Multiplexed Quantitative Proteomics Reveals Proteomic Alterations in Two Rodent Traumatic Brain Injury Models.

In many cases of traumatic brain injury (TBI), conspicuous abnormalities, such as scalp wounds and intracranial hemorrhages, abate over time. However, many unnoticeable symptoms, including cognitive, emotional, and behavioral dysfunction, often last from several weeks to years after trauma, even for mild injuries. Moreover, the cause of such persistence of symptoms has not been examined extensively. Recent studies have implicated the dysregulation of the molecular system in the injured brain, necessitating an in-depth analysis of the proteome and signaling pathways that mediate the consequences of TBI. Thus, in this study, the brain proteomes of two TBI models were examined by quantitative proteomics during the recovery period to determine the molecular mechanisms of TBI. Our results show that the proteomes in both TBI models undergo distinct changes. A bioinformatics analysis demonstrated robust activation and inhibition of signaling pathways and core proteins that mediate biological processes after brain injury. These findings can help determine the molecular mechanisms that underlie the persistent effects of TBI and identify novel targets for drug interventions.

Differentiating perinatal Insomnia Disorder and sleep disruption: a longitudinal study from pregnancy to 2 years postpartum.

STUDY OBJECTIVES: Insomnia Disorder diagnoses require persistent sleep complaints despite "adequate sleep opportunity." Significant Perinatal Sleep Disruption makes this diagnosis challenging. This longitudinal study distinguished between Insomnia Disorder and Perinatal Sleep Disruption and their sleep and mental health correlates. METHODS: One hundred sixty-three nulliparous females (age M ± SD = 33.35 ± 3.42) participating in a randomized controlled trial repeated the Insomnia Disorder module of the Duke Structured Interview for Sleep Disorders and Patient-Reported Outcome Measurement Information System measures for sleep and mental health at 30- and 35-weeks' gestation, and 1.5, 3, 6, 12, and 24 months postpartum (944 interviews, 1009 questionnaires completed). We compared clinical features when Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Insomnia Disorder criteria (without the Duration criterion) were: (1) met (Insomnia Disorder), (2) not met only because of the sleep opportunity criteria (Perinatal Sleep Disruption), and (3) not met due to other criteria (Low Complaint). RESULTS: Proportions of Insomnia Disorder were 16.0% and 19.8% during early and late third trimester, and ranged 5.3%-11.7% postpartum. If the sleep opportunity criteria were not considered, rates of Insomnia would be 2-4 times higher (21.4%-40.4%) across time-points. Mixed-effects models adjusting for covariates showed that compared to Low Complaint, both Insomnia Disorder and Perinatal Sleep Disruption scored significantly higher on insomnia and sleep disturbance scales, sleep effort, and sleep-related impairments (p values < .01), but depression and anxiety were comparable (p values > .12). CONCLUSION: Assessing sleep complaints without considering sleep opportunities can result in over-diagnosis of Insomnia Disorder in the perinatal periods. Insomnia Disorder and Perinatal Sleep Disruption were both associated with adverse sleep and mood outcomes, and need to be carefully differentiated and appropriately addressed. Clinical Trial Registration: The SEED Project (Sleep, Eat, Emotions, and Development): A randomized controlled pilot study of a perinatal sleep intervention on sleep and wellbeing in mothers and infants. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371634, Australian New Zealand Clinical Trials Registry: ACTRN12616001462471.

Exploring Australian regional cancer patients' experiences of clinical trial participation via telehealth.

INTRODUCTION: Regional cancer patients face various barriers in accessing specialist cancer services. Teletrials are a new model of care that utilise communications technologies to enable access to and participation in clinical trials close to home. The present study aimed to explore the experiences of regional cancer patients and their carers while participating in a teletrial, and those of regional patients who travelled to a metropolitan centre for trial participation. METHODS: A concurrent, mixed methods study design was used to address the study aim. Patient quality of life data were gathered for both groups and an audio-recorded semi-structured interview undertaken to explore patients' and carers' experiences of the two modes of trial participation. Greater weighting was given to the qualitative data. RESULTS: Participants described teletrials as an acceptable and valuable initiative that reduced overall burden of trial participation. Irrespective of mode of delivery, patients and carers identified access to trials and specialist cancer services as an important equity issue for regional cancer patients. DISCUSSION: From the perspective of regional cancer patients and carers, a teletrial offers convenient, acceptable access to a clinical trial. Although not all patients may want to engage in a teletrial, patients and carers agree that it offers equity of opportunity for trial participation, irrespective of where people live.

