Psychiatric disorders such as depression, anxiety and alcohol dependence are associated with serotonin metabolism. We assessed the methylation level of the serotonin transporter (5-HTT) promoter region in control and alcohol dependent patients.
Twenty seven male patients who met the Diagnostic and Statistical Manual of Mental Disorder IV (DSM-IV) criteria for alcohol dependence were compared with fifteen controls. Polymerase chain reaction (PCR) assays of bisulfate-modified DNA were designed to amplify a part of the CpG island in the 5HTT gene. Pyrosequencing was performed and the methylation level at seven CpG island sites was measured.
We found no differences in the methylation patterns of the serotonin transporter linked promoter region (5-HTTLPR) between
alcohol-dependent and control subjects.
Our negative finding may be because 5-HTT epigenetic variation may not affect the expression for 5-HTT or there may be other methylation site critical for its expression. To find out more conclusive result, repeating the study in more methylation sites with a larger number of samples in a well-controlled setting is needed.
Serotonin transporter region (5-HTTLPR); Methylation; Alcohol dependence
Biomarkers associated with response to therapy in tuberculosis could have broad clinical utility. We postulated that the frequency of Mycobacterium tuberculosis (Mtb) specific CD8+ T cells, by virtue of detecting intracellular infection, could be a surrogate marker of response to therapy and would decrease during effective antituberculosis treatment.
Objectives: We sought to determine the relationship of Mtb specific CD4+ T cells and CD8+ T cells with duration of antituberculosis treatment.
Materials and Methods
We performed a prospective cohort study, enrolling between June 2008 and August 2010, of HIV-uninfected Ugandan adults (n = 50) with acid-fast bacillus smear-positive, culture confirmed pulmonary TB at the onset of antituberculosis treatment and the Mtb specific CD4+ and CD8+ T cell responses to ESAT-6 and CFP-10 were measured by IFN-γ ELISPOT at enrollment, week 8 and 24.
There was a significant difference in the Mtb specific CD8+ T response, but not the CD4+ T cell response, over 24 weeks of antituberculosis treatment (p<0.0001), with an early difference observed at 8 weeks of therapy (p = 0.023). At 24 weeks, the estimated Mtb specific CD8+ T cell response decreased by 58%. In contrast, there was no significant difference in the Mtb specific CD4+ T cell during the treatment. The Mtb specific CD4+ T cell response, but not the CD8+ response, was negatively impacted by the body mass index.
Our data provide evidence that the Mtb specific CD8+ T cell response declines with antituberculosis treatment and could be a surrogate marker of response to therapy. Additional research is needed to determine if the Mtb specific CD8+ T cell response can detect early treatment failure, relapse, or to predict disease progression.
We aimed to determine the characteristic adverse events (AEs) of iodinated contrast media (IOCM) and to compare the safety profiles of different IOCM. This study used the database of AEs reports submitted by healthcare professionals from 15 Regional Pharmacovigilance Centers between June 24, 2009 and December 31, 2010 in Korea. All reports of IOCM, including iopromide, iohexol, iopamidol, iomeprol, ioversol, iobitridol and iodixanol, were analyzed. Safety profiles were compared between different IOCM at the system organ level using the proportional reporting ratio (PRR) and 95% confidence interval (95% CI). Among a total of 48,261 reports, 6,524 (13.5%) reports were related to the use of IOCM. Iopromide (45.5%), iohexol (16.9%), iopamidol (14.3%) and iomeprol (10.3%) were identified as frequently reported media. 'Platelet, bleeding & clotting disorders' (PRR, 29.6; 95%CI, 1.9-472.6) and 'urinary system disorders' (PRR, 22.3; 95% CI, 17.1-29.1) were more frequently reported for iodixanol than the other IOCM. In conclusion, the frequency of AEs by organ class was significantly different between individual media. These differences among different IOCM should be considered when selecting a medium among various IOCM and when monitoring patients during and after its use to ensure optimum usage and patient safety.
