Association between disease severity according to "MN criteria" and 30-day mortality in patients with Clostridioides difficile infection.

INTRODUCTION: A rapid membrane enzyme immunoassays (EIA) are frequently used to diagnose Clostridioides difficile infection (CDI). If EIA does not provide a definitive CDI diagnosis, whether treatment with anti-CD agents is to be performed depends on the pathogenesis and severity of the disease. In Japan, "MN criteria" have been proposed for the classification of disease severity. In this study, we investigated the association between disease severity and CDI prognosis when MN criteria are used. METHODS: This study included 102 patients diagnosed with CDI between April 2015 and March 2020. The disease serverity classification accorditng to MN criteria was divided into two groups: non-severely ill (mild to moderate) and severely ill (severe to critical) group. RESULTS: Mortality was significantly higher in severely ill patients than non-severely ill patients (46.7% vs. 13.8%, p = 0.0025). Multivariable analysis showed that the mortality of patients with CDI was significantly associated with advanced age (odds ratio [OR] = 1.1; 95% confidence interval [CI] = 1.0-1.2; p = 0.019) and disease severity (OR = 4.2; 95% CI = 1.2-14.8; p = 0.023). DISCUSSION: The classification of disease severity according to the MN criteria would be particularly useful in predicting the patients' prognoses.

Association between serotonin transporter polymorphisms (5-HTTLPR) and the MADRS Dysphoria, Retardation, and Vegetative Subscale scores in the treatment of depression.

OBJECTIVE: We investigated the association between serotonin- or 5-hydroxytryptamine (5-HT)-related gene polymorphisms and response to antidepressant treatment in a specific symptom cluster of major depression by using the three-factor model of the Montgomery-Åsberg Depression Rating Scale (MADRS), ie, dysphoria (items of sadness, pessimistic thoughts, and suicidal thoughts), retardation (items of lassitude, inability to feel, apparent sadness, and concentration difficulties), and vegetative symptoms (items of reduced sleep, reduced appetite, and inner tension). METHODS: This study was an open-label and nonrandomized trial. A total of 160 patients with baseline MADRS scores of ≥21, who were treated with fluvoxamine or milnacipran for 6 weeks, were included in the statistical analysis. Polymorphisms within a 5-HT transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR), a variable number of tandem repeats in the second intron of the 5-HTT gene (5-HTTVNTR), and 5HT2A receptor (1438G/A) were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The 5-HTTLPR polymorphisms affected the MADRS score change in dysphoria, but not in retardation, vegetative, or total symptoms. Dysphoria scores significantly decreased in patients with the S/S genotype compared to those in patients with the short (S)/long (L) + L/L genotype. However, 5-HTTVNTR and 1438G/A polymorphisms were not significantly associated with the treatment response to any cluster of depressive symptoms. When a Bonferroni correction was made, however, our results did not reach the criteria for statistical significance. CONCLUSION: The use of a single total depression rating scale may not be sufficient to accurately estimate the clinical response to antidepressants. Analyzing a subset of symptoms in psychological scales could be important when performing pharmacogenetic studies.

Bcl1 polymorphism of the glucocorticoid receptor gene and treatment response to milnacipran and fluvoxamine in Japanese patients with depression.

BACKGROUND: Polymorphisms in the glucocorticoid receptors (GRs) have been widely studied with rather less emphasis on relating their differences with possible pharmacological treatment outcomes. The purpose of this study was to investigate whether Bcl1 polymorphisms of GRs are associated with the antidepressant effect of milnacipran, a serotonin noradrenaline reuptake inhibitor (SNRI), and fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), in Japanese patients with depression. METHODS: Patients were prescribed either milnacipran (n = 98) or fluvoxamine (n = 95). The severity of depression was assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS) at 0, 1, 2, 4 and 6 weeks of treatment. RESULTS: Both agents were similarly effective in reducing MADRS scores in 6 weeks. In all subjects receiving milnacipran or fluvoxamine, our data showed no significant interaction between Bcl1 polymorphisms and therapeutic effects. However, when milnacipran- and fluvoxamine-treated subjects were analyzed independently, patients with G allele in Bcl1 polymorphism had a significantly better response to fluvoxamine than those with C/C genotype. On the other hand, no significant relationship was found between treatment response to milnacipran and Bcl1 polymorphism. CONCLUSION: Bcl1 polymorphism may be one of the genetic factors in predicting treatment response to SSRI but not SNRI in Japanese patients with depression.

Relationship of the 24-item dysfunctional attitude scale with the temperament and character inventory in healthy subjects.

