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.

History of diabetes and risk of suicide and accidental death in Japan: The Japan Public Health Centre-based Prospective Study, 1990-2012.

AIM: This study looked at whether a history of diabetes mellitus (DM) is associated with a higher risk of externally caused death (by suicide and accident), using data for a large population-based prospective cohort from an Asian population. METHODS: Data collected between 1990 and 2012 from the Japan Public Health Centre-based Prospective Study were analyzed, and Poisson regression models were used to calculate adjusted risk ratios (RR) for external causes of death. RESULTS: The population-based cohort comprised 105,408 Japanese residents (49,484 men and 55,924 women; mean age: 51.2 [SD 7.9] years). At baseline, 3250 (6.6%) men and 1648 (3.0%) women had a history of DM. During the follow-up period, 113 external deaths (41 suicides and 72 accidents) were noted among those with a history of DM, with 1304 external deaths (577 suicides and 727 accidents) among those without such a history. A higher risk of external death (men, RR: 1.4, 95% CI: 1.2-1.8; women, RR: 1.6, 95% CI: 1.01-2.4) was observed in those with a history of DM. Also, among those aged 40-49 years (RR: 1.9, 95% CI: 1.3-2.7) and 50-59 years (RR: 1.4, 95% CI: 1.05-1.9) at baseline, the risk of external death was significantly higher in those with a history of DM. CONCLUSION: Compared with people with no history of DM, those with such a history had a significantly greater risk of externally caused death (particularly accidental deaths) in both genders and in those aged≤59 years at baseline.

Bovine κ-casein inhibits human rotavirus (HRV) infection via direct binding of glycans to HRV.

Human rotavirus (HRV) is a major etiologic agent of severe infantile gastroenteritis. κ-Casein (κ-CN) from both human and bovine mature milk has been reported to have anti-HRV activity; however, the mechanism of this activity is poorly understood. The present study examined the molecular basis for the protective effect of bovine κ-CN derived from late colostrum (6-7 d after parturition) and from mature milk. Among the components of casein, κ-CN is the only glycosylated protein that has been identified. Therefore, we investigated whether the glycan residues in κ-CN were involved in the anti-HRV activity. Desialylated CN obtained by neuraminidase treatment exhibited anti-HRV activity, whereas deglycosylated CN obtained by o-glycosidase treatment lacked antiviral activity, indicating that glycans were responsible for the antiviral activity of CN. Furthermore, an evanescent-field fluorescence-assisted assay showed that HRV particles directly bound to heated casein (at 95°C for 30 min) in a viral titer-dependent manner. Although the heated κ-CN retained inhibitory activity in a neutralization assay, the activity was weaker than that observed before heat treatment. Our findings indicate that the inhibitory mechanism of bovine κ-CN against HRV involves direct binding to viral particles via glycan residues. In addition, heat-labile structures in κ-CN may play an important role in maintenance of κ-CN binding to HRV.

The p90 ribosomal S6 kinase (RSK) inhibitor BI-D1870 prevents gamma irradiation-induced apoptosis and mediates senescence via RSK- and p53-independent accumulation of p21WAF1/CIP1.

The p90 ribosomal S6 kinase (RSK) family is a group of highly conserved Ser/Thr kinases that promote cell proliferation, growth, motility and survival. As they are almost exclusively activated downstream of extracellular signal-regulated kinases 1 and 2 (ERK1/2), therapeutic intervention by RSK inhibition is less likely to produce such severe side effects as those observed following inhibition of the upstream master regulators Raf, MEK and ERK1/2. Here, we report that BI-D1870, a potent small molecule inhibitor of RSKs, induces apoptosis, although preferentially, in a p21-deficient background. On the other hand, BI-D1870 also induces a strong transcription- and p53-independent accumulation of p21 protein and protects cells from gamma irradiation (γIR)-induced apoptosis, driving them into senescence even in the absence of γIR. Although we identified p21 in in vitro kinase assays as a novel RSK substrate that specifically becomes phosphorylated by RSK1-3 at Ser116 and Ser146, RNA-interference, overexpression and co-immunoprecipitation studies as well as the use of SL0101, another specific RSK inhibitor, revealed that BI-D1870 mediates p21 accumulation via a yet unknown pathway that, besides its off-site targets polo-like kinase-1 and AuroraB, also does also not involve RSKs. Thus, this novel off-target effect of BI-D1870 should be taken into serious consideration in future studies investigating the role of RSKs in cellular signaling and tumorigenesis.

Serum levels of IL-6 and IL-1ß can predict the efficacy of gemcitabine in patients with advanced pancreatic cancer.

