Trajectory of criterion symptoms of major depression under newly started antidepressant treatment: sleep disturbances and anergia linger on while suicidal ideas and psychomotor symptoms disappear early.

OBJECTIVE: In modern psychiatry, depression is diagnosed with the diagnostic criteria; however, the trajectory of each of the criterion symptoms is unknown. This study aims to examine this. METHODS: We made repeated assessments of the nine diagnostic criterion symptoms with the Patient Health Questionnaire-9 (PHQ-9) among 2011 participants of a 25-week pragmatic randomised controlled trial of sertraline and/or mirtazapine for hitherto untreated major depressive episodes. The changes from baseline were estimated with the mixed-effects model with repeated measures. The time to disappearance of each symptom was modeled using the Kaplan-Meier survival analysis. RESULTS: The total score on PHQ-9 was 18.5 (SD = 3.9, n = 2011) at baseline, which decreased to 15.3 (5.2, n = 2011) at week 1, to 11.5 (5.9, n = 1953) at week 3, to 7.8 (6.0, n = 1927) at week 9, and to 6.0 (5.9, n = 1910) at week 25. Suicidal ideas, psychomotor symptoms decreased rapidly, while anergia and sleep disturbance also decreased but only slowly. The survival analyses confirmed the primary analyses. CONCLUSIONS: Upon initiation of antidepressant treatment, patients with newly treated major depressive episodes can expect their suicidal ideas and psychomotor symptoms to disappear first but sleep disturbances and anergia to linger on.

High-resolution copy number variation analysis of schizophrenia in Japan.

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

Initial severity of major depression and efficacy of new generation antidepressants: individual participant data meta-analysis.

OBJECTIVE: The role of baseline severity as effect modifier in various psychiatric disorders is a topic of controversy and of clinical import. This study aims to examine whether baseline severity modifies the efficacy of various antidepressants for major depression through individual participant data (IPD) meta-analysis. METHOD: We identified all placebo-controlled, double-blind randomised trials of new generation antidepressants in the acute phase treatment of major depression conducted in Japan and requested their IPD through the public-private partnerships (PPPs) between the relevant academic societies and the pharmaceutical companies. The effect modification by baseline depression severity was examined through six increasingly complex competing mixed-effects models for repeated measures. RESULTS: We identified eleven eligible trials and obtained IPD from six, which compared duloxetine, escitalopram, mirtazapine, paroxetine or bupropion against placebo (total n = 2464). The best-fitting model revealed that the interaction between baseline severity and treatment was not statistically significant (coefficient = -0.04, 95% confidence interval: -0.16 to 0.08, P = 0.49). Several sensitivity analyses confirmed the robustness of the findings. CONCLUSION: We may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression. Clinical practice guidelines will need to take these findings into consideration.

Interpretable inference on the mixed effect model with the Box-Cox transformation.

We derived results for inference on parameters of the marginal model of the mixed effect model with the Box-Cox transformation based on the asymptotic theory approach. We also provided a robust variance estimator of the maximum likelihood estimator of the parameters of this model in consideration of the model misspecifications. Using these results, we developed an inference procedure for the difference of the model median between treatment groups at the specified occasion in the context of mixed effects models for repeated measures analysis for randomized clinical trials, which provided interpretable estimates of the treatment effect. From simulation studies, it was shown that our proposed method controlled type I error of the statistical test for the model median difference in almost all the situations and had moderate or high performance for power compared with the existing methods. We illustrated our method with cluster of differentiation 4 (CD4) data in an AIDS clinical trial, where the interpretability of the analysis results based on our proposed method is demonstrated. Copyright © 2017 John Wiley & Sons, Ltd.

Waiting list may be a nocebo condition in psychotherapy trials: a contribution from network meta-analysis.

OBJECTIVE: Various control conditions have been employed in psychotherapy trials, but there is growing suspicion that they may lead to different effect size estimates. The present study aims to examine the differences among control conditions including waiting list (WL), no treatment (NT) and psychological placebo (PP). METHOD: We comprehensively searched for all randomized controlled trials (RCTs) comparing cognitive-behaviour therapies (CBT) against various control conditions in the acute phase treatment of depression, and applied network meta-analysis (NMA) to combine all direct and indirect comparisons among the treatment and control arms. RESULTS: We identified 49 RCTs (2730 participants) comparing WL, NT, PP and CBT. This network of evidence was consistent, and the effect size estimates for CBT were substantively different depending on the control condition. The odds ratio of response for NT over WL was statistically significant at 2.9 (95% CI: 1.3-5.7). However, the quality of evidence, including publication bias, was less than ideal and none of the preplanned sensitivity analyses limiting to high-quality studies could be conducted, while findings of significant differences did not persist in post hoc sensitivity analyses trying to adjust for publication bias. CONCLUSION: There may be important differences in control conditions currently used in psychotherapy trials.

