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Patients with schizophrenia experiences varying clinical courses in the symptoms and up to 30-60% of patients with schizophrenia do not respond sufficiently to antipsychotics. Treatment-resistant Schizophrenia (TRS) can have several reasons, including early onset, nonadherence to oral medication regimens, and persistent negative symptoms known as deficit syndrome. Patients with TRS experience frequent exacerbations, leading to the need for higher doses of antipsychotics to achieve a clinical result.
Recently, dopamine supersensitivity psychosis (DSP) and tardive dyskinesia (TD), both of which could be caused by inappropriate pharmacotherapy, as typified by excessive dosages of antipsychotics, have also been presumed relevant to TRS. Several lines of evidence suggest that both DSP and withdrawal psychosis are closely linked to the supersensitivity of dopamine D2 receptors; this could be caused by a potent blockade of the receptors by antipsychotics. Indeed our study recently has found that patients with DSP are overlapped with the concept of treatment-resistance, and these patients can be recovered by long-acting injectable form, via amelioration of Dopamine supersensitivity state. However, it was also observed that one group did not improve at the clinical symptomatic level, despite the presence of DSP.
Here, we try to verify relation in patients with treatment-resistant schizophrenia between several classes of antipsychotics or clinical symptoms and treatment process with oral antipsychotics after the initiation of RLAI. This study is a naturalistic, one-arm design with a 12-month observation period of a moderate sample size (N=115).
Although treatment-resistant schizophrenia (TRS) is a highly heterogeneous disorder, an established and efficacious treatment for those patients to date is pharmacotherapy with clozapine. Dopamine supersensitivity psychosis (DSP) is characterized by profound unstable positive symptoms and tardive dyskinesia, and its mechanism is related to up-regulation of dopamine D2 receptors (DRD2) which can be induced by long-term treatment with antipsychotics. Patients with DSP take generally excessive high dosages of neuroleptics and thus meet easily the criteria of TRS. A drug with secure and stable pharmacokinetic, which can keep an appropriate blockade of DRD2, may contribute to amelioration and prevention of the dopamine supersensitivity state. Risperidone long-acting injection (RLAI) is a candidate agent which meets this hypothesis.
For 115 patients with TRS, we divided them into two groups; the one is those with a history of DSP and the other is without DSP, and treatment with RLAI was conducted for 12-month duration. This is an observational study which did not control concomitant medications or dosage of RLAI.
Clinical symptomatology and medications at baseline did not differ between the two groups. The results from the final analysis for remaining 95 patients revealed that the group with DSP showed greater improvements in the change of BPRS total score than the group without DSP.
These results suggested strongly that the dopamine supersensitivity state could be related partly with the etiology of TRS. An atypical agent with long half-life time such as RLAI, can provide beneficial effect for patients with DSP.
Recent studies have shown that it is important to understand the brain mechanism specifically by focusing on the common and unique functional connectivity in each disorder including depression.
To specify the biomarker of major depressive disorder (MDD), we applied the sparse machine learning algorithm to classify several types of affective disorders using the resting state fMRI data collected in multiple sites, and this study shows the results of depression as a part of those results.
The aim of this study is to understand some specific pattern of functional connectivity in MDD, which would support diagnosis of depression and development of focused and personalized treatments in the future.
The neuroimaging data from patients with major depressive disorder (MDD, n = 100) and healthy control adults (HC: n = 100) from multiple sites were used for the training dataset. A completely separate dataset (n = 16) was kept aside for testing. After all preprocessing of fMRI data, based on one hundred and forty anatomical region of interests (ROIs), 9730 functional connectivities during resting states were prepared as the input of the sparse machine-learning algorithm.
As results, 20 functional connectivities were selected with the classification performance of Accuracy: 83.0% (Sensitivity: 81.0%, Specificity: 85.0%). The test data, which was completely separate from the training data, showed the performance accuracy of 83.3%.
The selected functional connectivities based on the sparse machine learning algorithm included the brain regions which have been associated with depression.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
To characterise the dissemination patterns of uropathogenic Escherichia coli (UPEC) in a community, we conducted a study utilising molecular and fundamental descriptive epidemiology. The subjects, consisted of women having community-acquired acute urinary tract infection (UTI), were enrolled in the study from 2011 to 2012. UPEC isolates were subjected to antibacterial-susceptibility testing, O serogrouping, phylotyping, multilocus-sequence typing with phylogenetic-tree analysis and pulsed-field-gel electrophoresis (PFGE). From the 209 unique positive urinary samples 166 UPEC were isolated, of which 129 were fully susceptible to the tested antibiotics. Of the 53 sequence types (STs), the four most prevalent STs (ST95, ST131, ST73 and ST357) accounted for 60% of all UPEC strains. Antimicrobial resistance was less frequently observed for ST95 and ST73 than for the others. A majority of rare STs and a few common STs constituted the diversity pattern within the population structure, which was composed of the two phylogenetically distinct clades. Eleven genetically closely related groups were determined by PFGE, which accounted for 42 of the 166 UPEC isolates, without overt geo-temporal clustering. Our results indicate that a few major lineages of UPEC, selected by unidentified factors, are disseminated in this community and contribute to a large fraction of acute UTIs.