Postpartum fatigue and depression: A systematic review and meta-analysis.

BACKGROUND: New parents are vulnerable to fatigue and depressive symptoms. Many studies have reported significant positive correlations between the two in postpartum parents, but the size of correlations varies considerably between studies. The relationship between postpartum fatigue and depression is yet to be systematically synthesized and meta-analyzed. METHODS: A PROSPERO registered systematic review and meta-analysis (CRD42017065240) was conducted on the correlation between fatigue and depression within the first two years postpartum in parents. Moderation analysis was used to examine the influence of demographic and measurement factors on the effect sizes. RESULTS: Thirty-five eligible papers were identified (34 on mothers, 1 on fathers). The meta-analytic summary effect size for simultaneously measured fatigue and depressive symptoms among women in the postpartum period was r = 0.52, 95% CI [0.45, 0.59], p < .001. There was a high degree of heterogeneity in the strength of the correlation between studies. This heterogeneity was not accounted for by demographic (e.g., infant age, maternal age, population type) or methodology (e.g., measurement) related moderators. LIMITATIONS: Studies not reporting or providing correlation between fatigue and depression were not included. Unable to assess some moderators due to limited sample size. CONCLUSIONS: There is a strong correlation between fatigue and depressive symptoms among women in the first two years after child-birth, but a high degree of heterogeneity in correlation strength exists between studies. Careful assessment of both fatigue and depression when either symptom is reported could facilitate accurate differential diagnosis and prioritizing treatment in postpartum women. Further implications for assessment, treatment, and future research are discussed.

Crystallization of Local Anesthetics When Mixed With Corticosteroid Solutions.

OBJECTIVE: To evaluate at which pH level various local anesthetics precipitate, and to confirm which combination of corticosteroid and local anesthetic crystallizes. METHODS: Each of ropivacaine-HCl, bupivacaine-HCl, and lidocaine-HCl was mixed with 4 different concentrations of NaOH solutions. Also, each of the three local anesthetics was mixed with the same volume of 3 corticosteroid solutions (triamcinolone acetonide, dexamethasone sodium phosphate, and betamethasone sodium phosphate). Precipitation of the local anesthetics (or not) was observed, by the naked eye and by microscope. The pH of each solution and the size of the precipitated crystal were measured. RESULTS: Alkalinized with NaOH to a certain value of pH, local anesthetics precipitated (ropivacaine pH 6.9, bupivacaine pH 7.7, and lidocaine pH 12.9). Precipitation was observed as a cloudy appearance by the naked eye and as the aggregation of small particles (<10 µm) by microscope. The amount of particles and aggregation increased with increased pH. Mixed with betamethasone sodium phosphate, ropivacaine was precipitated in the form of numerous large crystals (>300 µm, pH 7.5). Ropivacaine with dexamethasone sodium phosphate also precipitated, but it was only observable by microscope (a few crystals of 10-100 µm, pH 7.0). Bupivacaine with betamethasone sodium phosphate formed precipitates of non-aggregated smaller particles (<10 µm, pH 7.7). Lidocaine mixed with corticosteroids did not precipitate. CONCLUSION: Ropivacaine and bupivacaine can precipitate by alkalinization at a physiological pH, and therefore also produce crystals at a physiological pH when they are mixed with betamethasone sodium phosphate. Thus, the potential risk should be noted for their use in interventions, such as epidural steroid injections.

STAT6 expression and IL-13 production in association with goblet cell hyperplasia and worm expulsion of Gymnophalloides seoi from C57BL/6 mice.