Changes of vascular endothelial growth factor after vitrectomy for macular edema secondary to retinal vein occlusion.

PURPOSE: To examine whether vitrectomy combined with retinal photocoagulation reduces the vitreous level of vascular endothelial growth factor (VEGF) in patients with macular edema associated with retinal vein occlusion (RVO). METHODS: The authors measured VEGF levels in vitreous samples from four eyes of four patients with RVO during vitrectomy and fluid samples obtained during revitrectomy 3 to 9 months postoperatively for complications: an epiretinal membrane in two patients, macular holes in one patient, and vitreous hemorrhage in one patient. During vitrectomy, retinal photocoagulation was performed on the ischemic region of the retina in all cases (mean of 510 shots). RESULTS: In four eyes with RVO, there was a difference in the vitreous VEGF levels between the vitreous samples obtained during vitrectomy (mean of 2692 pg/mL, range of 15.6-9040 pg/mL) and the fluid samples obtained at the time of revitrectomy (mean of 947 pg/mL, range of 15.6-3430 pg/mL). CONCLUSIONS: The results suggest that the vitreous levels of VEGF may be reduced by vitrectomy combined with retinal photocoagulation for macular edema with RVO. It may be important to reduce the vitreous levels of VEGF by vitrectomy and retinal photocoagulation for ischemic retina in macular edema with RVO.

Correlation between reduction of syndecan-1 expression and clinico-pathological parameters in squamous cell carcinoma of tongue.

We examined expression of syndecan-1 in squamous cell carcinoma (SCC) of tongue using immunohistochemistry. Forty-three cases of SCC arising in lateral border of tongue were investigated. From the immunohistochemical staining pattern, the cases were divided into two groups based on expression of syndecan-1 at the supra-peripheral cells of the tumor nest: Group A, completely or mainly positive; Group B, sporadically positive or negative. Most poorly differentiated SCC cases were classified into Group B (81.8%). The number of Group B cases in T1-2 was different from that in T3-4. The number of cases where syndecan-1 expression was reduced was much greater in T3-4, and represented the majority of Group B (86.7%). More than 80% of Grade 4D cases were in Group B (83.3%) based on the Yamamoto-Kohama criteria. These results indicate that reduction of syndecan-1 correlates to histological grade, tumor size and mode of invasion in tongue SCC.

A study of osteoclast-related cytokines in mandibular invasion by squamous cell carcinoma.

The purpose of this study was to analyze the mechanism of bone invasion in carcinoma of the mandibular gingiva. We investigated 38 specimens of lower gingival carcinoma and histopathologically classified them into an invasion group (23 cases) and a non-invasion group (15 cases) on the basis of light microscopy evidence. These specimens were examined using immunohistochemical techniques involving antibodies of parathyroid hormone-related protein (PTHrP), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, -1beta, -6, -11, -18 and transforming growth factor (TGF)-beta. The invasion group showed a high level of expression of PTHrP, TNF-alpha, IL-6 and IL-11 positive cells (P<0.01 versus non-invasion group). The difference in the levels of expression of IL-1alpha, -1beta, -18 and TGF-beta positive cells was not significant between these two groups. Our results suggest that various cancer-derived cytokines, such as PTHrP, TNF-alpha, IL-6 and IL-11, play an important role in the mechanism of bone invasion associated with lower gingival squamous cell carcinoma.

The roles of Nramp1 and Tnfa genes in nitric oxide production and their effect on the growth of Salmonella typhimurium in macrophages from Nramp1 congenic and tumor necrosis factor-alpha-/- mice.