Contrast Media; Adverse Drug Reaction Reporting Systems; Patient Safety
We verified the reliability and validity of the Korean version of the Minneapolis-Manchester Quality of Life Instrument-Adolescent Form (KMMQL-AF) among Korean childhood cancer survivors. A total of 107 childhood cancer patients undergoing cancer treatment and 98 childhood cancer survivors who completed cancer treatment were recruited. To assess the internal structure of the KMMQL-AF, we performed multi-trait scaling analyses and exploratory factor analysis. Additionally, we compared each domains of the KMMQL-AF with those of the Karnofsky Performance Status Scale and the Revised Children's Manifest Anxiety Scale (RCMAS). Internal consistency of the KMMQL-AF was sufficient (Cronbach's alpha: 0.78-0.92). In multi-trait scaling analyses, the KMMQL-AF showed sufficient construct validity. The "physical functioning" domain showed moderate correlation with Karnofsky scores and the "psychological functioning" domain showed moderate-to-high correlation with the RCMAS. The KMMQL-AF discriminated between subgroups of different adolescent cancer survivors depending on treatment completion. The KMMQL-AF is a sufficiently reliable and valid instrument for measuring quality of life among Korean childhood cancer survivors.
Quality of Life; Questionnaires; Validation Studies; Child Psychology; Neoplasms; Survivors
Nerve growth factor (NGF) is a neurotrophin and has been suggested to induce heme oxygenase-1 (HO1) expression. Although the role of HO1 in tumorigenesis remains controversial, recent evidence suggests NGF and HO1 as tumor-progressing factors. However, the correlative role of NGF and HO1 and their prognostic impact in breast carcinoma is unknown.
We investigated the expression and prognostic significance of the expression of NGF and HO1 in 145 cases of breast carcinoma.
Immunohistochemical expression of NGF and HO1 was observed in 31% and 49% of breast carcinoma, respectively. The expression of NGF and HO1 significantly associated with each other, and both have a significant association with histologic grade, HER2 expression, and latent distant metastasis. The expression of NGF and HO1 predicted shorter overall survival of breast carcinoma by univariate and multivariate analysis. NGF expression was an independent prognostic indicator for relapse-free survival by multivariate analysis. The combined expression pattern of NGF and HO1 was also an independent prognostic indicator of overall survival and relapse-free survival. The patients with tumors expressing NGF had the shortest survival and the patients with tumor, which did not express NGF or HO1 showed the longest survival time.
This study has demonstrated that individual expression of NGF or HO1, and the combined NGF/HO1 expression pattern could be prognostic indicators for breast carcinoma patients.
Nerve growth factor; Heme oxygenase-1; Carcinoma; Breast
Cytokines activate several inflammatory signals that mediate β-cell destruction. We recently determined that SPA0355 is a strong anti-inflammatory compound, thus reporting its efficacy in protecting β cells from various insults. The effects of SPA0355 on β-cell survival were studied in RINm5F cells and primary islets. The protective effects of this compound on the development of type 1 diabetes were evaluated in non-obese diabetic (NOD) mice. SPA0355 completely prevented cytokine-induced nitric oxide synthase (iNOS) expression and cytotoxicity in RINm5F cells and isolated islets. The molecular mechanism of SPA0355 inhibition of iNOS expression involves the inhibition of nuclear factor κB and Janus kinase signal transducer and activator of transcription pathways. The protective effects of SPA0355 against cytokine toxicity were further demonstrated by normal insulin secretion and absence of apoptosis of cytokine-treated islets. In experiments with NOD mice, the occurrence of diabetes was efficiently reduced when the mice were treated with SPA0355. Therefore, SPA0355 might be a valuable treatment option that delays the destruction of pancreatic β cells in type 1 diabetes.
β-cell; cytokine; NF-κB; SPA0355; STAT; type 1 diabetes
This study estimated the association of cardiovascular health behaviors with the risk of all-cause and cardiovascular disease (CVD) mortality in middle-aged men in Korea.
In total, 12 538 men aged 40 to 59 years were enrolled in 1993 and followed up through 2011. Cardiovascular health metrics defined the following lifestyle behaviors proposed by the American Heart Association: smoking, physical activity, body mass index, diet habit score, total cholesterol, blood pressure, and fasting blood glucose. The cardiovascular health metrics score was calculated as a single categorical variable, by assigning 1 point to each ideal healthy behavior. A Cox proportional hazards regression model was used to estimate the hazard ratio of cardiovascular health behavior. Population attributable risks (PARs) were calculated from the significant cardiovascular health metrics.