BACKGROUND: The 24-item Dysfunctional Attitude Scale (DAS-24) has three subscales to evaluate dysfunctional attitudes predisposing to depression in the areas of achievement, dependency and self-control. AIM: The purpose of the present investigation was to characterize the three subscales in relation to broad dimensions of personality. METHODS: The subjects were 528 healthy Japanese volunteers. Personality assessment was conducted by the Temperament and Character Inventory (TCI), which has seven dimensions. The correlations of the DAS-24 subscales with the TCI dimensions were examined by the multiple regression analysis. RESULTS: All DAS-24 subscales had negative correlations with the self-directedness dimension. However, the three subscales had differential patterns of correlations with the reward dependence, persistence, cooperativeness and harm avoidance dimensions. CONCLUSIONS: The present study suggests that dysfunctional attitudes measured by the DAS-24 are closely related to low self-directedness of the TCI. Also, the differential patterns of correlations with some TCI dimensions support the content-specificity of the three subscales.

Interaction effect between the BDNF Val66Met polymorphism and parental rearing for interpersonal sensitivity in healthy subjects.

Interpersonal sensitivity is defined as undue and excessive awareness of, and sensitivity to, the behaviour and feelings of others and is one of the vulnerable factors to depression. In a twin study, it was suggested that this personality trait was characterised by both genetic and environmental factors. In the present study, we examined the effects of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and parental rearing on interpersonal sensitivity in 725 healthy Japanese subjects. Assessment of interpersonal sensitivity was performed by the Japanese version of the Interpersonal Sensitivity Measure (IPSM). Perceived parental rearing was assessed by the Parental Bonding Instrument (PBI), which consists of the care and protection factors. The BDNF polymorphism was detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. There was no main effect of the BDNF genotype on the IPSM score, while the PBI factors except maternal care had significant main effect on the IPSM score. There was significant interaction effect between the BDNF genotype and maternal care of the PBI on the IPSM score. Post-hoc analysis of simple slopes showed that the negative relationship between the IPSM score and maternal care was strongest and significant in the Met/Met genotype group, intermediate in the Val/Met genotype group and weakest in the Val/Val genotype group. The present study suggests that the interaction between the BDNF Val66Met polymorphism and parental rearing, especially maternal care, influences interpersonal sensitivity in healthy subjects.

Interpersonal sensitivity is correlated with sociotropy but not with autonomy in healthy subjects.

Interpersonal sensitivity is a depression-prone personality trait closely related to anxious attachment, whereas sociotropy and autonomy are personality vulnerability factors in the cognitive theory of depression. In the present study, the relationships of interpersonal sensitivity with sociotropy and autonomy were studied in 362 healthy subjects. Interpersonal sensitivity was assessed using the Interpersonal Sensitivity Measure (IPSM), whereas sociotropy and autonomy were evaluated using the Sociotropy and Autonomy subscales, respectively, of the Sociotropy-Autonomy Scale. The IPSM was significantly correlated with the Sociotropy subscale (ß = 0.61, p < 0.001) but not with the Autonomy subscale. All subscales of the IPSM correlated significantly with the Sociotropy subscale, and the correlation for the Separation Anxiety subscale (ß = 0.56, p < 0.001) was strongest. The present study suggests that interpersonal sensitivity is correlated with sociotropy but not with autonomy in healthy subjects.

Parental overprotection increases sociotropy with gender specificity in parents and recipients.

BACKGROUND: There have been few studies which examined the developmental origins of cognitive vulnerability of depression. The purpose of the present study was to examine the effects of parental rearing on sociotropy and autonomy, the personality vulnerability factors in the cognitive theory of depression. METHODS: The subjects were 416 healthy subjects. Perceived parental rearing was assessed by the Parental Bonding Instrument (PBI), which has care and protection factors, and sociotropy and autonomy were assessed by the Sociotropy-Autonomy Scale. RESULTS: In males, neither sociotropy nor autonomy was affected by paternal rearing or maternal rearing. In females, higher levels of sociotropy were related to higher maternal protection (ß=0.308, p<0.01), while autonomy was affected neither by paternal rearing nor by maternal rearing. LIMITATIONS: Parental behaviors not covered by the PBI may affect formation of autonomy. CONCLUSIONS: The present study suggests that parental overprotection increases sociotropy with gender specificity in parents and recipients.

Genetic polymorphisms in the serotonergic system and symptom clusters of major depressive disorder.

