High Tumoral STMN1 Expression Is Associated with Malignant Potential and Poor Prognosis in Patients with Neuroblastoma.

BACKGROUND: Stathmin 1 (STMN1), a marker for immature neurons and tumors, controls microtubule dynamics by destabilizing tubulin. It plays an essential role in cancer progression and indicates poor prognosis in several cancers. This potential protein has not been clarified in clinical patients with neuroblastoma. Therefore, this study aimed to assess the clinical significance and STMN1 function in neuroblastoma with and without MYCN amplification. METHODS: Using immunohistochemical staining, STMN1 expression was examined in 81 neuroblastoma samples. Functional analysis revealed the association among STMN1 suppression, cellular viability, and endogenous or exogenous MYCN expression in neuroblastoma cell lines. RESULT: High levels of STMN1 expression were associated with malignant potential, proliferation potency, and poor prognosis in neuroblastoma. STMN1 expression was an independent prognostic factor in patients with neuroblastoma. Furthermore, STMN1 knockdown inhibited neuroblastoma cell growth regardless of endogenous and exogenous MYCN overexpression. CONCLUSION: Our data suggest that assessing STMN1 expression in neuroblastoma could be a powerful indicator of prognosis and that STMN1 might be a promising therapeutic candidate against refractory neuroblastoma with and without MYCN amplification.

Pneumonia Risk Increased by Dementia-Related Daily Living Difficulties: Poor Oral Hygiene and Dysphagia as Contributing Factors.

OBJECTIVE: Although pneumonia is the leading cause of death among patients with dementia, the specific underlying causes remain unclear. In particular, the potential connection between pneumonia risk and dementia-related daily living difficulties, such as oral hygiene practice and mobility impairment, and the use of physical restraint as a management practice, has not been extensively studied. METHODS: In our retrospective study, we included 454 admissions corresponding to 336 individual patients with dementia who were admitted to a neuropsychiatric unit due to behavioral and psychological symptoms. The admissions were divided into two groups: those who developed pneumonia while hospitalized (n=62) and those who did not (n=392). We investigated differences between the two groups in terms of dementia etiology, dementia severity, physical conditions, medical complications, medication, dementia-related difficulties in daily living, and physical restraint. To control potential confounding variables, we used mixed effects logistic regression analysis to identify risk factors for pneumonia in this cohort. RESULTS: Our study found that the development of pneumonia in patients with dementia was associated with poor oral hygiene, dysphagia, and loss of consciousness. Physical restraint and mobility impairment showed a weaker, nonsignificant association with the development of pneumonia. CONCLUSIONS: Our findings suggest that pneumonia in this population may be caused by two primary factors: increased pathogenic microorganisms in the oral cavity due to poor hygiene, and an inability to clear aspirated contents due to dysphagia and loss of consciousness. Further investigation is needed to clarify the relationship between physical restraint, mobility impairment, and pneumonia in this population.

Intravenous pulse methylprednisolone and corticosteroid-induced psychiatric disorders: A retrospective study.

OBJECTIVE: Corticosteroids can cause psychiatric symptoms known as corticosteroid-induced psychiatric disorders (CIPDs). Little is known regarding the relationship between intravenous pulse methylprednisolone (IVMP) and CIPDs. Therefore, we aimed to examine the relationship between corticosteroid use and CIPDs in this retrospective study. METHODS: Patients who were prescribed corticosteroids during their hospitalization at a university hospital and referred to our consultation-liaison service were selected. Patients diagnosed with CIPDs according to the ICD-10 codes were included. The incidence rates were compared between patients receiving IVMP and those receiving any other corticosteroid treatment. The association between IVMP and CIPDs was examined by classifying patients with CIPD into three groups according to the use of IVMP and timing of CIPD onset. RESULTS: Of the 14,585 patients who received corticosteroids, 85 were diagnosed with CIPDs, with an incidence rate of 0.6%. Among the 523 patients who received IVMP, the incidence rate of CIPDs was 6.1% (n = 32), which was significantly higher than that in patients receiving any other corticosteroid treatment. Among the patients with CIPDs, 12 (14.1%) developed CIPDs during IVMP, 19 (22.4%) developed CIPDs after IVMP, and 49 (57.6%) developed CIPDs without IVMP. There was no significant difference in the doses at the time of CIPD improvement among the three groups when we excluded one patient whose CIPD improved during IVMP. CONCLUSION: Patients receiving IVMP were more likely to develop CIPDs than those who did not receive IVMP. Furthermore, corticosteroid doses at the time of improvement of CIPDs were constant, regardless of IVMP use.