There were 1054 total and 171 CVD deaths over 230 690 person-years of follow-up. The prevalence of meeting all 7 cardiovascular health metrics was 0.67%. Current smoking, elevated blood pressure, and high fasting blood glucose were significantly associated with all-cause and CVD mortality. The adjusted PARs for the 3 significant metrics combined were 35.2% (95% confidence interval [CI], 21.7 to 47.4) and 52.8% (95% CI, 22.0 to 74.0) for all-cause and CVD mortality, respectively. The adjusted hazard ratios of the groups with a 6-7 vs. 0-2 cardiovascular health metrics score were 0.42 (95% CI, 0.31 to 0.59) for all-cause mortality and 0.10 (95% CI, 0.03 to 0.29) for CVD mortality.
Among cardiovascular health behaviors, not smoking, normal blood pressure, and recommended fasting blood glucose levels were associated with reduced risks of all-cause and CVD mortality. Meeting a greater number of cardiovascular health metrics was associated with a lower risk of all-cause and CVD mortality.
Cardiovascular diseases; Cohort studies; Cox proportional hazards models; Life style; Mortality
There is growing evidence that inflammatory processes of activated microglia could play an important role in the progression of nerve cell damage in neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease which harbor features of chronic microglial activation, though the precise mechanism is unknown. In this study, we presented in vivo and ex vivo experimental evidences indicating that activated microglia could exacerbate the survival of axotomized dopaminergic neurons and that appropriate inactivation of microglia could be neuroprotective.
The transection of medial forebrain bundle (MFB) of a rat induced loss of dopaminergic neurons in a time-dependent manner and accompanied with microglial activation. Along with microglial activation, production of reactive oxygen species (ROS) was upregulated and TH/OX6/hydroethidine triple-immunofluorescence showed that the microglia mainly produced ROS. When the activated microglial cells that were isolated from the substantia nigra of the MFB axotomized animal, were transplanted into the substantia nigra of which MFB had been transected at 7 days ago, the survival rate of axotomized dopaminergic neurons was significantly reduced as compared with sham control. Meanwhile, when the microglial activation was attenuated by administration of tuftsin fragment 1-3 (microglia inhibitory factor) into the lateral ventricle using mini-osmotic pump, the survival rate of axotomized dopaminergic neurons was increased.
The present study suggests that activated microglia could actively produce and secrete unfavorable toxic substances, such as ROS, which could accelerate dopaminergic neuronal cell loss. So, well-controlled blockade of microglial activation might be neuroprotective in some neuropathological conditions.
Medial forebrain bundle (MFB); Axotomy; Activated microglia; Reactive oxygen species; Tuftsin fragment 1-3
Simian-human immunodeficiency virus (SHIV) models for human immunodeficiency virus (HIV) infection have been widely used in passive studies with HIV neutralizing antibodies (NAbs) to test for protection against infection. However, because SHIV-infected adult macaques often rapidly control plasma viremia and any resulting pathogenesis is minor, the model has been unsuitable for studying the impact of antibodies on pathogenesis in infected animals. We found that SHIVSF162P3 infection in 1-month-old rhesus macaques not only results in high persistent plasma viremia but also leads to very rapid disease progression within 12 to 16 weeks. In this model, passive transfer of high doses of neutralizing IgG (SHIVIG) prevents infection. Here, we show that at lower doses, SHIVIG reduces both plasma and peripheral blood mononuclear cell (PBMC)-associated viremia and mitigates pathogenesis in infected animals. Moreover, production of endogenous NAbs correlated with lower set-point viremia and 100% survival of infected animals. New SHIV models are needed to investigate whether passively transferred antibodies or antibodies elicited by vaccination that fall short of providing sterilizing immunity impact disease progression or influence immune responses. The 1-month-old rhesus macaque SHIV model of infection provides a new tool to investigate the effects of antibodies on viral replication and clearance, mechanisms of B cell maintenance, and the induction of adaptive immunity in disease progression.
The aim of this study is to observe the outcome of critically ill patients in relation to blood glucose level at admission and to determine the optimal range of blood glucose at admission predicting lower hospital mortality among critically ill patients.
