Modulation of error monitoring in obsessive-compulsive disorder by individually tailored symptom provocation.

BACKGROUND: The enhanced error monitoring in patients with obsessive-compulsive disorder (OCD), typically measured with the error-related negativity (ERN), has been found to be temporally stable and independent of symptom expression. Here, we examined whether the error monitoring in patients with OCD could be experimentally modulated by individually tailored symptom provocation. METHOD: Twenty patients with OCD and 20 healthy controls performed a flanker task in which OCD-relevant or neutral pictures were presented prior to a flanker stimulus. An individualized stimulus set consisting of the most provoking images in terms of OCD symptoms was selected for each patient with OCD. Response-locked event-related potentials were recorded and used to examine the error-related brain activity. RESULTS: Patients with OCD showed larger ERN amplitudes than did control subjects in both the OCD-symptom provocation and neutral conditions. Additionally, while patients with OCD exhibited a significant increase in the ERN under the OCD-symptom provocation condition when compared with the neutral condition, control subjects showed no variation in the ERN between the conditions. CONCLUSIONS: Our results strengthen earlier findings of hyperactive error monitoring in OCD, as indexed by higher ERN amplitudes in patients with OCD than in controls. Importantly, we showed that the patients' overactive error-signals were experimentally enhanced by individually tailored OCD-symptom triggers, thus suggesting convincing evidence between OCD-symptoms and ERN. Such findings imply that therapeutic interventions should target affective regulation in order to alleviate the perceived threatening value of OCD triggers.

Selection of GP. Mur antigen-negative RBC for blood recipients with anti-'Mia ' records decreases transfusion reaction rates in Taiwan.

OBJECTIVES: To evaluate the clinical significance of GP. Mur antigen-negative blood selection for transfusion in patients with anti-'Mia ' records. BACKGROUND: The GP. Mur RBC phenotype is prevalent (7·3%) in Taiwan. Antibodies against GP. Mur (anti-'Mia ') are identified in 1·24% of our population, and anti-'Mia ' screening using GP. Mur RBC has been routine for Taiwan's blood banks. However, due to the lack of commercial antibodies, only cross-matching was used to prevent transfusion of GP. Mur-positive blood to patients with anti-'Mia ' in most hospitals. There is still a risk of GP. Mur-positive RBC exposure and subsequent anti-'Mia '-related transfusion reactions. METHODS: Since February 2014, GP. Mur antigen-negative RBCs identified by reaction with anti-'Mia '-positive serum were selected for blood recipients with anti-'Mia ' records. The transfusion reactions between January 2013 and January 2014 were compared with those that occurred between February 2014 and July 2015. RESULTS: The transfusion reaction rate was significantly higher in anti-'Mia '-positive blood recipients compared to total subjects receiving an RBC transfusion before GP. Mur-negative donor RBC selection. After antigen-negative RBC selection, the transfusion reaction frequency in subjects with anti-'Mia ' became similar to total blood recipients. IgG form anti-'Mia ' antibodies were present in all cases of probable anti-'Mia '-related transfusion reactions. The time required for anti-'Mia ' boosting after transfusion was around 4-21 days. CONCLUSION: Selection of GP. Mur-negative RBC for transfusion to patients with anti-'Mia ' records could decrease the rate of transfusion reaction and antibody boosting. This procedure should be incorporated into blood bank routines in areas where anti-'Mia ' is prevalent.

Root-soil air gap and resistance to water flow at the soil-root interface of Robinia pseudoacacia.

During periods of water deficit, growing roots may shrink, retaining only partial contact with the soil. In this study, known mathematical models were used to calculate the root-soil air gap and water flow resistance at the soil-root interface, respectively, of Robinia pseudoacacia L. under different water conditions. Using a digital camera, the root-soil air gap of R. pseudoacacia was investigated in a root growth chamber; this root-soil air gap and the model-inferred water flow resistance at the soil-root interface were compared with predictions based on a separate outdoor experiment. The results indicated progressively greater root shrinkage and loss of root-soil contact with decreasing soil water potential. The average widths of the root-soil air gap for R. pseudoacacia in open fields and in the root growth chamber were 0.24 and 0.39 mm, respectively. The resistance to water flow at the soil-root interface in both environments increased with decreasing soil water potential. Stepwise regression analysis demonstrated that soil water potential and soil temperature were the best predictors of variation in the root-soil air gap. A combination of soil water potential, soil temperature, root-air water potential difference and soil-root water potential difference best predicted the resistance to water flow at the soil-root interface.