In intestinal helminth infections, Th2 immune respones are generally associated with mucin secretion for worm expulsion from the host intestine. In particular, IL-4 and IL-13 are the important cytokines related with intestinal mucus production via STAT6 signalling in nematode infections. However, this perspective has never been studied in Gymnophalloides seoi infection. The present study aimed to observe the STAT6 signalling and cytokine responses in C57BL/6 mice, a mouse strain resistant to infection with this trematode. The results showed that worm expulsion occurred actively during days 1-2 post-infection (PI), when goblet cells began to proliferate in the small intestine. The STAT6 gene expression in the mouse spleen became remarkable from day 2 PI. Moreover, G. seoi infection induced a significant increase of IL-13 from day 4 PI in the spleen of infected mice. Our results suggested that goblet cell hyperplasia and worm expulsion in G. seoi-infected mice should be induced by STAT6 signalling, in which IL-13 may be involved as a dominant triggering cytokine.

Computationally modeling interpersonal trust.

We present a computational model capable of predicting-above human accuracy-the degree of trust a person has toward their novel partner by observing the trust-related nonverbal cues expressed in their social interaction. We summarize our prior work, in which we identify nonverbal cues that signal untrustworthy behavior and also demonstrate the human mind's readiness to interpret those cues to assess the trustworthiness of a social robot. We demonstrate that domain knowledge gained from our prior work using human-subjects experiments, when incorporated into the feature engineering process, permits a computational model to outperform both human predictions and a baseline model built in naiveté of this domain knowledge. We then present the construction of hidden Markov models to investigate temporal relationships among the trust-related nonverbal cues. By interpreting the resulting learned structure, we observe that models built to emulate different levels of trust exhibit different sequences of nonverbal cues. From this observation, we derived sequence-based temporal features that further improve the accuracy of our computational model. Our multi-step research process presented in this paper combines the strength of experimental manipulation and machine learning to not only design a computational trust model but also to further our understanding of the dynamics of interpersonal trust.

Quantitative analysis of methylation status at 11p15 and 7q21 for the genetic diagnosis of Beckwith-Wiedemann syndrome and Silver-Russell syndrome.

Methylation-specific (MS) multiplex ligation-dependent probe amplification (MLPA) at two differentially methylated regions (DMRs) at chromosome 11p15, H19-DMR and LIT1-DMR, and microsatellite analysis for uniparental disomy (UPD) at chromosome 7 or 11, have been recommended for the genetic diagnosis of the Beckwith-Wiedemann syndrome (BWS) and the Silver-Russell syndrome (SRS). In this study, the efficacy of the MS pyrosequencing method at H19-DMR and LIT1-DMR at 11p15 and SGCE-DMR at 7q21 was evaluated for the genetic diagnosis of BWS (n=18) and SRS (n=20) patients. Epigenetic alterations or UPD were detected in 83% of BWS and 50% of SRS individuals by MS-MLPA, but the detection rate increased to 95% of BWS and 70% of SRS by MS pyrosequencing. Thirteen BWS patients (72%) harbored loss-of-methylation (LOM) at LIT1-DMR and two patients (11%) harbored gain-of-methylation (GOM) at H19-DMR, whereas two patients (11%) had both LOM at LIT1-DMR and GOM at H19-DMR, reflecting paternal UPD 11. Thirteen SRS patients (65%) harbored LOM at H19-DMR, whereas one patient (5%) had GOM at SGCE-DMR, reflecting maternal UPD 7. Birth anthropometric profiles were significantly correlated to methylation scores at either H19-DMR or LIT1-DMR. In conclusion, MS pyrosequencing enhanced the detection rate of molecular defects in BWS and SRS. Moreover, it indicates that methylation status at 11p15.5 might have an important role in fetal growth.

Detecting the trustworthiness of novel partners in economic exchange.

