lifestyle variables from general survey instrument and for depression score from the questionnaire on depression. Dietary intakes of subjects were estimated by 24 hour dietary recall method. Also we analysed iron indices and pregnancy outcomes. We classified subjects by 10 point, which was the average depression score, into two groups [Low depression score group (LS) : High depression score group (HS)]. As to the intakes of total calcium, plant-calcium, plant-iron, potassium, total folate and dietary folate, LS group was far higher than HS group (P < 0.05, P < 0.05, P < 0.01, P < 0.001, P < 0.05, and P < 0.01, respectively). As to pre-pregnancy alcohol drinking, LS group had 41.9% in non-drinker, which was far higher than 28% in HS group in non-drinker (P < 0.05). As for drinking coffee during pre-pregnancy, pregnant women who don't drink coffee in LS group took 43.6%, which was higher than 38% in HS group (P < 0.01). Regarding delivery type, the cesarean section in LS group (18%) was significantly lower than that in HS group (45%) (P < 0.01). Bivariate analysis showed that birth weight was significantly associated with the gestational age (P < 0.01). The pregnant women with higher depression score tended to have undesirable life habit, which might affect negative pregnancy outcomes. A better understanding of how depression and intake of nutrients work together to modulate behavior will be benefit nutritional research.

The purpose of this study was to examine consumers' behaviors toward ready-to-eat foods and to develop ready-to-eat food market segmentation in Korea. The food-related lifestyle and purchase behaviors of ready-to-eat foods were evaluated using 410 ready-to-eat food consumers in the Republic of Korea. Four factors were extracted by exploratory factor analysis (health-orientation, taste-orientation, convenience-orientation, and tradition-orientation) to explain the ready-to eat food consumers' food-related lifestyles. The results of cluster analysis indicated that "tradition seekers" and "convenience seekers" should be regarded as the target segments. Chi-square tests and t-tests of the subdivided groups showed there were significant differences across marital status, education level, family type, eating-out expenditure, place of purchase, and reason for purchase. In conclusion, the tradition seekers consumed more ready-to-eat foods from discount marts or specialty stores and ate them between meals more often than the convenience seekers. In contrast, the convenience seekers purchased more ready-to-eat foods at convenience stores and ate them as meals more often than the tradition seekers. These findings suggest that ready-to-eat food market segmentation based on food-related lifestyles can be applied to develop proper marketing strategies.

This study was performed to analyze the relationship among sebum · hydration content of the skin and nutritional intake, serum antioxidant minerals and antioxidant enzymes, and lipid peroxide concentration in 50 female subjects in their 20s. The skin type was divided into Dry Skin, Mixed Skin, and Oily Skin, and the dry skin group was 14%, the mixed skin group was 56%, and the oily skin group was 30% of all subjects. The average age of the subjects was 20.54 ± 1.43 years and BMI was 20.66. The average sebum content in each group was in the order of T-zone>forehead>chin>cheek. In case of the T-zone, a significant difference between the dry skin group and the oily skin group was observed, suggesting that the area is most sensitive to sebum content by skin type. Significant differences were not observed in energy and nutrient intakes by skin type. Serum concentrations of antioxidant minerals such as copper, manganese, zinc and selenium were not significantly different among the groups, but the dry skin group tended to be higher than the oily skin group. Serum catalase was significantly higher in the oily skin group (P < 0.05), and MDA was significantly higher in the mixed skin group (P < 0.05). The hydration of the cheek and serum zinc showed a negative correlation, and the sebum content of the cheek and GPx showed a significant negative correlation. The hydration of the forehead and serum copper showed a significant negative correlation, and the hydration of the forehead and GPx showed a significant positive correlation. The hydration of the chin and serum SOD showed a significant positive correlation. With these results, it is considered that the basic condition of nutritional status can affect the skin health.

A 16-yr-old girl received liver transplantation for fulminant hepatitis. Aplastic anemia developed, and she received hematopoietic stem cell transplantation (HSCT). Eleven months after liver transplantation, abdominal lymph node enlargement and colon ulcers were observed, and colon biopsy showed posttransplant lymphoproliferative disorder (PTLD). Immunosuppression reduction was attempted, but it produced no therapeutic effect. Fourteen months after liver transplantation, she received a second HSCT due to engraftment failure, and PTLD resolved completely. The second HSCT can serve as cellular therapy for PTLD.