The macrophages from Nramp1 congenic mice and tumor necrosis factor (TNF)-alpha(-/-) mice were used to examine the functions of Nramp1 and Tnfa genes in nitric oxide (NO) production and Salmonella typhimurium infection. It was confirmed that the level of inducible NO synthase (iNOS)-mediated NO production in Nramp1(r) peritoneal macrophages was generally higher than that of Nramp1(s) macrophages after stimulation by interferon-gamma (IFN-gamma), lipopolysaccharide (LPS), and tumor necrosis factor-alpha (TNF-alpha) alone or in combination. Nramp1 mRNA expression in both Nramp1 congenic macrophages was constitutive notwithstanding cytokine stimulation. During infection with S. typhimurium strain 6203, Nramp1(r) macrophages produced a lower amount of NO because of an initial strong reaction and unsustained iNOS gene expression as compared with Nramp1(s) macrophages. An inhibitory effect of the Nramp1(r) gene on bacterial replication was also observed during the early stage of S. typhimurium infection, whereas the effect of TNF-alpha occurred later. NO production and iNOS expression in TNF-alpha(-/-) macrophages were not detected from the start of the bacterial infection or at 24 h after infection. We also observed that S. typhimurium strain 6203 grew more profoundly without TNF-alpha, especially in Nramp1(s) macrophages. These data, therefore, demonstrate that there is cooperation of the Nramp1 and Tnfa genes in NO production and a growth inhibitory effect in response to S. typhimurium infection.

Low-dose ACTH therapy for West syndrome: initial effects and long-term outcome.

BACKGROUND: Most Japanese pediatric neurologists attempt other treatments before using adrenocorticotropic hormone (ACTH) therapy for West syndrome (WS), and even then, they use only a low-dose synthetic ACTH to avoid serious adverse effects. In this multi-institutional study, the authors analyzed the initial effects, adverse effects, and long-term outcome in patients treated with low-dose synthetic ACTH in Japan. METHODS: The medical records of 138 patients with WS, who were treated with low-dose synthetic ACTH therapy for the first time at the authors' institutions between 1989 and 1998, were analyzed. RESULTS: At the end of ACTH therapy, excellent effect on seizures was noted in 106 of 138 (76%) patients, good effect in 23 (17%), and poor effect in 9 (7%). Initial effects on EEG were excellent in 53 of 138 (38%) patients, good in 76 (55%), and poor in 9 (7%). As for seizure prognosis at the time of follow-up, 51 of 99 (52%) patients were seizure-free, whereas 48 (48%) patients had seizures. Mental outcome was normal in 6 of 98 (6%) patients, mild mental retardation in 16 (16%), moderate mental retardation in 26 (27%), and severe mental retardation in 50 (51%). The initial effects of ACTH on seizures and long-term outcome were not dose dependent (daily dosage 0.005 to 0.032 mg/kg, 0.2 to 1.28 IU/kg; total dosage 0.1 to 0.87 mg/kg, 4 to 34.8 IU/kg). The severity of adverse effects correlated with total dosage of ACTH, and the severity of brain volume loss due to ACTH correlated well with the daily dosage and total dosage of ACTH. CONCLUSION: Low-dose synthetic ACTH therapy is as effective for the treatment of WS as the higher doses used in previous studies. The dosage of synthetic ACTH used in the treatment of WS can be decreased as much as possible to avoid serious adverse effects.

High-resolution and analytical electron microscopic studies of new crystals induced by a bioactive ceramic (diopside).

Diopside has been developed for use in dental root implants and for the filling of bone defects. In previous studies, diopside developed hydroxyapatite (HA) on its surface and achieved a direct bond with bone. The purpose of this study was to investigate the mechanism of crystal formation on the diopside surface. We ultrastructurally evaluated the interface between new diopside-induced crystals and diopside. Specimens were prepared in three experiments: (1) Granular diopside was immersed in simulated body fluid (SBF); (2) granular diopside was implanted into a cavity in rabbit bone; and (3) a diopside dental root implant was implanted into a Japanese monkey. The specimens were examined by contact microradiography, high-resolution transmission electron microscopy, and analytical electron microscopy. In the experiment with SBF, many platelet-like crystals formed in the diopside surface layer. The lattice of diopside and that of the new crystals were very close, but no clear continuation of the lattice was observed. In the experiments which used a rabbit and a monkey, contact microradiography showed close contact between bone and diopside. High-resolution transmission electron microscopy revealed crystal growth from the diopside surface layer, and continuity between the diopside lattice and that of the new crystals. The morphological characteristics of the new crystals and the results of these analyses suggest that these new crystals are HA. With regard to the mechanism by which crystals are formed on the diopside surface layer, it is possible that epitaxial crystal growth could originate as a nucleus on the surface. In this case, epitaxial crystal growth of primarily octacalcium phosphate (OCP) may have occurred, and this may have changed to HA by a phase transition. However, epitaxial growth of OCP on the diopside surface is still highly speculative, since there is no direct supporting evidence.