We conducted a retrospective cohort study of a total 1,224 subjects (males, 798; females, 426) admitted to intensive care unit (ICU) from 1 January 2009 to 31 December 2010. Blood glucose levels at admission were categorized into four groups (group 1, <100 mg/dL; group 2, 100 to 199 mg/dL; group 3, 200 to 299 mg/dL; and group 4, ≥300 mg/dL).
Among 1,224 patients, 319 patients were already known diabetics, and 296 patients died in ICU. Five hundred fifty-seven subjects received insulin therapy, and 118 received oral hypoglycemic agents. The overall mortality rate was 24.2% (296 patients). The causes of death and mortality rates of diabetic patients were not different from nondiabetic subjects. The mortality curve showed J shape, and there were significant differences in mortality between the groups of blood glucose levels at admission. Group 2 had the lowest mortality rate (P<0.05).
These results suggest that serum glucose levels upon admission into ICU is associated with clinical outcomes in ICU patients. Blood glucose level between 100 and 199 mg/dL at the time of ICU admission could predict lower hospital mortality among critically ill patients.
Blood glucose; Intensive care units; Mortality
To translate the English Victorian Institute of Sport Assessment for patellar tendinopathy (VISA-P) questionnaire into a Korean version and to determine the reliability and validity of the Korean version.
The English VISA-P questionnaire was translated into Korean according to the internationally recommended guidelines. Then, 28 adolescent elite volleyball athletes (average age, 16 years; range, 14 to 19 years) were asked to complete the questionnaire three times (before examination, after examination, and 1 week later) for reliability. They were evaluated through a physical examination and ultrasonography to diagnosis patellar tendinopathy.
The internal consistency of the VISA-P questionnaire by Cronbach's alpha was 0.80 for the first, 0.78 for the second, and 0.79 for the third assessment. The intraclass correlation coefficient (ICC) between the first and second assessments was 0.97. The ICC between the second and third assessments was 0.96. The mean VISA-P scores were 67.6±15.7 for the patellar tendinopathy group (n=23) and 92.6±8.6 for the normal group (n=5). There were significantly lower VISA-P scores in the patellar tendinopathy group compared to the normal group.
The translated Korean version VISA-P questionnaire has good internal consistency, test-retest reliability and validity. In addition, this study indicated that most adolescent elite volleyball athletes had patellar tendon problems. Therefore, the Korean version VISA-P is a useful self-administered outcome score of athletes with patellar tendinopathy.
Patellar tendon; Tendinopathy; Athletes; Reliability; Validity
To estimate effective dose during CT-guided cryoablation of liver tumors, and to assess which procedural factors contribute most to dose.
Materials and methods
Our institutional review board approved this retrospective, HIPAA-compliant study. A total of 20 CT-guided percutaneous liver tumor cryoablation procedures were performed in 18 patients. Effective dose was determined by multiplying the dose length product for each CT scan obtained during the procedure by a conversion factor (0.015 mSv/mGy-cm), and calculating the sum for each phase of the procedure: planning, targeting, monitoring, and post-ablation survey. Effective dose of each phase was compared using a repeated measures analysis. Using Spearman correlation coefficients, effective doses were correlated with procedural factors including number of scans, ratio of targeting distance to tumor size, anesthesia type, number of applicators, performance of ancillary procedures (hydrodissection and biopsy), and use of CT fluoroscopy.
Effective dose per procedure was 72 ± 18 mSv. The effective dose of targeting (37.5 ± 12.5 mSv) was the largest component compared to the effective dose of the planning phase (4.8 ± 2.2 mSv), the monitoring phase (25.5 ± 6.8 mSv), and the post-ablation survey (4.1 ± 1.9 mSv) phase (p < 0.05). Effective dose correlated positively only with the number of scans (p < 0.01).
The effective dose of CT-guided percutaneous cryoablation of liver tumors can be substantial. Reducing the number of scans during the procedure is likely to have the greatest effect on lowering dose.