Antipsychotic Monotherapy for Major Depressive Disorder: A Systematic Review and Meta-Analysis.

Although several randomized controlled trials (RCTs) have compared the effectiveness, efficacy, and safety of antipsychotic monotherapy (APM) versus placebo in patients with major depressive disorder (MDD), no meta-analysis has examined this topic. We conducted a systematic literature search using MEDLINE and Embase to identify relevant RCTs and performed a meta-analysis to compare the following outcomes between APM and placebo: response and remission rates, study discontinuation due to all causes, lack of efficacy, and adverse events, changes in total scores on depression severity scales, and individual adverse event rates. A total of 13 studies were identified, with 14 comparisons involving 3,197 participants that met the eligibility criteria. There were significant differences between APM and placebo in response and remission rates and changes in the primary depression severity scale in favor of APM, and study discontinuation due to adverse events and several individual adverse events in favor of placebo. No significant difference was observed in discontinuation due to all causes. APM could have antidepressant effects in the acute phase of MDD, although clinicians should be aware of an increased risk of some adverse events.

Examination of the effectiveness of bedside nasojejunal tube placement using a portable imaging device with a flat panel detector.

Transporting pediatric patients with severe cardiovascular complications to the fluoroscopy room can be difficult. Therefore, we started using a portable imaging device with a flat panel detector (FPD) for nasojejunal tube (NJT) placement. The purpose of this study was to investigate the differences in length of time of NJT placement and dosage of radiation exposure using a portable imaging device with FPD versus fluoroscopy. Pediatric patients who underwent NJT placement between April 2016 and December 2018 were identified retrospectively from the clinical records. The age, sex, body weight, and height of each child at the time of the procedure as well as the procedure time, outcomes of the procedure, and dosage of radiation exposure was compared between the two groups. In 76 cases of NJT placement (41 patients), there was no significant difference in the success rate of NJT placement between the FPD (90%) and fluoroscopy groups (95%). However, the NJT placement time was significantly longer in the FPD group than in the fluoroscopy group (488 s vs 291 s). According to our calculations, the radiation dosage was lower in the FPD group than in the fluoroscopy group (136 µGy per procedure vs 2819 µGy per procedure). These results suggest that NJT placement using a portable imaging device with an FPD can be an effective method for children who are difficult to transport with an equal success rate and lower dosage of radiation exposure compared with conventional fluoroscopy.

Differentiating autoimmune encephalitis from schizophrenia spectrum disorders among patients with first-episode psychosis.

BACKGROUND: Although differential diagnosis between autoimmune encephalitis and schizophrenia spectrum disorders is crucial for a good outcome, the psychiatric symptoms that distinguish these two conditions have not been identified even though psychiatric symptoms are often the main manifestation of autoimmune encephalitis. Also, there are many situations in clinical psychiatry in which laboratory testing and imaging studies are not available. Because no comparative study of the psychiatric symptoms between these two conditions has been carried out, we explored diagnostically useful psychiatric symptoms in a retrospective case-control study. METHODS: We recruited 187 inpatients with first-episode psychosis who were admitted to our psychiatric unit and categorized them into two groups: the autoimmune encephalitis group (n = 10) and the schizophrenia spectrum disorders group (n = 177). Differences in the symptoms and signs between the two groups were investigated. RESULTS: Schneider's first-rank symptoms (e.g., verbal commenting hallucinations and delusional self-experience) were observed only in the schizophrenia spectrum disorders group, whereas altered perception was found more frequently in the autoimmune encephalitis group. Functional status was worse in the autoimmune encephalitis group, and neurological and neuropsychological signs were revealed almost exclusively in this group. A history of mental illness was more frequently reported in the schizophrenia spectrum disorders group than in the autoimmune encephalitis group. CONCLUSIONS: The psychiatric symptoms, i.e., Schneider's first-rank symptoms and altered perception, together with neurological and neuropsychological signs, functional status, and past history, may help clinicians accurately differentiate these two conditions among patients with first-episode psychosis.