Bilateral thermal capsulotomy with MR-guided focused ultrasound for patients with treatment-refractory obsessive-compulsive disorder: a proof-of-concept study.

Despite optimal pharmacotherapy and cognitive-behavioral treatments, a proportion of patients with obsessive-compulsive disorder (OCD) remain refractory to treatment. Neurosurgical ablative or nondestructive stimulation procedures to treat these refractory patients have been investigated. However, despite the potential benefits of these surgical procedures, patients show significant surgery-related complications. This preliminary study investigated the use of bilateral thermal capsulotomy for patients with treatment-refractory OCD using magnetic resonance-guided focused ultrasound (MRgFUS) as a novel, minimally invasive, non-cranium-opening surgical technique. Between February and May 2013, four patients with medically refractory OCD were treated with MRgFUS to ablate the anterior limb of the internal capsule. Patients underwent comprehensive neuropsychological evaluations and imaging at baseline, 1 week, 1 month and 6 months following treatment. Outcomes were measured with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A), and treatment-related adverse events were evaluated. The results showed gradual improvements in Y-BOCS scores (a mean improvement of 33%) over the 6-month follow-up period, and all patients showed almost immediate and sustained improvements in depression (a mean reduction of 61.1%) and anxiety (a mean reduction of 69.4%). No patients demonstrated any side effects (physical or neuropsychological) in relation to the procedure. In addition, there were no significant differences found in the comprehensive neuropsychological test scores between the baseline and 6-month time points. This study demonstrates that bilateral thermal capsulotomy with MRgFUS can be used without inducing side effects to treat patients with medically refractory OCD. If larger trials validate the safety, effectiveness and long-term durability of this new approach, this procedure could considerably change the clinical management of treatment-refractory OCD.

Increased expression of PRL-1 protein correlates with shortened patient survival in human hepatocellular carcinoma.

BACKGROUND: The purposes of the current study were to investigate whether overexpression of the PRL-1 is clinically relevant to hepatocellular carcinoma (HCC) and whether expression patterns of PRL-1 in HCC have diagnostic and prognostic value. METHODS: Immunohistochemistry analysis was performed for PRL-1 in 60 HCC samples. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine their prognostic significance. RESULTS: PRL-1 protein was overexpressed (83%) in HCC as compared with the adjacent normal tissue. PRL-1 expression was not influenced by chronic alcohol exposure or cirrhosis. High expression of PRL-1 was correlated with smoking (p=0.012), cirrhosis (p=0.047) and histological grade (p=0.055). The Kaplan-Meier survival curves showed that high PRL-1 expression related to a poor survival with statistical significance (I vs. III, p=0.010; II vs. III, p=0.001). Univariate analysis showed that PRL-1 expression was associated with tumour size, stage and PRL-1 score. Multivariate analysis revealed that the PRL-1 protein expression level was an independent factor for overall survival (HR, 5.367; 95% CI, 2.270-12.692; p=0.001). This is the first demonstration that the expression level of PRL-1 is correlated with tumour progression and prognosis in HCC. CONCLUSIONS: Along with other results, the PRL-1 protein is a candidate biomarker and a potential target for novel therapies against human HCC progression.

Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy.

OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of hydroxyurea (HU) in spinal muscular atrophy (SMA) in a randomized, double-blind, placebo-controlled trial. METHODS: Twenty-eight patients with type 2 SMA and 29 patients with type 3 SMA were randomly assigned (2:1) to receive HU or matching placebo for 18 months. HU was initiated at 10 mg/kg/day with an 8-week titration to 20 mg/kg/day. Subjects were assessed at baseline (T0) and monthly for the first 2 months (T1-T2) and then every 2 months throughout treatment (T3-T10) and posttreatment periods (T11-T13). The primary outcome measures were the Gross Motor Function Measure (GMFM), Manual Muscle Test (MMT), and serum full-length survivor motor neuron (flSMN) mRNA. The secondary outcome measures were Modified Hammersmith Functional Motor Scale and forced vital capacity (FVC). RESULTS: Fifty-five patients completed this trial, which lasted from March 2007 to June 2009. Except for neutropenia, we found no differences in adverse events between the 2 groups. Compared with the placebo group, the HU group had -1.88 for GMFM (p = 0.11), -0.55 for MMT (p = 0.49), and 2.17 for flSMN mRNA (p = 0.13). Similarly, we found no difference in mean improvement of the secondary endpoints. Both groups had a trend toward a decline in FVC with little change in strength and motor function. CONCLUSION: Under the current regimen and schedule, HU brought about no improvement in patients with type 2 and 3 SMA, and its main side effect was neutropenia. CLASSIFICATION OF EVIDENCE: This trial provides Class I evidence that HU 20 mg/kg/day does not effectively treat SMA.