Because trusting strangers can entail high risk, an ability to infer a potential partner's trustworthiness would be highly advantageous. To date, however, little evidence indicates that humans are able to accurately assess the cooperative intentions of novel partners by using nonverbal signals. In two studies involving human-human and human-robot interactions, we found that accuracy in judging the trustworthiness of novel partners is heightened through exposure to nonverbal cues and identified a specific set of cues that are predictive of economic behavior. Employing the precision offered by robotics technology to model and control humanlike movements, we demonstrated not only that experimental manipulation of the identified cues directly affects perceptions of trustworthiness and subsequent exchange behavior, but also that the human mind will utilize such cues to ascribe social intentions to technological entities.

Comparative morphology of minute intestinal fluke eggs that can occur in human stools in the republic of Korea.

The egg morphology of minute intestinal flukes (MIF) that can occur as human infections in the Republic of Korea, i.e., Metagonimus yokogawai, M. miyatai, M. takahashii, Heterophyes nocens, Heterophyopsis continua, Stellantchasmus falcatus, Stictodora fuscata, Pygidiopsis summa, and Gymnophalloides seoi, was studied in comparison with Clonorchis sinensis. The adult worms were obtained from residents of endemic areas, and their intrauterine eggs were studied and measured using light microscopy; the length, width, length-width ratio (LWR), and Faust-Meleney index (FMI). Several specimens were processed for scanning electron microscopy (SEM), and before gold-coating, the uterine portion of each fluke was etched with a sharp pin in order to expose the eggs. The MIF eggs were ovoid, pyriform, or elliptical with a size range of 21-35×12-21 µm. S. fuscata eggs revealed the highest FMI (largest in the area) and lowest LWR, whereas P. summa eggs showed the lowest FMI and medium LWR. SEM revealed that G. seoi and S. fuscata had remarkably clean shell surface lacking the muskmelon-like structure which is prominent in C. sinensis eggs. In Metagonimus spp., H. continua, H. nocens, and S. falcatus eggs, minute surface ridges were recognizable though less prominent compared with C. sinensis. On the surface of P. summa eggs, thread-like curly structures were characteristically seen. The results revealed that important differential keys for MIF eggs include the length, width, area (FMI), shape of the eggs, and the extent of the muskmelon-like structure or ridges on their shell surface and operculum.

Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson's disease cohort.

INTRODUCTION AND AIMS: Wide phenotypic and genotypic heterogeneities in Wilson's disease (WD) have been reported, hampering the study of their correlations. The goal of this study was to identify the factors related to these diversities. METHODS: Clinical courses and molecular genetic characteristics were analysed in 237 unrelated Korean WD families. The average follow-up period was 8.2 ± 5.8 years. RESULTS: Presenting phenotypes were classified as H1 (12.2%), H2 (42.4%), N1 (21.6%), N2 (0.4%), NX (0.4%), presymptomatic (22.4%) and other (0.4%), modifying the guidelines by Ferenci and colleagues. Age at presentation was youngest and cirrhosis was rarest in the presymptomatic group. Decompensated cirrhosis was the highest in the H1 group. Favourable outcome was rarest in the N1 group. Forty-seven (11 novel) ATP7B mutations were identified in 85% of the 474 alleles. Multiplex ligation-dependent probe amplification assays in ATP7B and analyses of ATOX1 and COMMD1 genes identified no additional mutations. Yeast complementation assays demonstrated functional perturbation of the seven novel missense mutants. Five major mutations, p.Arg778Leu, p.Ala874Val, p.Asn1270Ser, p.Lys838SerfsX35 and p.Leu1083Phe, accounted for 63% of the alleles. H1 was more common, age at presentation was younger and N1+N2+NX tended to be less common in patients with nonsense, frame shifting or splicing mutations than in those with missense mutations alone. Patients with both mutations in the transduction (Td) or the ATP hinge domain showed presymptomatic or hepatic manifestations but no neurological manifestation. CONCLUSIONS: The presenting phenotype strongly affects the clinical outcome of WD, and is related to the ATP7B mutation type and location, providing an evidence for genotype-phenotype correlations in WD.

CD8 T-cell activation in mice injected with a plasmid DNA vaccine encoding AMA-1 of the reemerging Korean Plasmodium vivax.