Previous studies have shown that the renin–angiotensin system (RAS) is affected by adverse maternal nutrition during pregnancy. The aim of this study was to investigate the effects of a maternal low-protein diet on proinflammatory cytokines, reactive oxygen species and RAS components in kidney samples isolated from adult male offspring. We hypothesized that post-weaning losartan treatment would have beneficial effects on RAS activity and inflammatory and oxidative stress markers in these animals. Pregnant Sprague–Dawley rats were fed with a control (20% casein) or low-protein diet (LP) (6% casein) throughout gestation. After weaning, the LP pups were randomly assigned to LP and LP-losartan groups (AT1 receptor blockade: 10 mg/kg/day until 20 weeks of age). At 20 weeks of age, blood pressure levels were higher and renal RAS was activated in the LP group. We also observed several adverse effects in the kidneys of the LP group, including a higher number of CD3, CD68 and proliferating cell nuclear antigen-positive cells and higher levels of collagen and reactive oxygen species in the kidney. Further, our results revealed that post-weaning losartan treatment completely abolished immune cell infiltration and intrarenal RAS activation in the kidneys of LP rats. The prevention of augmentation of angiotensin (Ang II) concentration abolished inflammatory and fibrotic events, indicating that Ang II via the AT1 receptor is essential for pathological initiation. Our results suggest that the prenatal programming of hypertension is dependent on the up-regulation of local RAS and presence of immune cells in the kidney.
An outbreak of enterohaemorrhagic Escherichia coli O157 occurred in multiple prefectures of Japan in November 2009. We conducted two case–control studies with trace-back and trace-forward investigations to determine the source. The case definition was met by 21 individuals; 14 (66.7%) were hospitalised, but no haemolytic uraemic syndrome, acute encephalopathy or deaths occurred. Median age was 23 (range 12–48) years and 14 cases were male (66.7%). No significant associations with food were found in a case–control study by local public health centres, but our matched case–control study using Internet surveys found that beef hanging tender (or hanger steak), derived from the diaphragm of the cattle, was significantly associated with illness (odds ratio = 15.77; 95% confidence interval, 2.00–124.11). Pulsed-field gel electrophoresis analysis of isolates from patients and the suspected food showed five different patterns: two in faecal and food samples, and another three in patient faecal samples only, although there were epidemiological links to the meat consumed at the restaurants. Trace-back investigation implicated a common food processing company from outside Japan. Examination of the logistics of the meat processing company suggested that contamination did not occur in Japan. We concluded that the source of the outbreak was imported hanging tender. This investigation revealed that Internet surveys could be useful for outbreak investigations.
Recently, many superflares on solar-type stars were discovered as white-light flares (WLFs). A correlation between the energies (E) and durations (t) of superflares is derived as t∝E0.39, and this can be theoretically explained by magnetic reconnection (t∝E1/3). In this study, we carried out a statistical research on 50 solar WLFs with SDO/HMI to examine the t-E relation. As a result, the t-E relation on solar WLFs (t∝E0.38) is quite similar stellar superflares, but the durations of stellar superflares are much shorter than those extrapolated from solar WLFs. We present the following two interpretations; (1) in solar flares, the cooling timescale of WL emission may be longer than the reconnection one, and the decay time can be determined by the cooling timescale; (2) the distribution can be understood by applying a scaling law t∝E1/3B−5/3 derived from the magnetic reconnection theory.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
Public stigma alters attitudes towards people with mental illness, and is a particular concern for young people since most mental health problems occur in adolescence and young adulthood. However, little is known about the long-term effects of repeated filmed social contact (FSC) on reducing mental health-related stigma among young adults in the general population, compared with self-instructional Internet search (INS) and control interventions.
This study is a parallel-group randomised controlled trial over 12 months conducted in Tokyo, Japan. A total of 259 university students (male n = 150, mean age = 20.0 years, s.d. = 1.2) were recruited from 20 colleges and universities between November 2013 and July 2014, without being provided information about the mental health-related survey or trial. Participants were assigned to one of three groups before completion of the baseline survey (FSC/INS/control = 89/83/87). The FSC group received a computer-based 30-min social contact film with general mental health education and five follow-up web-based FSCs at 2-month intervals. The INS group undertook a 30-min search for mental health-related information with five follow-up web-based reminders for self-instructional searches at 2-month intervals. The control group played PC games and had no follow-up intervention. The main outcome measures were the future (intended behaviour) domain of the Reported and Intended Behaviour Scale at 12 months after the intervention. Analysis was conducted in September 2015.