Hematological features and molecular lesions of hemoglobin gene disorders in Taiwanese patients.

Hemoglobin (Hb) gene disorders are one of the most common inherited diseases in Taiwan, which include alpha-thalassemia, beta-thalassemia, and Hb variants. In this study, we collected and analyzed mutations found in 930 patients with Hb gene disorders except Hb Bart's Hydrops and beta-thalassemia major. The patients included 650 cases of alpha-thalassemia, 225 cases of beta-thalassemia, 9 cases of alpha-thalassemia combined with beta-thalassemia, and 46 cases of Hb variants or Hb variants combined with alpha-thalassemia or beta-thalassemia. The most common type of alpha0-thalassemia and alpha++-thalassemia mutations in our study were the SEA type deletion and the alpha3.7 deletion, respectively; the most common beta-thalassemia mutation was the IVS-2 nt 654 C-->T mutation; and the most common Hb variant was the HbE. We compared the relationships between genotype and hematological phenotypes of various Hb gene disorders and found that different genotypes of alpha0-thalassemia have similar hematological features. In conclusion, the results of our study provide data of the complex interaction of thalassemias and Hb variants which might be useful for other researchers in this field.

Mutation analysis of the tumor suppressor gene PPP2R1B in human cervical cancer.

Protein phosphatase 2A (PP2A) holoenzyme plays a critical role in cell cycle control and growth factor signaling. The PPP2R1B gene encodes the beta isoforms of the subunit A of the PP2A. We aimed to evaluate the role of the PPP2R1B gene in the pathogenesis of cervical cancer. Twenty-four women with primary cervical cancer were included. All resected specimens were divided into two groups: (1) cervical cancers (n = 24), (2) nearby noncancerous tissues (n = 24). We performed nested reverse transcriptase-polymerase chain reaction analysis and complementary DNA sequencing on the genomic DNA samples of all specimens. The aberrant transcripts and gene mutation as well as the genotype and allele frequencies of codon 66 CTA/CTG of PPP2R1B genes in both groups were compared. The percentages of aberrant transcripts between both groups were nonsignificantly different (20.8% vs 33.3%). There was no mutation in all specimens. The genotype and allele frequencies between both groups were non-different. Proportions of CTA homozygote/heterozygote/CTG homozygote were (1) 66.7/8.3/25% and (2) 58.3/12.5/29.2%. Proportions of CTA/CTG alleles in both groups were (1) 70.8/29.2% and (2) 64.6/35.4%. We conclude that PPP2R1B genes may not play a role in the carcinogenesis of cervical cancer. Mutations of PPP2R1B gene are not frequent in cervical cancer.

Molecular analysis of thiopurine S-methyltransferase alleles in Taiwan aborigines and Taiwanese.

BACKGROUND: Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme involved in the metabolism of these thiopurine drugs. Methylation of thiopurine drugs by TPMT competes with the formation of their active 6-thioguanine nucleotide metabolite, thereby potentially modulating the therapeutic and toxic effects of these drugs. OBJECTIVE: To analyze the thiopurine S-methyltransferase allelic frequencies in Taiwan aborigines and Taiwanese. METHODS: We used polymerase chain reaction-restriction fragment length polymorphism method to determine the allelic frequencies of TPMT variants (TPMT*1-TPMT*8) in 409 Taiwan aborigines and 117 Taiwanese. RESULTS AND DISCUSSION: The results showed that the allelic frequencies of TPMT*1 were 99.88% and 98.72% for Taiwan aborigines and Taiwanese respectively. The allelic frequencies of TPMT*3C were 0.12% and 1.28% for Taiwan aborigines and Taiwanese respectively. No TPMT*2, 3A, 3B, 3D and 4-8 were found in these populations. CONCLUSION: Our results provide useful information for using thiopurine drugs in these populations.