Interventional oncology; Radiation; Cryoablation; Liver; Cancer
Immune complex-mediated complement activation through the classic pathway plays a key role in the pathogenesis of lupus nephritis (LN). C4d deposition in renal tissue reflects the prognosis of systemic lupus erythematosus (SLE). The aim of the current study is to investigate the pathogenesis and clinicopathologic significance of glomerular C4d deposition in LN. We retrospectively analyzed clinical and histopathological data of 20 SLE patients with renal biopsy-proven LN and 10 non-SLE renal biopsy samples as control. LN biopsies showed varying degrees of glomerular C4d staining associated with immune complex deposits, IgG (p = 0.015), C1q (p = 0.032) and C3 (p = 0.049). 7 LN biopsies had all of C4d, C1q and C3 deposits in their glomeruli, indicative of the activation of the classical pathway, whereas 2 LN biopsies had C4d and C3 deposits without accompanying C1q deposits, indicating the activation of the lectin pathway. Glomerular C4d deposition was correlated with the LN subtype (p < 0.001). In particular, a diffusely intense and coarsely granular pattern of C4d deposition in all glomeruli was detected in class V membranous LN. However, glomerular C4d deposition was correlated with neither disease activity of SLE nor histological activity and chronicity of LN. In conclusion, the activation of the lectin pathway as well as the classical pathway seems to play a crucial role in the pathogenesis of LN. Glomerular C4d staining could be helpful for diagnosing class V membranous LN, although glomerular C4d deposition does not reflect SLE disease activity and histological activity and chronicity.
Lupus nephritis; C4d; classical pathway; lectin pathway; disease activity
HIV-1 Envelope (Env) protein is the sole target of neutralizing antibodies (NAbs) that arise during infection to neutralize autologous variants. Under this immune pressure, HIV escape variants are continuously selected and over the course of infection Env becomes more neutralization resistant. Many common alterations are known to affect sensitivity to NAbs, including residues encoding potential N-linked glycosylation sites (PNGS). Knowledge of Env motifs associated with neutralization resistance is valuable for the design of an effective Env-based vaccine so we characterized Envs isolated longitudinally from a SHIVSF162P4 infected macaque for sensitivity to neutralizing monoclonal antibodies (MAbs) B12, 2G12, 4E10 and 2F5. The early Env, isolated from plasma at day 56 after infection, was the most sensitive and the late Env, from day 670, was the most resistant to MAbs. We identified four PNGS in these Envs that accumulated over time at positions 130, 139, 160 and 397. We determined that removal of these PNGS significantly increased neutralization sensitivity to 2G12, and conversely, we identified mutations by in silico analyses that contributed resistance to 2G12 neutralization. In order to expand our understanding of these PNGS, we analyzed Envs from clade B HIV-infected human subjects and identified additional glycan and amino acid changes that could affect neutralization by 2G12 in a context-dependent manner. Taken together, these in vitro and in silico analyses of clade B Envs revealed that 2G12 resistance is achieved by previously unrecognized PNGS substitutions in a context-dependent manner and by subject-specific pathways.
To determine the effect of a 45° reclining sitting posture on swallowing in patients with dysphagia.
Materials and Methods
Thirty-four patients with dysphagia were evaluated. Videofluoroscopic swallowing study was performed for each patient in 90° upright and in 45° reclining sitting posture. Patients swallowed 5 types of boluses twice: sequentially 2 mL thin liquid, 5 mL thin liquid, thick liquid, yogurt, and cooked rice. Data such as the penetration-aspiration scale (PAS), oral transit time (OTT), pharyngeal delay time (PDT), pharyngeal transit time (PTT), residue in valleculae and pyriform sinuses, premature bolus loss, and nasal penetration were obtained.
The mean PAS on the 2 mL thin liquid decreased significantly in the 45° reclining sitting posture (p=0.007). The mean PAS on 5 mL thin liquid in the 45° reclining sitting posture showed decreasing tendency. The residue in valleculae decreased significantly for all boluses in the 45° reclining sitting posture (p<0.001, p=0.002, p=0.003, p<0.001, p=0.020, respectively). The residue in pyriform sinuses increased significantly on 5 mL thin liquid, thick liquid, and yogurt (p=0.031, p=0.020, p=0.002, respectively). There were no significant differences in OTT, PDT, PTT, premature bolus loss, and nasal penetration between both postures.
PAS on 2 mL thin liquid and residue in valleculae on all types of boluses were decreased in a 45° reclining sitting posture. Therefore, we believe that the 45° reclining sitting posture on swallowing is beneficial for the patients with penetration or aspiration on small amounts of thin liquid and large amounts of residue in valleculae.