Relatively little has been studied on the AMA-1 vaccine against Plasmodium vivax and on the plasmid DNA vaccine encoding P. vivax AMA-1 (PvAMA-1). In the present study, a plasmid DNA vaccine encoding AMA-1 of the reemerging Korean P. vivax has been constructed and a preliminary study was done on its cellular immunogenicity to recipient BALB/c mice. The PvAMA-1 gene was cloned and expressed in the plasmid vector UBpcAMA-1, and a protein band of approximately 56.8 kDa was obtained from the transfected COS7 cells. BALB/c mice were immunized intramuscularly or using a gene gun 4 times with the vaccine, and the proportions of splenic T-cell subsets were examined by fluorocytometry at week 2 after the last injection. The spleen cells from intramuscularly injected mice revealed no significant changes in the proportions of CD8(+) T-cells and CD4(+) T-cells. However, in mice immunized using a gene gun, significantly higher (P<0.05) proportions of CD8(+) cells were observed compared to UB vector-injected control mice. The results indicated that cellular immunogenicity of the plasmid DNA vaccine encoding AMA-1 of the reemerging Korean P. vivax was weak when it was injected intramuscularly; however, a promising effect was observed using the gene gun injection technique.

Gnathostoma hispidum infection in a Korean man returning from China.

Human Gnathostoma hispidum infection is extremely rare in the world literature and has never been reported in the Republic of Korea. A 74-year-old Korean man who returned from China complained of an erythematous papule on his back and admitted to our hospital. Surgical extraction of the lesion and histopathological examination revealed sections of a nematode larva in the deep dermis. The sectioned larva had 1 nucleus in each intestinal cell and was identified as G. hispidum. The patient recalled having eaten freshwater fish when he lived in China. We designated our patient as an imported G. hispidum case from China.

Clinical characteristics and VPS33B mutations in patients with ARC syndrome.

OBJECTIVES: ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome is a rare, fatal cause of neonatal intrahepatic cholestasis without known treatment modalities and has recently been ascribed to a mutation in the VPS33B gene. We assessed the clinical characteristics and investigated the VPS33B mutations in Korean patients with ARC syndrome. PATIENTS AND METHODS: We reviewed the medical records of 6 patients with ARC syndrome among 90 patients with neonatal cholestasis from 2000 to 2005 and assessed the relative incidence rate ratio, clinical symptoms, laboratory findings, and pathological findings. DNA samples from 5 patients, 4 parents, and 2 fetuses were analyzed for VPS33B mutations. RESULTS: The relative incidence rate ratio was 1/7 that of biliary atresia (95% CI 0.33-0.06). All 6 patients presented with ichthyosis and recurrent infection, and failed to thrive with the 3 main symptoms. All of the patients died within the age of 12 months. They had various severities of cholestasis, metabolic acidosis, nephrogenic diabetes insipidus, chronic diarrhea, platelet abnormalities, and central nervous system anomalies. We identified 1 novel c.403+2T>A splice-site mutation, 2 frame-shift mutations (c.1509_1510insG, c.790_791del), 1 nonsense mutation (c.661C>A), and 1 known nonsense mutation (c.1518C>T) in the VPS33B gene. Prenatal diagnosis was performed in 2 different families. CONCLUSIONS: This study indicates that the incidence of ARC syndrome is not as rare as has been thought. We found 4 novel and 1 known mutations in ARC syndrome patients and performed prenatal diagnosis in 2 families, which will facilitate genetic diagnosis and counseling for affected families.

Effects of a chemical chaperone on genetic mutations in alpha-galactosidase A in Korean patients with Fabry disease.