At the 12-month follow-up, 218 participants completed the survey (84.1%, 75:70:73). The FSC group showed the greatest change at the 12-month follow-up (FSC: mean change 2.11 [95% CI 1.49, 2.73], INS: 1.04 [0.29, 1.80], control: 0.71 [0.09, 1.33]; FSC v. INS p = 0.037, FSC v. controls p = 0.004). No adverse events were reported during the follow-up period.
FSC was more successful in reducing stigma at 12 months after intervention than INS or control interventions. FSC could be used to reduce stigma in educational lectures and anti-stigma campaigns targeted at young people.
This study is registered at UMIN-CTR (No. UMIN000012239).
Human parechoviruses (HPeVs) mainly infect young children, causing mild gastrointestinal and respiratory diseases; however, HPeV type 3 (HPeV3) causes severe systemic diseases in young infants. To clarify the characteristics of HPeV infections from the aspects of seropositivity and epidemiology, we measured neutralizing antibody titres against HPeVs in individuals of in different age groups and isolated HPeVs from various clinical specimens in Niigata, Japan. The seropositivity to HPeV1, 3, and 6 was higher in older age group. HPeV1 and HPeV6 seropositivities were maintained in adults, whereas HPeV3 seropositivity was significantly lower in subjects aged >40 years (P < 0·001, P = 0·003). This result suggests that adults have increased susceptibility to HPeV3 as they lack neutralizing antibodies against HPeV3. Of the HPeV isolates, HPeV1 and HPeV6 frequently caused gastrointestinal symptoms. Moreover, gastroenteritis patients with HPeV1 and HPeV6 were mainly aged 6 months–1 year and ⩾2 years, respectively. In contrast, only HPeV3 was isolated from neonates and young infants with sepsis or sepsis-like syndrome, often with respiratory symptoms. These results suggest that clinical symptoms are clinically related to HPeV genotype and patients’ age.
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the incretin hormones secreted from the intestine in response to enteral feeding to stimulate insulin secretion. We investigated the relationship serum GIP and GLP-1 levels with gestational age, and insulin secretion in preterm infants. Serum GIP and GLP-1 levels were measured at birth and at 1, 2 and 4 weeks after birth in 30 infants, including 12 born before 30th week of gestation (early group) and 18 born after 30th week of gestation (late group). Blood glucose and serum insulin levels were measured, and the quantitative insulin sensitivity check index (QUICKI) was also calculated. The levels of GLP-1 at 2 and 4 weeks were significantly higher in the early group than those in the late group. The levels of GIP were not significantly different between two groups. At 4 weeks, serum insulin level was significantly higher and QUICKI was significantly lower in the early group. Furthermore, GLP-1 levels were significantly correlated with QUICKI and the serum insulin levels in all infants at 4 weeks. In preterm infants, enteral feeding to premature intestine may be associated with GLP-1 secretion. GLP-1 is also related to stimulated insulin secretion in early postnatal period.
Overweight and obese individuals have an increased risk of developing the metabolic syndrome because of subsequent chronic inflammation and oxidative stress, which the antioxidant nutrient lycopene can reduce. However, studies indicate that different BMI statuses can alter the positive effects of lycopene. Therefore, the purpose of this study was to examine how BMI influences the association between serum lycopene and the metabolic syndrome. The tertile rank method was used to divide 13 196 participants, aged 20 years and older, into three groups according to serum concentrations of lycopene. The associations between serum lycopene and the metabolic syndrome were analysed separately for normal-weight, overweight and obese participants. Overall, the prevalence of the metabolic syndrome was significantly higher in the first tertile group (OR 38·6 %; 95 % CI 36·9, 40·3) compared with the second tertile group (OR 29·3 %; 95 % CI 27·5, 31·1) and the third tertile group (OR 26·6 %; 95 % CI 24·9, 28·3). However, the associations between lycopene and the metabolic syndrome were only significant for normal-weight and overweight participants (P<0·05), but not for obese participants (P>0·05), even after adjusting for possible confounding variables. In conclusion, BMI appears to strongly influence the association between serum lycopene and the metabolic syndrome.
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
Submillimetre observations of the externally irradiated protostar R CrA IRS7B show that this source has dramatically different chemical abundances in comparison with otherwise similar embedded protostars not subject to external irradiation.
Submillimetre observations of externally irradiated low-mass protostellar envelopes show that the gas temperature in the envelopes is dominated by the external irradiation. Detailed studies of the protostar IRS7B in Corona Australis also show that the chemistry is strongly affected by the irradiation, depleting the abundances of complex organic molecules.