Molecular analysis of the thiopurine S-methyltransferase alleles in Bolivians and Tibetans.

BACKGROUND: Thiopurine drugs are used as immunosuppressant or cytotoxic drugs. Thiopurine S-methyltransferase (TPMT) methylates and thereby modulates the therapeutic and toxic effects of these drugs. The activity of TPMT is affected by genetic polymorphism of TPMT alleles, and these alleles have not been studied in Tibetans and Bolivians. OBJECTIVES: To analyse the TPMT allelic frequencies in Tibetans and Bolivians. METHODS: We developed an inexpensive method for collecting blood and extracting genomic DNA. Genomic DNA was extracted from blood spots of 50 Tibetans and 115 Bolivians. The frequencies of allelic variants of TPMT gene (TPMT*1 to TPMT*8) were determined using polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: The allelic frequencies of TPMT*1 were 99 and 93.48% for Tibetans and Bolivians, respectively. The corresponding allelic frequencies of TPMT*3A were 0 and 6.52% and those of TPMT*3C were 1.0 and 0%. No TPMT*2, 3B, 3D, 4-8 were found in these two populations. CONCLUSIONS: As with Caucasian populations, TPMT*3A is the most prevalent mutant allele in Bolivians. Our results may be of value in helping to guide the prescription of thiopurine drugs in these populations.

Haemolytic disease of the newborn due to maternal irregular antibodies in the Chinese population in Taiwan.

From 1991 to 2000, amongst 23,886 full-term healthy Chinese babies delivered at our hospital, 2615 babies developed neonatal hyperbilirubinaemia. After excluding other causes of hyperbilirubinaemia and identifying the irregular antibodies, 15 cases of haemolytic disease of the newborn (HDN) due to maternal irregular antibodies were diagnosed; three cases were born in our hospital and 12 cases were referred. Amongst these 15 babies, six cases had HDN due to anti-E, three cases due to anti-E + c, three cases due to anti-D, one case due to anti-c and two cases due to 'Mi' antibodies reacting with MiIII phenotype cells (anti-Hil and anti-Mur). Although there were four cases of hydrops fetalis, only one of the patients expired. The prevalence of HDN caused by maternal irregular antibodies has been estimated to be 0.01%. Therefore, routine prenatal screening for irregular antibodies was not rational in the Chinese population in Taiwan. Anti-E and anti-E + c were the important irregular antibodies resulting in HDN. Although few cases of HDN due to anti-'Mi' have been reported, Anti-'Mi' is significant in regions with a high prevalence of the MiIII phenotype.

Association between apolipoprotein E genotype and outcome of traumatic brain injury.

BACKGROUND: The prognosis of traumatic brain injury is quite variable and not fully explained by the known factors. This study is to examine if the polymorphism of apolipoprotein E (apoE) influences the outcome of traumatic brain injury. METHODS: Over a period of twelve months, we prospectively studied 100 patients who sustained traumatic brain injuries and were admitted to our neurosurgical unit. FINDINGS: Nineteen patients were apoE4+ and 81 patients were apoE4-. There was no significant difference between apoE4+ and apoE4- groups in the cause of injury (p=0.288), type of brain injury (p=0.983) and choice of treatment (p=0.88). The proportion of patients with a lower GCS (<13), indicating a poor prognosis, was higher in the apoE4+ group (73.7%) than that in apoE4- group (61.7%), although the difference was not significant (p=0.654). Six patients (7.4%) in the apoE4- group and 5(26.3%) in the apoE4+ group had been drinking alcohol at the time of injury (p=0.018). The mean duration of hospital stay for apoE4+ patients was significantly longer than for apoE4- patients (p<0.001). Six months after injury, 10 of 19 patients (52.6%) with apoE4 had an unfavorable outcome (dead, vegetative state, or severe disability) compared with 20 of the 81 (24.1%) patients without apoE4 (p=0.017). The apoE4+ patients had a significantly longer hospital stay and unfavorable outcomes after brain injury. INTERPRETATION: This study discloses a significant genetic association between the apoE genotypes and outcomes of traumatic brain injury. Patients with apoE4 allele are more likely to have an unfavorable clinical outcome after brain injury.

Gene frequencies of the HPA-1 to HPA-13, Oe and Gov platelet antigen alleles in Taiwanese, Indonesian, Filipino and Thai populations.