Dysphagia; posture; swallowing
The authors present a rare of prenatally diagnosed congenital anaplastic astrocytoma. A 9-month-old boy had three recurrences despite two surgical resections and various chemotherapeutic regimens. He underwent the 3rd gross tumor removal at 11 months of age, followed by proton therapy, and now he remains disease-free for 3 yr without a significant neurocognitive dysfunction. This is the 1st case of a pediatric tumor treated by proton therapy in Korea, and proton therapy may be a treatment of choice for a congenital anaplastic astrocytoma in infants and young children, considering limitation of radiation therapy.
Congenital Anaplastic Astrocytoma; Proton Therapy; Recurrence
HIV-1 infection results in the development of a diverging quasispecies unique to each infected individual. Envelope (Env)-specific neutralizing antibodies (NAbs) typically develop over months to years after infection and initially are limited to the infecting virus. In some subjects, antibody responses develop that neutralize heterologous isolates (HNAbs), a phenomenon termed broadening of the NAb response. Studies of co-crystalized antibodies and proteins have facilitated the identification of some targets of broadly neutralizing monoclonal antibodies (NmAbs) capable of neutralizing many or most heterologous viruses; however, the ontogeny of these antibodies in vivo remains elusive. We hypothesize that Env protein escape variants stimulate broad NAb development in vivo and could generate such NAbs when used as immunogens. Here we test this hypothesis in rabbits using HIV Env vaccines featuring: (1) use of individual quasispecies env variants derived from an HIV-1 subtype A-infected subject exhibiting high levels of NAbs within the first year of infection that increased and broadened with time; (2) motif optimization of envs to enhance in vivo expression of DNA formulated as vaccines; and (3) a combined DNA plus protein boosting regimen. Vaccines consisted of multiple env variants delivered sequentially and a simpler regimen that utilized only the least and most divergent clones. The simpler regimen was as effective as the more complex approach in generating modest HNAbs and was more efficient when modified, motif-optimized DNA was used in combination with trimeric gp140 protein. This is a rationally designed strategy that facilitates future vaccine design by addressing the difficult problem of generating HNAbs to HIV by empirically testing the immunogenicity of naturally occurring quasispecies env variants.
In vivo magnetic resonance spectroscopy (MRS) has previously been used to directly monitor brain ethanol. It has been proposed that the ethanol methyl 1H resonance intensity is larger in ethanol-tolerant individuals than in sensitive individuals. To characterize the relationship between long-term ethanol exposure and the brain ethanol MRS intensity, we present data from a longitudinal experiment conducted using nonhuman primate subjects.
In vivo MRS was used to measure the gray matter (GM) and white matter (WM) ethanol methyl 1H MRS intensity in 18 adult male rhesus macaques at four time points throughout the course of a chronic drinking experiment. Time points were prior to ethanol drinking, following a 3-month ethanol induction procedure, and following six, and twelve subsequent months of 22-hours/day of “open access” to ethanol (4% w/v) and water.
The ethanol methyl 1H MRS intensity, which we observed to be independent of age over the range examined, increased with chronic ethanol exposure in GM and WM. In GM, MRS intensity increased from naive-level following the ethanol induction period (90 g/kg cumulative ethanol intake). In WM, MRS intensity was not significantly different from the ethanol-naïve state until after 6 months of 22-hours free access (110–850 g/kg cumulative intake range). The WM MRS intensity in the ethanol-naive state was positively correlated with future drinking, and the increase in WM MRS intensity was negatively correlated with the amount of ethanol consumed throughout the experiment.
Chronic exposure to ethanol is associated with brain changes that result in differential increases in ethanol MRS intensity in GM and WM. The ethanol-naïve WM MRS intensity pattern is consistent with its previously proposed relationship to innate tolerance to the intoxicating effects of ethanol. Ethanol-dependent MRS intensity changes in GM required less ethanol exposure than was necessary to produce changes in WM. Within WM, an unexpected, potentially age-dependent, enhanced sensitivity to ethanol in light drinkers relative to heavy drinkers was observed.