BACKGROUND: It has been suggested that the symptoms of major depressive disorder (MDD) are composed of some clusters, which are linked to distinct genetic mechanisms. The purpose of this study was to examine the associations of genetic polymorphisms in the serotonergic system with three factors of the Montgomery-Åsberg Depression Rating Scale (MADRS), i.e., dysphoria, retardation, and vegetative symptoms. METHODS: The subjects were 132 Japanese patients of MDD. The genotypes of tryptophan hydroxylase 218A/C, serotonin transporter gene-linked polymorphic region (5HTTLPR), and 5HT2A receptor -1438G/A polymorphisms were determined by PCR methods. Statistical analyses were performed by the multiple regression analysis. RESULTS: The A allele of 5HT2A polymorphism was associated with higher vegetative scores (p=0.001) and total MADRS scores (p=0.005), while the S allele of 5HTTLPR was related to higher dysphoric scores (p=0.012). The tryptophan hydroxylase genotype was not related to any factor scores or total MADRS scores. LIMITATIONS: The sample size was relatively small, and the subjects were composed of Japanese only. CONCLUSION: This study suggests that the genetic polymorphisms in 5HT2A receptor and serotonin transporter are linked to discrete symptom clusters of MDD.

Functional polymorphism of the GTP cyclohydrolase 1 gene affects the personality trait of novelty seeking in healthy subjects.

GTP cyclohydrolase 1 (GCH1) is the initial and rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin, which is an essential cofactor for biosynthetic enzymes of dopamine, serotonin, and nitric oxide. In the present study, the association of functional polymorphism of the GCH1 gene (C+243T, rs841) with personality traits was examined in 902 healthy Japanese subjects. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the GCH1 genotype was detected by a PCR-RFLP method. There were no significant main effects of the GCH1 genotype on the seven TCI dimension scores, but significant interaction effects between the GCH1 genotype and gender were found on the scores of novelty seeking. Post-hoc analysis revealed that males with the C/C genotype had higher scores of novelty seeking than those with the C/T genotype or those with the T/T genotype, while in females the scores of novelty seeking were not different among the genotype groups. The present study thus suggests that the C+243T polymorphism of the GCH1 gene affects the personality trait of novelty seeking in males.

Relationships of sociotropy and autonomy with dimensions of the Temperament and Character Inventory in healthy subjects.

The relationships of sociotropy and autonomy, the 2 personality traits postulated as vulnerability factors for depression, with 7 dimensions of the Temperament and Character Inventory, a comprehensive measure of personality, were studied in 305 healthy subjects. Sociotropy and autonomy were assessed by the sociotropy and autonomy subscales, respectively, of the original 60-item Sociotropy-Autonomy Scale. In multiple regression analysis, sociotropy was significantly correlated with higher harm avoidance, reward dependence (RD), and self-transcendence (ST), and lower self-directedness; and the correlation was strongest with higher RD (ß = 0.27) and second strongest with lower self-directedness (ß = -0.25). Meanwhile, autonomy was significantly correlated with higher persistence and ST, and lower RD; and the correlations were especially strong with higher ST (ß = 0.37) and lower RD (ß = -0.28). These results support Beck's concepts of these personality traits, that is, the orientation toward interpersonal relationships of sociotropy, and that toward mastery and independence of autonomy.

Association study between a functional polymorphism of FK506-binding protein 51 (FKBP5) gene and personality traits in healthy subjects.

Previous studies have shown that the function of hypothalamic-pituitary-adrenal (HPA) axis is involved in the characterization of personality traits. FK506-binding protein 51 (FKBP51 or FKBP5) is a co-chaperone of heat-shock protein 90, and plays an important role in the negative feedback regulation of HPA axis function. It has been reported that a C/T single nucleotide polymorphism in the intron 2 of FKBP5 gene (rs1360780) affects FKBP5 protein levels and cortisol response to dexamethasone and psychological stress tests. Therefore, it is hypothesized that the FKBP5 polymorphism affects personality traits. In the present study, we studied the association between this polymorphism and personality traits in 826 Japanese healthy subjects. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the FKBP5 genotype was detected by a real-time PCR and cycling probe technology for SNP typing. In total subjects, the group with the T allele predictive of impaired negative feedback regulation of the HPA axis had higher scores of harm avoidance (HA) (p=0.043) and lower scores of cooperativeness (CO) (p=0.019) compared to that without the T allele. The T allele was associated with higher scores of HA in females (p=0.020) and lower scores of CO in males (p=0.015). The present study thus suggests that the FKBP5 polymorphism affects HA and CO in healthy subjects, with gender specificity.