Mallory-Weiss syndrome complicated by severe aspiration pneumonitis in an infant.

A 1-month-old girl presented with hematemesis and dyspnea. A large amount of blood was aspirated through a nasogastric tube, and chest computed tomography showed bilateral centrilobular opacified lesions, which suggested aspiration pneumonitis due to upper gastrointestinal bleeding. Her respiratory condition exacerbated, and we initiated nitric oxide (NO) therapy. Bleeding stopped with conservative treatment. She was weaned off mechanical ventilation and extubated on Day 6 after admission. Afterward, upper gastrointestinal endoscopy showed a longitudinal linear scar indicative of Mallory-Weiss syndrome (MWS). MWS is rarely reported in early infancy since many of the risk factors are absent in infants. Patients with aspiration pneumonitis usually recover respiratory function within 24 h and severe respiratory failure is rare in aspiration pneumonitis. There are no pediatric case reports describing MWS with severe aspiration pneumonitis. Although MWS is a rare cause of neonatal hematemesis, patients can become severely ill and require multidisciplinary treatment.

Face and construct validity assessment of training models for intestinal anastomosis in low-birth-weight infants.

PURPOSE: It is difficult to perform intestinal anastomosis in low-birth-weight infants because the intestinal diameter is small and the discrepancy in diameter of the proximal and distal intestines is often large, but there has been no optimal-sized training model. Therefore, we developed a new intestinal anastomosis training model that imitated the size of the intestine in low-birth-weight infants, and evaluated its face and construct validity. METHODS: Two intestinal models were developed with crossMedical, Inc. using a hydrophilic acrylic material (wet model) or a polyurethane soft resin (dry model). The inner diameter of the simulated intestinal tract was 15 mm on the oral end and 6 mm on the anal end. Thirteen pediatric surgeons performed anastomosis and responded to the questionnaire. RESULTS: In the questionnaire, the wet model had significantly higher scores than the dry model in "appearance", "softness" and "usefulness for training". In the anastomotic results of the wet model, the anastomosis leak pressure was significantly correlated with the number of intestinal anastomotic experiences in low-birth-weight infants (correlation coefficient = 0.64, P = 0.035). CONCLUSIONS: The wet-type intestinal anastomosis model showed good face validity. Its leak pressure had a significant correlation with clinical experience; thus, construct validity was demonstrated.

Polygenic risk scores for major psychiatric and neurodevelopmental disorders contribute to sleep disturbance in childhood: Adolescent Brain Cognitive Development (ABCD) Study.