BACKGROUND: With this study, we sought to characterise the impact of pro-inflammatory cytokines on the outcomes of gemcitabine monotherapy (GEM) in patients with pancreatic cancer (PC). METHODS: Treatment-naive patients with advanced PC and no obvious infections were eligible for enrolment. All of the patients were scheduled to undergo systemic chemotherapy. Serum pro-inflammatory cytokines were measured using an electro-chemiluminescence assay method before chemotherapy. High cytokine levels were defined as values greater than the median. Clinical data were collected prospectively. RESULTS: Sixty patients who received GEM were included in the analysis. High IL-6 and IL-1ß levels were poor prognostic factors for overall survival in a multivariate analysis (P=0.011 and P=0.048, respectively). Patients with both a high IL-6 level and a high IL-1ß level exhibited shortened overall and progression-free survival, a reduction in the tumour control rate, and a high dose intensity of GEM compared with patients with low levels of both IL-6 and IL-1ß. CONCLUSION: The serum levels of IL-6 and IL-1ß predict the efficacy of GEM in patients with advanced PC.

Skimmed, sterilized, and concentrated bovine late colostrum promotes both prevention and recovery from intestinal tissue damage in mice.

Bovine colostrum is a rich source of tissue repair and growth factors, and inhibits gastrointestinal injury induced by the side effects of nonsteroidal antiinflammatory drugs (NSAID), such as indomethacin. Nonsteroidal antiinflammatory drugs are drugs with analgesic and antipyretic effects, but in higher doses they have inflammatory effects. The pathogenesis of small intestinal damage caused by NSAID is unclear. The present study was performed to investigate the antiinflammatory effects of skimmed, sterilized, and concentrated bovine late colostrum on intestinal injury induced by side effects of NSAID, and then to identify the active ingredient in the colostrum for intestinal tissue. In Japan, the sale of bovine colostrum within 5 d after parturition is prohibited by law. Therefore, we focused on bovine late colostrum obtained from healthy lactating cows 6 to 7 d after parturition. Proliferation of small intestine epithelial cells was stimulated in mice fed the colostrum for 1 wk. With regard to indomethacin-induced enteropathy, both prefeeding and postfeeding with colostrum facilitated growth of the intestinal villi, indicating preventive and healing effects. Furthermore, to identify the active ingredient in the colostrum responsible for this effect, the casein and whey fractions were prepared from the colostrum and fed to normal mice. Only the colostrum casein fraction stimulated intestinal villus elongation, whereas the whey fraction and mature milk casein showed no such effect. Taken together, these observations indicate that the skimmed, sterilized, and concentrated bovine late colostrum, especially the casein fraction, could be used to treat the injurious effects of NSAID in the intestine and could be effective for treatment of other ulcerative conditions in the bowel, suggesting that the colostrum has therapeutic potential for intestinal inflammation.

Age-adjusted relative suicide risk by marital and employment status over the past 25 years in Japan.

BACKGROUND: There have been no longitudinal studies in Japan examining national-level data for suicide risk by marital and employment status. We examined the age-adjusted relative suicide risk (RR) by marital and employment status from national data acquired for all suicides in Japan occurring in the past 25 years. METHODS: All deaths identified as suicides according to ICD-9 and ICD-10 were extracted from vital statistics data of Japan for the years 1980, 1985, 1990, 1995, 2000 and 2005. Population statistics for Japanese residents aged ≥15 years were obtained from the census. RESULTS: Suicide rates for almost all categories analyzed decreased in both genders between 1985 and 1990 and increased between 1995 and 2000, especially among men. Unemployed and divorced men had a consistently higher RR in each year analyzed. Unemployed and divorced women had a higher risk than those in other categories, especially in 2000 and 2005. In women, particularly in 1980, 1985 and 1990, those who were unemployed and never married had a similar RR to those who were unemployed and divorced. CONCLUSIONS: Unemployed and divorced people were at a high risk of suicide over the past 25 years, particularly in 2000 and 2005. Our findings suggest that the effects of divorce and unemployment on suicide risk are synergistic.

Multiple-dose therapy with bovine colostrum confers significant protection against diarrhea in a mouse model of human rotavirus-induced gastrointestinal disease.

Rotavirus is the most important etiologic agent of severe gastroenteritis. Previously, we reported that skimmed and concentrated bovine late colostrum (SCBLC) obtained from normal unimmunized cows at 6 to 7d after parturition effectively prevented against human rotavirus (HRV)-induced severe gastroenteritis in vivo, when administered as a single dose 60 min before viral inoculation. In the present study, we examined the efficacy of multiple administrations of SCBLC at smaller dosages after viral inoculation in vivo. We demonstrate that multiple administrations within 24h after virus inoculation resulted in earlier recovery from diarrheal symptoms, in an administration frequency-dependent manner. Furthermore, we investigated whether isolated IgG anti-HRV activity in SCBLC was equivalent to that of IgG isolated from bovine mature milk as measured by in vitro activity assays. We found that IgG-containing fractions from SCBLC and mature milk exhibited approximately the same level of anti-HRV activity. We concluded that the SCBLC contains a high level of IgG against HRV-induced severe gastroenteritis, which will be possible to use in protective effects in immunocompromised hosts, such as children and the elderly. Multiple doses of SCBLC during the early stages of infection or lower dosage of SCBLC given as a single dose both resulted in relief of diarrheal symptoms.