Expression of an inhibitor of apoptosis, survivin, in oral carcinogenesis.

A novel inhibitor of apoptosis, survivin, plays a role in oncogenesis. To determine the potential involvement of survivin in oral carcinogenesis, we investigated the distribution of survivin protein expression in oral squamous cell carcinomas (OSCCs) and oral pre-malignant lesions. The mRNA expression level and methylation status of the gene also were evaluated in OSCCs and OSCC-derived cell lines. In immunohistochemistry, 58% of tumors and 37% of pre-malignant lesions examined were positive for survivin, while no immunoreaction was observed in corresponding normal tissues. The reverse-transcription/polymerase chain-reaction revealed similar changes in survivin gene expression levels. Furthermore, of the 9 normal oral tissues with no survivin gene expression, 4 showed methylation of the gene, while no methylation was detected in the corresponding tumorous tissues. The results suggest that survivin plays an important role during oral carcinogenesis, and that the gene expression may be regulated by an epigenetic mechanism.

Frequent allelic loss/imbalance on the long arm of chromosome 21 in oral cancer: evidence for three discrete tumor suppressor gene loci.

Frequent allelic imbalances including loss of heterozygosity (LOH) and microsatellite instability (MI) on the long arm of chromosome 21 (21q) have been found in several types of human cancer. This study was designed to identify tumor suppressor locus (or loci) associated with oral squamous cell carcinoma (SCC) on 21q. Among 38 patients with oral SCC tested, 15 (44%) of 34 informative cases showed LOH at one or more loci. Deletion mapping of these 15 tumors revealed three discrete commonly deleted regions on the chromosome arm. A minimal region with frequent LOH was found at the marker D21S236 mapped on 21q11.1. Another region of frequent deletion was identified between markers D21S11 and D21S1436 on 21q21, and a further commonly deleted region was found at D21S1254 on 21q22.1. In addition, we have detected MI on the chromosome arm in our oral SCC samples with significant correlation with tumor stage. Thus, our results strongly suggest that allelic imbalances on 21q may be involved in the development of oral SCC; and that at least three different putative tumor suppressor genes contributing to the pathogenesis of this disease are present on 21q.

Risk evaluation of outcome of vitreous surgery for proliferative diabetic retinopathy based on vitreous level of vascular endothelial growth factor and angiotensin II.

AIMS: To ascertain whether measurement of the vitreous fluid levels of vascular endothelial growth factor (VEGF) or angiotensin II (Ang II) could predict the outcome of vitreous surgery in patients with proliferative diabetic retinopathy (PDR). METHODS: A prospective observational case study was performed in 61 consecutive patients (61 eyes) with PDR who underwent vitreoretinal surgery. Vitreous fluid samples were obtained during surgery. The VEGF level in vitreous fluid and plasma was determined by enzyme linked immunosorbent assay, while the Ang II level was measured by radioimmunoassay. Patients were prospectively followed for 6 months and the postoperative outcome was analysed by logistic regression analysis. RESULTS: No improvement and/or progression of PDR was seen in 15 (25%) of the 61 eyes. Vitreous levels of VEGF and Ang II were significantly higher in eyes with progression of PDR than in eyes with regression of PDR (p = 0.0044, and p = 0.0178, respectively). Multivariate logistic regression analysis showed that the vitreous VEGF level increased along with the progression of PDR after vitreous surgery (odds ratio 2.48, p = 0.0008). CONCLUSION: A high vitreous fluid VEGF level is associated with a significant risk of postoperative progression of PDR. The vitreous level of VEGF at the time of surgery may be a useful predictor of the outcome.

Effect of subconjunctival steroid injection on intraocular inflammation and blood glucose level after cataract surgery in diabetic patients.