Efficacy of milnacipran in the treatment of chronic pain syndromes.

Abstract Eleven outpatients with chronic pain syndromes other than fibromyalgia were treated for 12 weeks with milnacipran, a novel serotonin noradrenaline reuptake inhibitor. The agent was administered at 50-150 mg/day, and the mean ± SD dose at 12 weeks or at the time drug treatment was stopped was 84.1 ± 32.2 mg/day. None of the patients met the DSM-IV criteria for a major depressive disorder. Abdominal, chest, back, arm, leg or glossal pain, or headache was involved. Pain was assessed clinically by means of a visual analog scale (VAS) before and 12 weeks after the start of milnacipran treatment, or at the time drug treatment was stopped. The mean ± SD decrease in VAS scores was 42.3 ± 31.6 (50.8 ± 49.2%). One patient discontinued treatment after 4 weeks because of nausea, whereas others tolerated the agent well. These results suggest that the use of milnacipran in patients with a variety of chronic pain syndromes is beneficial.

Association study between a functional polymorphism of tyrosine hydroxylase gene promoter and personality traits in healthy subjects.

According to the Cloninger's theory, personality consists of temperaments, which are automatic emotional reactions and habits, and characters, which are the self-concepts about goals and values. It has been suggested that temperaments are highly heritable and related to catecholaminergic neurotransmission. Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme in the biosynthesis of catecholamines such as dopamine and norepinephrine, which are deeply involved in human mental functions and behaviors. It has recently been reported that the C-824T single nucleotide polymorphism in the promoter region of the TH gene (rs10770141) affects promoter activity of the TH gene and urinary catecholamine levels. In the present study, the association of this polymorphism with personality traits was examined in 740 healthy Japanese subjects. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the TH genotype was detected by a PCR-RFLP method. In total subjects, there were no significant differences in the seven TCI dimension scores between the TH genotype groups. In males, the subjects with the T allele predictive of elevated levels of dopamine and norepinephrine had lower scores of novelty seeking than those without this allele, while in females none of the TCI scores was different between the two genotype groups. The present study thus suggests that the C-824T polymorphism in the TH gene promoter may affect the personality trait of novelty seeking in healthy males. However, taken the effects of multiple comparisons into account, the present result should be interpreted with caution, necessitating a replication in a different sample.

Dysfunctional parenting styles increase interpersonal sensitivity in healthy subjects.

The effects of dysfunctional parenting styles on interpersonal sensitivity were studied in 640 Japanese volunteers. Interpersonal sensitivity was assessed by the Interpersonal Sensitivity Measure (IPSM), and perceived parental rearing was evaluated by the Parental Bonding Instrument (PBI), which is consisted of care and protection factors. Parental rearing was classified into 4 types, i.e., optimal parenting (high care/low protection), affectionate constraint (high care/high protection), neglectful parenting (low care/low protection), and affectionless control (low care/high protection). Males with paternal affectionless control showed higher total IPSM scores than those with paternal optimal parenting (p = 0.022). Females with maternal affectionate constraint (p = 0.001), neglectful parenting (p = 0.022), and affectionless control (p = 0.003) showed higher total IPSM scores than those with maternal optimal parenting. In males and females, dysfunctional parenting styles by the opposite-sex parents did not affected total IPSM scores. The present study suggests that in both males and females interpersonal sensitivity is increased by dysfunctional parenting styles by the same-sex parents.

Influence of serotonergic/noradrenergic gene polymorphisms on nausea and sweating induced by milnacipran in the treatment of depression.

The present study was conducted to find out the predictors of side effects such as nausea and excessive sweating induced by milnacipran, a serotonin/norepinephrine reuptake inhibitor. Both clinical characteristics prior to the treatment and gene polymorphisms such as serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR), a variable number of tandem repeats in the second intron of the 5-HTT gene (5-HTTVNTR), 5-HT2A receptor gene (5-HT2A G-1438A), a TPH gene polymorphism in intron 7 (TPH A218C), norepinephrine transporter (NET) gene polymorphism in the promoter region (NET T-182C) and in the exon 9 (NET G1287A), a variable number of tandem repeats in the promoter region of monoamine oxidase A, were items to be assessed in this study. Ninety-six patients with major depressive disorder were treated with milnacipran. Side effects were assessed at 1, 2, 4, and 6 weeks of treatment with Udvalg for Kliniske Undersogelser side effects scale. The results showed that no gene polymorphisms included in this study affected the susceptibility of nausea and excessive sweating induced by milnacipran. Patients with older age are more likely to develop excessive sweating than others. The major limitation of this study is a small sample size. Further studies with larger populations and more kinds of gene polymorphisms should be needed to see if specific gene polymorphisms determine the susceptibility of side effects induced by milnacipran.