Human platelet antigen (HPA) systems consist of more than twelve bi-allelic antigen polymorphisms in which a base pair substitution leads to change in an amino acid of a glycoprotein expressed on the platelet. The neonatal alloimmune thrombocytopenia (NAIT), post transfusion purpura, and refractoriness to platelet transfusion can be induced by antibodies against human platelet antigens: e.g. HPA-1a, 3a, 4a, 5a, and Gova. HPA typing is essential for the diagnosis and treatment of a variety of diseases. We developed a PCR-based method to detect HPA-1 to HPA-13, Oe and Gov platelet alloantigens. In this method, the amplified PCR products were used to recognize the polymorphism after restriction enzyme digestions. Among 566 Taiwanese, 107 Indonesian, 100 Filipino and 137 Thai subjects studied, HPA-1a, 2a, 4a, 5a, 6a, 7aW, 8aW, 9a, 10a, 11a, 12a, 13a, Oea genes were present in every sample; while HPA-1b, 2b, 4b, 5b and 6b were rarely found. HPA-7aW, 8aW, 9, 10, 11, 12, 13, and Oea alleles were noted to be monomorphic only. HPA-3a/3b alleles had frequencies of 0.595/0.405, 0.505/0.495, 0.507/0.493, 0.530/0.470, while Gova/Govb of 0.462/0.538, 0.450/0.550, 0.463/0.537, 0.520/0.480 among Taiwanese, Indonesians, Thais and Filipinos respectively. The prevalence rates of HPA-1 to 13 in this study were also consistent with other previous reports using different methods. The alloimmunization due to Gov and HPA-3 antigens need to be emphasized in these populations.

Molecular basis of weak D in Taiwanese.

Two genes, RHD and RHCE, encode the antigens of the RH blood group system. The weak D phenotype is caused by many different RHD alleles encoding aberrant RhD proteins, resulting in distinct serologic phenotypes and anti-D immunization. We analyzed seven weak D phenotypes excluding D(el), using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing methods to detect the changes of all ten RHD exons. The results show that there are four types of weak D in Taiwanese: one case each for CGG to CAG mutation at codon 10, GTG to ATG mutation at codon 174, and GTG to GAG mutation at codon 270, and four cases for GGT to GAT mutation at codon 282. In conclusion, we present the first data of a molecular basis of weak D in Taiwanese, which suggest a clinically relevant potential for anti-D immunization and may improve transfusion strategy in weak D Taiwanese patients.

Molecular characterization of deletional forms of beta-thalassemia in Taiwan.

beta-Thalassemia is one of the most common genetic diseases in Taiwan. The most common mutations of beta-globin are point mutations, and six mutations account for over 90% of cases. Less than 5% of the cases with beta-globin gene deletion result in beta-thalassemia minor. The mutational type of the deletion is not clear in Taiwanese. We used polymerase chain reaction (PCR)-based methods to detect the breakpoint junctions of different deletional types of beta-thalassemia. In total, six cases of clinically suspected deletional type of beta-thalassemia were studied. The results showed that there were three types of deletions in these cases: two cases each for hereditary persistent fetal hemoglobinemia (HPFH) of the Southeast Asian (SEA) type, HPFH of the Yunnanese type, and gamma(G)+(gamma(A)deltabeta)(0)deletions, respectively. The clinical features of these deletional mutations are milder than the beta(o) types of the point mutation. The patients with compound heterozygous mutations of the point mutation and the deletional mutation are always transfusion independent.

Hydrops foetalis caused by anti-Mur in first pregnancy--a case report.

Anti-'Mia' is the most common alloantibody of potential clinical significance in the Taiwanese population. The Mi.III phenotype is rare among Caucasians but has a high incidence in various Oriental populations. We describe a nulliparous woman with no history of transfusions, who had hydrops foetalis at 28 weeks gestation. Foetal haemoglobin was 4.4 g dL-1, and a positive direct antiglobulin test was positive in the foetal blood. Intrauterine intravascular transfusion was given, and the baby was discharged healthy. Anti-'Mia' was identified in the maternal serum, the cord blood serum and the eluate from red cells of the cord blood. Anti-'Mia' in the maternal serum was confirmed to be anti-Mur. The polymerase chain reaction-restriction fragment length polymorphism method confirmed that both the baby and her father had the Mi.III gene. Therefore, our report documents that anti-Mur has the potential to cause hydrops foetalis.