PURPOSE: To prospectively evaluate the usefulness of a subconjunctival steroid injection given at the completion of cataract surgery in patients with diabetes mellitus. SETTING: University of Tokyo School of Medicine, Tokyo, Kaiya Eye Clinic, Hamamatsu, and Jyosai Hospital, Tokyo, Japan. METHODS: One hundred four eyes of 104 diabetic patients having routine small incision cataract surgery were randomized into 2 groups. One group received a subconjunctival injection of dexamethasone and the other group did not. Aqueous flare intensity was measured with the laser flare meter preoperatively and 1, 2, 5, 7, and 14 days postoperatively. Another 19 diabetic patients having routine cataract surgery were randomized to receive a subconjunctival steroid injection or not; blood glucose concentration was measured 4 times a day for 3 days postoperatively. RESULTS: There was no significant difference between the 2 groups in aqueous flare values at any postoperative time. The subconjunctival steroid injection induced a transient but significant increase in blood glucose on the day of surgery. CONCLUSION: A subconjunctival steroid injection given at the completion of cataract surgery in diabetic patients had no beneficial effects.

Aldehyde dehydrogenase 2 and glutathione S-transferase M 1 polymorphisms in relation to the risk for oral cancer in Japanese drinkers.

We investigated 191 patients with oral cancer (121 males and 70 females) and 121 non oral cancer patients (69 males and 52 females), both groups with a history of alcohol use. Blood was analyzed with aldehyde dehydrogenase 2 (ALDH 2) and glutathione S-transferase M 1 (GSTM 1) genotyping. ALDH 2 genotyping was performed by polymerase chain reaction (PCR)-Restriction fragment length polymorphism (RFLP) method and GSTM 1 genotyping was amplified with PCR using GSTM 1 specific primers. In the oral cancer group, the alcohol-drinking rate (59.7%) was significantly higher than in the non cancer group (alcohol-drinking rate 27.3%, p < 0.01). The incidence of inactive ALDH 2 and GSTM 1 in the cancer group with an alcohol-drinking habit was 34.2 and 67.5% and was higher than in the non cancer group with an alcohol-drinking habit (15.1, 45.5%).

Quantification of telomerase activity of regions unstained with iodine solution that surround oral squamous cell carcinoma.

The aim of this study was to analyze the iodine-unstained region expanding around oral squamous cell carcinoma (SCC) by quantification of telomerase activity. The epithelial dysplasia often observed around SCC is considered to cause local recurrence or a second primary cancer. However these areas are hard to distinguish from normal mucosa. To clear the border of the expanding epithelial dysplasia around SCC, we stained with 3% iodine solution, and then decided the surgical margin. We measured quantification of telomerase activity in tumor, in epithelial dysplasia, and also in normal epithelium. Thirty-three primary cases of oral SCC which have iodine-unstained region around lesions were investigated. Fluorescense-based TRAP was applied to obtain quantification of telomerase activity. We obtained the following results: histological examination confirmed that every patient's unstained region consisted of various degrees of epithelial dysplasia. The quantified telomerase activities for squamous cell carcinoma, epithelial dysplasia and normal epithelium were 53.9, 39.6 and 2.7 U/microgP, respectively, and there was a significant difference between carcinoma and normal areas, and between dysplasia and normal epithelium. Therefore, these findings suggest that the areas of epithelial dysplasia unstained by iodine consist of cells that are nearly cancerous and excessively proliferative, and that epithelial dysplasia around SCC should be resected together with the tumor. Vital staining with iodine is useful for identifying epithelial dysplasia around SCC.

Oncocytic carcinoma arising in submandibular gland with immunohistochemical observations and review of the literature.

We report a case of oncocytic carcinoma arising in submandibular gland. The tumour occurred in the left submandibular gland of an 82-year-old Japanese man. Histologically, the tumour was mostly composed of large cells with eosinophilic granules in the cytoplasm and they were arranged in the solid sheets, islands with duct-like structure and cords. The tumour cells had aggressively invaded muscles and perineural tissues, and cervical lymphatic metastasis was frequently observed. Histochemically, the tumour cells were strongly positive for phosphotungstic acid-hematoxylin (PTAH) stain, and we diagnosed this malignant tumour as oncocytic carcinoma. Immunohistochemically, the tumour cells reacted positively for cytokeratin 7, 8, 19, epithelial membrane antigen (EMA), alpha-1-antichymotrypsin and carcinoembryonic antigen (CEA), but negative for cytokeratin 13, 14, smooth muscle actin (HHF35) and S-100 protein (S-100). Tumour was diagnosed as oncocytic carcinoma in submandibular gland. Its characteristics are discussed in term of its histopathological and immunohistochemical features.