Sleep disturbance is a common symptom of psychiatric and neurodevelopmental disorders and, especially in childhood, can be a precursor to various mental disorders. However, the genetic etiology of mental illness that contributes to sleep disturbance during childhood is poorly understood. We investigated whether the polygenic features of psychiatric and neurodevelopmental disorders are associated with sleep disturbance during childhood. We conducted polygenic risk score (PRS) analyses by utilizing large-scale genome-wide association studies (GWASs) (n = 46,350-500,199) of five major psychiatric and neurodevelopmental disorders (autism spectrum disorder, schizophrenia, attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and bipolar disorder) and, additionally, anxiety disorders as base datasets. We used the data of 9- to 10-year-olds from the Adolescent Brain Cognitive Development study (n = 9683) as a target dataset. Sleep disturbance was assessed based on the Sleep Disturbance Scale for Children (SDSC) scores. The effects of PRSs for these psychiatric and neurodevelopmental disorders on the total scores and six subscale scores of the SDSC were investigated. Of the PRSs for the five psychiatric and neurodevelopmental disorders, the PRSs for ADHD and MDD positively correlated with sleep disturbance in children (ADHD: R2 = 0.0033, p = 6.19 × 10-5, MDD: R2 = 0.0042, p = 5.69 × 10-6). Regarding the six subscale scores of the SDSC, the PRSs for ADHD positively correlated with both disorders of initiating and maintaining sleep (R2 = 0.0028, p = 2.31 × 10-4) and excessive somnolence (R2 = 0.0023, p = 8.44 × 10-4). Furthermore, the PRSs for MDD primarily positively correlated with disorders of initiating and maintaining sleep (R2 = 0.0048, p = 1.26 × 10-6), followed by excessive somnolence (R2 = 0.0023, p = 7.74 × 10-4) and sleep hyperhidrosis (R2 = 0.0014, p = 9.55 × 10-3). Despite high genetic overlap between MDD and anxiety disorders, PRSs for anxiety disorders correlated with different types of sleep disturbances such as disorders of arousal or nightmares (R2 = 0.0013, p = 0.011). These findings suggest that greater genetic susceptibility to specific psychiatric and neurodevelopmental disorders, as represented by ADHD, MDD, and anxiety disorders, may contribute to greater sleep problems among children.

Clinical features of 35 Down syndrome patients with transient abnormal myelopoiesis at a single institution.

Transient abnormal myelopoiesis (TAM) is a unique clonal myeloproliferation characterized by immature megakaryoblasts that occurs in 5-10% of neonates with Down syndrome (DS). Although TAM regresses spontaneously in most patients, approximately 20% of TAM cases result in early death, and approximately 20% of survivors develop acute megakaryoblastic leukemia (AMKL). We retrospectively reviewed records of 35 DS patients with TAM to determine the correlation between clinical characteristics and blast percentage. Thirteen of the 35 patients were classified as low blast percentage TAM (LBP-TAM), defined as TAM with a peak peripheral blast percentage ≤ 10%. Although no patient with LBP-TAM experienced systemic edema, disseminated intravascular coagulation, or early death, eight patients had elevated direct bilirubin levels (> 2 mg/dl) and one developed AMKL. All patients with LBP-TAM had serum markers of liver fibrosis that exceeded the normal limits, and two patients underwent liver biopsy to clarify the etiology of pathological jaundice. Taken together, our results suggest that patients with LBP-TAM may be at risk of liver fibrosis and liver failure, similarly to patients with classical TAM. Although these patients generally have a good prognosis, they should be carefully monitored for potential development of liver disease and leukemia.

Optimal Viewing Direction of the Oblique Laparoscope in Single-Incision Laparoscopic Percutaneous Extraperitoneal Closure for Inguinal Hernia.

Background: It is difficult for novice surgeons to manipulate the oblique laparoscope in single-incision laparoscopic percutaneous extraperitoneal closure (SILPEC) for inguinal hernia because of collisions between the instruments. To standardize manipulation of the laparoscope, we studied the viewing direction of the oblique laparoscope, and assessed the optimal manipulation of the laparoscope to avoid collisions. Methods: A retrospective chart review was performed on patients who underwent SILPEC between April 2016 and April 2017. The viewing direction of the 30° oblique laparoscope was measured according to the location of the field stop pointer. Patients were divided into three groups according to the viewing direction at the beginning of the procedure: the inside viewing direction was from -90° to -11°, upward viewing direction was from -10° to 10°, and outside viewing direction was from 11° to 90°. The length of the procedure, viewing direction at the end, and the percentage of cases in which there was a change in viewing direction during the procedure were compared. Results: Ninety-eight cases of SILPEC were performed during the study period. The percentage of patients with a change in category of viewing direction in the inside, upward, and outside groups was 35%, 21%, and 11%, respectively, showing a significant difference among the three groups. Conclusions: Setting the initial viewing direction to the outside can reduce correction of the viewing direction during SILPEC. Because the intersection angle between the outside-viewing laparoscope and forceps is close to a right angle, this might reduce collisions.