Nonhuman primate; Magnetic resonance spectroscopy; Self administration; Gray matter; Ethanol
Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumors characterized by a multistep process of tumor development. Nodular lesions that differ from the surrounding liver parenchyma and are characterized by cytological or structural atypia are termed dysplastic nodules (DNs). DNs are well-known precancerous HCC lesions. Expression of keratin (K) 19 and K7, molecular markers of hepatic progenitor cells and cholangiocytes, has been reported in certain HCCs. However, it remains unclear whether K19-positive HCC cells are derived from true hepatic progenitor cells or mature cells that have undergone a dedifferentiation or a transdifferentiation process. In total, 107 tissue sections (13 low-grade DNs, 15 high-grade DNs, 27 small HCCs and 52 large HCCs) from resected liver samples and 132 HCC tissue microarray (TMA) cores were subjected to immunohistochemical analysis for K19 and K7. Clinicopathological data of the HCC patients were evaluated. K19 expression was found in 0% of DNs, 19% of small HCCs (≤2 cm), 8% of large HCCs (>2 cm) and 8% of TMA samples. K7 expression was found in 14% of DNs, 41% of small HCCs, 15% of large HCCs and 6% of TMA samples. Among the five K19-positive small HCCs, four were distinctly nodular and one tumor was an infiltrative type. No vaguely nodular HCC was positive for K19. K19 expression was significantly associated with histological grade (P=0.023), serum α-fetoprotein level (P=0.001) and K7 expression (P=0.001) in HCC. K19 expression was an independent prognostic factor for overall survival in non-viral HCC patients (P=0.003). K19 expression is extremely rare in DNs and occurs in progressed small HCCs. Our results suggest that K19 expression may be an acquired feature of carcinoma cells during HCC progression in certain HCCs.
carcinoma; hepatocellular; keratin; dysplastic nodule
Contribution of the vestibular end organ to regulation of arterial pressure was quantitatively compared with the role of baroreceptors in terms of baroreflex sensitivity and c-Fos protein expression in the rostral ventrolateral medulla (RVLM). Baroreflex sensitivity and c-Fos protein expression in the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or baroreceptor unloading. BL attenuated baroreflex sensitivity during intravenous infusion of sodium nitroprusside (SNP), but did not significantly affect the sensitivity following infusion of phenylephrine (PE). Baroreflex sensitivity became positive following sinoaortic denervation (SAD) during infusion of PE and attenuated sensitivity during infusion of SNP. Baroreflex sensitivity also became positive following double ablation (BL+SAD) during infusion of PE, and attenuated sensitivity during infusion of SNP. c-Fos protein expression increased significantly in the RVLM in the sham group after SNP administration. However, the BL, SAD, and SAD+BL groups showed significant decreases in c-Fos protein expression compared with that in the sham group. The SAD group showed more reduced c-Fos protein expression than that in the BL group, and the SAD+BL group showed less expression than that in the SAD group. These results suggest that the vestibular system cooperates with baroreceptors to maintain arterial pressure during hypotension but that baroreceptors regulate arterial pressure during both hypotension and hypertension. Additionally, afferent signals for maintaining blood pressure from the vestibular end organs and the baroreceptors may be integrated in the RVLM.
Baroreceptor; Blood pressure; c-Fos protein; Rostral ventrolateral medulla; Vestibular system
Airway remodeling and exacerbated airway narrowing in asthma have been attributed to the regulation of intracellular Ca2+ by sarcoplasmic reticulum (SR) of the airway smooth muscle cells. The protein encoded by obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF (OBSCN) is a crucial factor in determining the SR architecture in Obscn−/− mice. This study genotyped a total of 55 common single-nucleotide polymorphisms (SNPs) in 592 Korean asthmatics including 163 aspirin exacerbated respiratory disease (AERD) cases and 429 aspirin-tolerant asthma (ATA) controls. Eight SNPs, including two nonsynonymous polymorphisms rs1188722C>T (Leu2116Phe) and rs1188729G>C (Cys4642Ser), and one haplotype BL2_ht1 showed statistically significant associations with AERD development (p=0.003–0.03). Two variants, rs1188722C>T (Leu2116Phe) and rs369252C>A, also revealed nominal association with FEV1 decline by aspirin provocation in asthmatics (p=0.03–0.04). Intriguingly, rs1188722C>T (Leu2116Phe) is a highly conserved amino acid residue among species, suggesting its functional relevance to AERD. In addition, the A allele of rs369252C>A, which was more prevalent in AERD than in ATA, was predicted as a potential branch point (BP) site for alternative splicing (BP score=4.29). Although further functional evaluation is required, our findings suggest that OBSCN polymorphisms, in particular, highly conserved nonsynonymous Leu2116Phe variant, might contribute to aspirin hypersensitivity in asthmatics.