Fabry disease is an X-linked inborn error of glycosphingolipid catabolism that results from mutations in the gene encoding the alpha-galactosidase A (GLA) enzyme. We have identified 15 distinct mutations in the GLA gene in 13 unrelated patients with classic Fabry disease and 2 unrelated patients with atypical Fabry disease. Two of the identified mutations were novel (i.e., the D231G missense mutation and the L268delfsX1 deletion mutation). This study evaluated the effects of the chemical chaperones 1-deoxygalactonojirimycin (DGJ) on the function of GLA in vitro, in cells containing missense mutations in the GLA gene. Nine missense and a nonsense mutations, including one novel mutation were cloned into mammalian expression vectors. After transient expression in COS-7 cells, GLA enzyme activity and protein expression were analyzed using fluorescence spectrophotometry and Western blot analysis, respectively. DGJ enhanced GLA enzyme activity in the M42V, I91T, R112C and F113L mutants. Interestingly, the I91T and F113L mutations are associated with the atypical form of Fabry disease. However, DGJ treatment did not have any significant effect on the GLA enzyme activity and protein expression of other mutants, including C142W, D231G, D266N, and S297F. Of note, GLA enzyme activity was not detected in the novel mutant (i.e., D231G), although protein expression was similar to the wild type. In the absence of DGJ, the E66Q mutant had wild-type levels of GLA protein expression and approximately 40% GLA activity, indicating that E66Q is either a mild mutation or a functional single nucleotide polymorphism (SNP). Thus, the results of this study suggest that the chemical chaperone DGJ enhances GLA enzyme activity and protein expression in milder mutations associated with the atypical form of Fabry disease.

Estimation of Wilson's disease incidence and carrier frequency in the Korean population by screening ATP7B major mutations in newborn filter papers using the SYBR green intercalator method based on the amplification refractory mutation system.

Wilson's disease (WD), an autosomal recessive disorder of copper transport, is one of the most common inherited metabolic disorders in Korea. Despite its frequency, the incidence and carrier frequency of WD has not yet been estimated in the Korean population. We therefore screened for four major missense mutations (p.Arg778Leu, p.Ala874Val, p.Leu1083Phe, and p.Asn1270Ser) of the ATP7B gene in 476 newborn filter papers by real-time multiplex PCR and melting curve analysis using the SYBR Green intercalator method based on the amplification refractory mutation system test. Newborn filter papers with abnormal melting curves were subjected to subsequent sequence analysis. Three mutated alleles, one p.Arg778Leu and two p.Ala874Val, were detected among the 476 newborn filter papers (952 alleles). The carrier frequency and incidence of WD in the Korean population were determined as 1 in 88.2 and 30,778, respectively, by reversely calculating based on the Hardy-Weinberg law.

Role of chemotherapy and rituximab for treatment of posttransplant lymphoproliferative disorder in solid organ transplantation.

OBJECTIVE: To evaluate the role of chemotherapy and/or rituximab for treatment of posttransplant lymphoproliferative disorder (PTLD) in solid organ transplantation. DATA SOURCES: A MEDLINE search (1966-May 2007) was conducted using the key words posttransplant lymphoproliferative disorder, solid organ transplantation, chemotherapy, and rituximab. References of relevant articles and abstracts from recent hematology, oncology, and transplantation scientific meetings (2004-May 2007) were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Prospective and retrospective studies identified from the data sources were evaluated, and all information deemed relevant was included for this review. DATA SYNTHESIS: Overall response rates ranged from 53% to 68%, 25% to 83%, and 74% to 100% for rituximab monotherapy, chemotherapy, and chemotherapy plus rituximab, respectively. Positive response to treatment was influenced by prognostic factors, including presence of Epstein-Barr virus in tumor cells, normal lactate dehydrogenase levels, good performance status, early disease onset after transplantation, and early disease stages. These factors in study patients likely contribute to the variability in response rates seen between treatment options. Severe adverse effects, ranging from grade 3 neutropenia to infection resulting in death, occurred more frequently in patients receiving chemotherapy than in patients receiving only rituximab. CONCLUSIONS: Although reduction in immunosuppressive medications remains the first-line therapy for PTLD treatment, many cases do not respond to this treatment alone, especially monomorphic or more aggressive cases of lymphoma. Therefore, it is reasonable to begin active treatment including rituximab and/or chemotherapy initially, along with reduction in immunosuppression in many cases. Further prospective, comparative studies are urgently needed to confirm the efficacy of these treatment strategies as well as to clarify which subset of patients may benefit most from them.