Discovery of Candidate Stool Biomarker Proteins for Biliary Atresia Using Proteome Analysis by Data-Independent Acquisition Mass Spectrometry.

Biliary atresia (BA) is a destructive inflammatory obliterative cholangiopathy of the neonate that affects various parts of the bile duct. If early diagnosis followed by Kasai portoenterostomy is not performed, progressive liver cirrhosis frequently leads to liver transplantation in the early stage of life. Therefore, prompt diagnosis is necessary for the rescue of BA patients. However, the prompt diagnosis of BA remains challenging because specific and reliable biomarkers for BA are currently unavailable. In this study, we discovered potential biomarkers for BA using deep proteome analysis by data-independent acquisition mass spectrometry (DIA-MS). Four patients with BA and three patients with neonatal cholestasis of other etiologies (non-BA) were recruited for stool proteome analysis. Among the 2110 host-derived proteins detected in their stools, 49 proteins were significantly higher in patients with BA and 54 proteins were significantly lower. These varying stool protein levels in infants with BA can provide potential biomarkers for BA. As demonstrated in this study, the deep proteome analysis of stools has great potential not only in detecting new stool biomarkers for BA but also in elucidating the pathophysiology of BA and other pediatric diseases, especially in the field of pediatric gastroenterology.

A large superior mesenteric artery aneurysm and ileal obstruction: a rare presentation of polyarteritis nodosa in an infant.

Polyarteritis nodosa (PAN) is a rare form of vasculitis that occurs in childhood and affects small- and medium-sized arteries. Large aneurysms due to PAN can induce fatal complications like rupturing or occlusion of the affected arteries. Here, we report a case of a 4-month-old girl with PAN complicated by a large superior mesenteric artery aneurysm and ileal obstruction. We controlled her blood pressure to prevent the artery from rupturing. A combination of prednisolone, intravenous cyclophosphamide, and plasma exchange reduced the inflammation. She developed mechanical ileus due to ileum stricture and underwent bowel resection. Histopathological examinations revealed reparative arteritis around the healed ulcer. Her postoperative course was uneventful without further dilatation of the aneurysm. This case highlights the importance of intensive immunosuppressive therapy and appropriate blood pressure control in pediatric patients with PAN complicated by large aneurysms. Mechanical ileus can develop and may require surgical management even after remission of vasculitis.

A pediatric case of pheochromocytoma without apparent hypertension associated with von Hippel-Lindau disease.

Pheochromocytomas are catecholamine-secreting tumors. These tumors are rare in children, and they may be associated with hereditary syndromes such as von Hippel-Lindau (VHL) disease. Most pediatric patients with pheochromocytoma present with sustained hypertension, while 10% to 69% of adult patients are asymptomatic. Herein, we present the case of a 12-yr-old Japanese girl with pheochromocytoma due to a germline mutation in the VHL (Arg161Gln). The only complaint was loss of weight. Pyrexia, anemia, and increases in C-reactive protein (CRP) and ferritin were observed. Abdominal ultrasonography revealed a right adrenal gland tumor. Fractionated catecholamines and metanephrines in plasma and 24-h collected urine revealed elevated levels of norepinephrine and normetanephrine. Although hypertension and tachycardia were inapparent by an ordinary physical examination, paroxysmal mild hypertension and tachycardia were identified by a thorough examination after walking and abdominal compression. Paroxysmal hypertension and tachycardia were profound during operation. In conclusion, pheochromocytoma can be a consideration in the differential diagnosis of weight loss. Hypertension and tachycardia can be inapparent and paroxysmal in pediatric patients as well as in adults; thus, thorough assessment should be repeated.