Diagnosis of scrub typhus is difficult because its symptoms are very similar to other acute febrile illnesses, such as leptospirosis, murine typhus, and other viral hemorrhagic fevers. To differentiate scrub typhus from other acute febrile diseases, a rapid and reliable serological diagnosis is important. We have developed a chimeric recombinant antigen cr56 and two other recombinant antigens, r21 and kr56, from various serotypes of Orientia tsutsugamushi. They were tested for the detection of antibodies against O. tsutsugamushi in the patient's serum samples using enzyme-linked immunosorbent assay (ELISA) and dot-blot analyses. As of conventional immunofluorescence assay (IFA), when the mixture of these three recombinant antigens was used, both sensitivity and specificity of the recombinant antigens were increased up to 98% in IgM and IgG at ELISA and dot blotting. Additionally, both sensitivity and specificity by detection of IgM and IgG antibodies at rapid diagnostic test (RDT), using the mixture of three antigens and gold conjugated antibodies, were 99%. Our results suggest the use of mixture of these recombinant antigen proteins in ELISA or RDT is suitable as a diagnostic test for scrub typhus.
Scrub Typhus; Orientia tsutsugamushi; Recombinant Antigen; IFA; ELISA; RDT
Recent studies have documented that Janus-activated kinase (JAK)–signal transducer and activator of transcription (STAT) pathway can modulate the apoptotic program in a myocardial ischemia/reperfusion (I/R) model. To date, however, limited studies have examined the role of JAK3 on myocardial I/R injury. Here, we investigated the potential effects of pharmacological JAK3 inhibition with JANEX-1 in a myocardial I/R model. Mice were subjected to 45 min of ischemia followed by varying periods of reperfusion. JANEX-1 was injected 1 h before ischemia by intraperitoneal injection. Treatment with JANEX-1 significantly decreased plasma creatine kinase and lactate dehydrogenase activities, reduced infarct size, reversed I/R-induced functional deterioration of the myocardium and reduced myocardial apoptosis. Histological analysis revealed an increase in neutrophil and macrophage infiltration within the infarcted area, which was markedly reduced by JANEX-1 treatment. In parallel, in in vitro studies where neutrophils and macrophages were treated with JANEX-1 or isolated from JAK3 knockout mice, there was an impairment in the migration potential toward interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), respectively. Of note, however, JANEX-1 did not affect the expression of IL-8 and MCP-1 in the myocardium. The pharmacological inhibition of JAK3 might represent an effective approach to reduce inflammation-mediated apoptotic damage initiated by myocardial I/R injury.
apoptosis; infiltration; ischemia/reperfusion; JAK3; JANEX-1
In contrast to seasonal influenza virus infections, which typically cause significant morbidity and mortality in the elderly, the 2009 H1N1 virus caused severe infection in young adults. This phenomenon was attributed to the presence of cross-protective antibodies acquired by older individuals during previous exposures to H1N1 viruses. However, this hypothesis could not be empirically tested. To address this question, we compared viral replication and the development of the immune response in naïve young adult and aged female rhesus macaques infected with A/California/04/2009 H1N1 (CA04) virus. We show higher viral loads in the bronchoalveolar lavage (BAL) fluid and nasal and ocular swabs in aged animals, suggesting increased viral replication in both the lower and upper respiratory tracts. T cell proliferation was higher in the BAL fluid but delayed and reduced in peripheral blood in aged animals. This delay in proliferation correlated with a reduced frequency of effector CD4 T cells in old animals. Aged animals also mobilized inflammatory cytokines to higher levels in the BAL fluid. Finally, we compared changes in gene expression using microarray analysis of BAL fluid samples. Our analyses revealed that the largest difference in host response between aged and young adult animals was detected at day 4 postinfection, with a significantly higher induction of genes associated with inflammation and the innate immune response in aged animals. Overall, our data suggest that, in the absence of preexisting antibodies, CA04 infection in aged macaques is associated with changes in innate and adaptive immune responses that were shown to correlate with increased disease severity in other respiratory disease models.