Effect of the cytochrome P450 19 (aromatase) gene polymorphism on personality traits in healthy subjects.

There have been several studies showing the relationship between sex hormones and personality traits. Cytochrome P450 19 (CYP 19, aromatase) is the rate-limiting enzyme for the conversion of androgens into estrogens, and it has been reported that the C/T single nucleotide polymorphism in the 3'-untranslated region (3'UTR) of CYP19 gene (rs10046) affects dispositions of estradiol and testosterone. Therefore, it is hypothesized that this polymorphism affects personality traits. In the present study, the association of this polymorphism with personality traits was examined in 633 healthy Japanese subjects. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the CYP19 genotype was detected by a PCR-RFLP method. In males, the group with the T allele predictive of elevated levels of estradiol and decreased levels of testosterone had lower scores of harm avoidance than that without the T allele (p=0.015). In females, none of the seven TCI dimensions was different between the two genotype groups. The present study thus suggests that the C/T polymorphism in the 3'UTR of CYP19 gene affects personality trait of harm avoidance in healthy males.

Differential clinical effects of fluvoxamine by the effect of age in Japanese female major depressive patients.

The effects of gender differences and age on the treatment response to fluvoxamine were investigated in major depressive Japanese patients. A total of 100 Japanese patients participated in this study. The daily dose of fluvoxamine was fixed to 100, 150 or 200 mg in the fourth week. This fixed dose was maintained until the end of the 6-week study. The patients were divided into 3 groups: younger females, older females, and males. Depressive symptoms were evaluated using the Montgomery and Asberg Depression Rating Scale (MADRS) at pretreatment and at 1, 2, 4, and 6 weeks after the commencement of the study. Seven of the 100 patients were excluded, and the remaining 93 patients constituted the subjects (50 females, 43 males). The number of intent-to-treat responders and non-responders was 55 and 38, respectively. There was a significant difference in the changes in the time course of the MADRS score and changes in the MADRS scores at each evaluation point between the younger and older females. Younger females demonstrated a significantly better response than older females. The results suggest that fluvoxamine is more effective in younger female patients than in older female patients.

Association study between the -1021C/T polymorphism of the dopamine-beta-hydroxylase gene promoter and personality traits in healthy subjects.

Dopamine and norepinephrine are implicated in the characterization of personality traits. Dopamine-beta-hydroxylase (DBH) is the enzyme responsible for conversion of dopamine to norepinephrine, and thus plays an important role in controlling dispositions of these neurotransmitters. Previous studies have shown that the -1021C/T polymorphism of the DBH gene promoter influences plasma DBH activity. Therefore, we examined the association between the -1021C/T DBH polymorphism and personality traits in 627 Japanese healthy volunteers. The DBH genotypes were identified by a PCR-RFLP method, and personality traits were assessed by the Temperament and Character Inventory (TCI). In the two-factor analysis of covariance with the DBH genotype and sex as factors and with age as a covariate, there was no main effect of the DBH genotype on any TCI score, while the interaction between the factors was significant in harm avoidance. In the post hoc analysis, the group with the T allele predictive of lower DBH activity had higher scores of harm avoidance than that without the T allele in females (p=0.006), but not in males. The present study suggests that the -1021C/T DBH polymorphism affects the personality trait of harm avoidance in healthy females.

The -67 A/T promoter polymorphism in the dopamine transporter gene affects personality traits of Japanese healthy females.

Dopamine transporter (DAT) plays a major role in terminating dopamine neurotransmission, which may be involved in the characterization of personality traits. Recently, polymorphisms of the promoter region (-67 A/T) and intron 8 (40-bp variable number of tandem repeats, VNTRs) in the DAT gene were reported to affect DAT expression. In the present study, we examined the associations of these polymorphisms with personality traits in 654 healthy Japanese. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the DAT polymorphisms were identified by PCR-based methods. Regarding the -67 A/T promoter polymorphism, the females without the A allele predictive of high DAT activity had lower scores of self-directedness (p=0.005) and cooperativeness (p=0.038) than those with the A allele. In males, none of the TCI scores was different between the two genotype groups. The intron 8 VNTR polymorphism did not affect any TCI score either in males or in females. The present study thus suggests that the -67 A/T promoter polymorphism, but not intron 8 VNTR polymorphism, in the DAT gene affects personality traits of Japanese healthy females.