CNS high-grade neuroepithelial tumor with BCOR internal tandem duplication: a comparison with its counterparts in the kidney and soft tissue.

Central nervous system high-grade neuroepithelial tumors with BCOR alteration (CNS HGNET-BCOR) are a recently reported rare entity, identified as a small fraction of tumors previously institutionally diagnosed as so-called CNS primitive neuroectodermal tumors. Their genetic characteristic is a somatic internal tandem duplication in the 3' end of BCOR (BCOR ITD), which has also been found in clear cell sarcomas of the kidney (CCSK) and soft tissue undifferentiated round cell sarcomas/primitive myxoid mesenchymal tumors of infancy (URCS/PMMTI), and these BCOR ITD-positive tumors have been reported to share similar pathological features. In this study, we performed a clinicopathological and molecular analysis of six cases of CNS HGNET-BCOR, and compared them with their counterparts in the kidney and soft tissue. Although these tumors had histologically similar structural patterns and characteristic monotonous nuclei with fine chromatin, CNS HGNET-BCOR exhibited glial cell morphology, ependymoma-like perivascular pseudorosettes and palisading necrosis, whereas these features were not evident in CCSK or URCS/PMMTI. Immunohistochemically, diffuse staining of Olig2 with a mixture of varying degrees of intensity, and only focal staining of GFAP, S-100 protein and synaptophysin were observed in CNS HGNET-BCOR, whereas these common neuroepithelial markers were negative in CCSK and URCS/PMMTI. Therefore, although CNS HGNET-BCOR, CCSK and URCS/PMMTI may constitute a group of BCOR ITD-positive tumors, only CNS HGNET-BCOR has histological features suggestive of glial differentiation. In conclusion, we think CNS HGNET-BCOR are a certain type of neuroepithelial tumor relatively close to glioma, not CCSK or URCS/PMMTI occurring in the CNS.

De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity.

Here we report de novo non-synonymous single-nucleotide variants (SNVs) by conducting whole exome sequencing of 18 trios consisting of Japanese patients with sporadic schizophrenia and their parents. Among nine SNVs, we explored the functional impact of the de novo mutation in TBL1XR1 [c.30 C > G (p.Phe10Leu)], a gene previously found to be associated with autism spectrum disorder and epilepsy. Protein structural analysis revealed that Phe10Leu mutation may decrease the structural stability of the TBL1XR1 protein. We demonstrate that Phe10Leu mutation alters the interaction of TBL1XR1 with N-CoR and ß-catenin, which play critical roles in regulation of Wnt-mediated transcriptional activity. Consistently, TBL1XR1-mediated activation of Wnt signaling was up-regulated by Phe10Leu mutation. These results suggest that a de novo TBL1XR1 point mutation could alter Wnt/ß-catenin signaling activity. Further studies are required to clarify the involvement of TBL1XR1 mutations in neuropsychiatric conditions.

Cumulative effect of the plasma total homocysteine-related genetic variants on schizophrenia risk.

Previous studies suggest that elevated total homocysteine levels and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which correlates with plasma total homocysteine levels, are risk factors for schizophrenia (SCZ). Recently, a large genome-wide association study (GWAS) of plasma total homocysteine levels in individuals of European ancestry identified many single-nucleotide polymorphisms (SNPs) (n=13,974). The primary purpose of this study was to examine the association between these plasma total homocysteine-related SNPs and SCZ in the Japanese population. First, we investigated associations between six SNPs and plasma total homocysteine levels in non-psychiatric subjects in the Japanese population (n=1030). Then, we evaluated the cumulative effects of three SNPs on SCZ risk by calculating the Genotype Risk Score (GRS) (1120 cases, 2643 controls). Of the six SNPs examined, we replicated similar associations with the European GWAS at four loci (CENPQ, CPS1, MTHFR, and MUT). GRS based on three SNPs (CENPQ, CPS1, and MTHFR) was significantly associated with SCZ. Our findings suggest that common polygenic variations, which are associated with the plasma total homocysteine levels, may contribute to the risk of SCZ.

Calcium Signaling Pathway Is Associated with the Long-Term Clinical Response to Selective Serotonin Reuptake Inhibitors (SSRI) and SSRI with Antipsychotics in Patients with Obsessive-Compulsive Disorder.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRI) are established first-line pharmacological treatments for obsessive-compulsive disorder (OCD), while antipsychotics are used as an augmentation strategy for SSRI in OCD patients who have either no response or a partial response to SSRI treatment. The goal of the present study was to identify genetic variants and pathways that are associated with the long-term clinical response of OCD patients to SSRI or SSRI with antipsychotics. METHODS: We first performed a genome-wide association study of 96 OCD patients to examine genetic variants contributing to the response to SSRI or SSRI with antipsychotics. Subsequently, we conducted pathway-based analyses by using Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS) to examine the combined effects of genetic variants on the clinical response in OCD. RESULTS: While we failed to detect specific genetic variants associated with clinical responses to SSRI or to SSRI with an atypical antipsychotic at genome-wide levels of significance, we identified 8 enriched pathways for the SSRI treatment response and 5 enriched pathways for the treatment response to SSRI with an antipsychotic medication. Notably, the calcium signaling pathway was identified in both treatment responses. CONCLUSIONS: Our results provide novel insight into the molecular mechanisms underlying the variability in clinical response to SSRI and SSRI with antipsychotics in OCD patients.

Association study of polymorphism in the serotonin transporter gene promoter, methylation profiles, and expression in patients with major depressive disorder.

The serotonin transporter (5HTT) may be associated with the pathogenesis of major depressive disorder (MDD). The 5HTT-linked polymorphic region (5HTTLPR) genotype may determine how levels of 5HTT mRNA are influenced by promoter methylation. We examined the association of 5HTT gene methylation, which influences gene expression, and the 5HTTLPR genotype before antidepressant treatment and expression before and after treatment. The aims of this study were (1) to investigate the association between 5HTT methylation or expression in leukocytes and depression and (2) to investigate a possible effect of 5HTT methylation, expression, and genotype on clinical symptoms in MDD. The 5HTTLPR genotype was significantly associated with mean methylation levels in patients only (patients: r = 0.40, p = 0.035, controls: p = 0.96). The mean methylation level was significantly increased in patients compared with controls (patients: 5.30 ± 0.24, controls: 4.70 ± 0.19, unpaired t-test, p = 0.04). 5HTT expression using real-time PCR and Taqman probes was increased in unmedicated patients compared with controls and then decreased 8 weeks after antidepressant treatment. The mean 5HTT expression level was not associated with the 5HTTLPR genotype in patients or controls. Increased depressive symptoms were related to decreased levels of methylation. Copyright © 2016 John Wiley & Sons, Ltd.

Molecular Histochemistry Identifies Peptidomic Organization and Reorganization Along Striatal Projection Units.

Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) (MALDI-IMS) provides a technical means for simultaneous analysis of precise anatomic localization and regulation of peptides. We explored the technical capability of matrix-assisted laser desorption ionization mass spectrometry for characterization of peptidomic regulation by an addictive substance along two distinct projection systems in the mouse striatum. The spatial expression patterns of substance P and proenkephalin, marker neuropeptides of two distinct striatal projection neurons, were negatively correlated at baseline. We detected 768 mass/charge (m/z) peaks whose expression levels were mostly negatively and positively correlated with expression levels of substance P and proenkephalin A (amino acids 218-228), respectively, within the dorsal striatum. After nicotine administration, there was a positive shift in correlation of mass/charge peak expression levels with substance P and proenkephalin A (218-228). Our exploratory analyses demonstrate the technical capacity of MALDI-IMS for comprehensive identification of peptidomic regulation patterns along histochemically distinguishable striatal projection pathways.