Effect of a prostaglandin EP4 receptor agonist on early fixation of hydroxyapatite/titanium composite- and titanium-coated rough-surfaced implants in ovariectomized rats.

The agonist of the prostaglandin EP4 receptor can increase bone density in osteoporosis. Using ovariectomized (OVX) and sham-operated (SO) rats, the effects of the EP4 receptor agonist, ONO-4819, and hydroxyapatite (HA) on implant-bone fixation in implants with a rough surface were investigated. Female Wistar rats (12 weeks old) were divided into either SO or bilateral OVX groups. Twenty four weeks later, either hydroxyapatite/titanium (HA/Ti) composite-coated or Ti-coated implants were implanted into the femora, and the animals were treated with either ONO-4819 or saline for 4 weeks. The fixation strength of the HA/Ti-coated implants was higher than that of the Ti-coated implants in the saline-treated OVX rats. In the OVX rats, ONO-4819 enhanced fixation of the rough Ti-coated implants to levels similar to that of HA/Ti-coated implants. These data suggest that a combination of treatment with an EP4 receptor agonist and a rough-surfaced implant might be useful in increasing the early fixation of cement-less arthroplasty, particularly in elderly patients with osteoporosis.

Bronchovascular cuff formation and lung lymph flow in edema formation of anesthetized sheep.

The relationship between bronchovascular cuff formation and lung lymph flow in hydrostatic edema was evaluated. After a balloon was inserted into the left atrium to increase left atrial pressure for 5 hrs, peripheral lung tissues were resected for analysis of the wet-dry ratio and cuff formation. The degree of cuff formation was expressed as the cuff ratio (outer diameter of cuff/outer diameter of microvessel or airway) in three size categories: 80-200, 200-400, and 400-750 microm in diameter. The amount of excess lung lymph (Ex LL) for 5 hrs was calculated from the recorded data for the whole lymph flow wave. The wet-dry ratio showed a significant correlation with ALAP and lung lymph flow increased significantly (flow rate, 0.67 +/- 0.46 ml/min (mean +/- SD); Ex LL, 56.4 +/- 47.6 ml). Cuff formation was found at all levels of the bronchovascular tree, with a larger cuff ratio (> 1.3) observed at arteries and veins of 80-200 microm in diameter, but a significant correlation with Ex LL was found only for arteries of 80-200 microm. Fluid accumulation in lung interstitium first occurred at smaller extra-alveolar arteries even under mild hydrostatic pressure elevation with a significant increase in lymph flow.

Ezetimibe improves postprandial hyperlipidaemia in patients with type IIb hyperlipidaemia.

BACKGROUND: Postprandial hyperlipidaemia is known to be a high-risk factor for atherosclerotic disease because of rapid and lasting accumulations of triglyceride-rich lipoproteins and remnants. The Niemann-Pick C1-Like 1 (NPC1L1) protein acts as an intestinal cholesterol transporter and ezetimibe, which inhibits NPC1L1, has been used in patients with hypercholesterolaemia. We investigated effects of ezetimibe on fasting lipid and lipoprotein profiles and postprandial hyperlipidaemia in patients with type IIb hyperlipidaemia. MATERIALS AND METHODS: Ezetimibe 10 mg per day was administered in ten patients with type IIb hyperlipidaemia for 2 months, and lipid and lipoprotein profiles were examined during fasting and after an oral fat loading (OFL) test. RESULTS: In the fasting state, ezetimibe significantly decreased not only total cholesterol, low density lipoprotein (LDL)-cholesterol and apolipoproteinB-100 (apoB-100) levels but triglycerides (TG), apoB-48 and remnant lipoprotein cholesterol (RemL-C) levels. High performance liquid chromatography analysis showed that ezetimibe decreased cholesterol and TG levels in the very low density lipoprotein (VLDL) and LDL size ranges as well as apoB-100 levels, suggesting a decrease in numbers of VLDL and LDL particles. After OFL, ezetimibe decreased the area under the curve for TG, apoB-48 and RemL-C. Ezetimibe decreased postprandial elevations of cholesterol and TG levels in the chylomicrons (CM) size range, suggesting that the postprandial production of CM particles was suppressed by ezetimibe. CONCLUSIONS: These findings suggest that ezetimibe improves fasting lipoprotein profiles and postprandial hyperlipidaemia by suppressing intestinal CM production in patients with type IIb hyperlipidaemia and such treatment may prove to be effective in reducing atherosclerosis.

[Lipofibroadenoma of the thymus].

Here we report a case of a rare thymic tumors histologically diagnosed as lipofibroadenoma. The patient was a 32-year-old male who displayed an anterior mediastinal tumor on a chest computed tomography (CT) scan while being treated for pneumonia. The tumor was localized within the thymus, and the diameter was 3 cm. No significant change was observed in the tumor on a CT scan taken 6 months after the 1st scan. Suspecting a thymoma from the CT and magnetic resonance imaging (MRI) findings, we performed a thymothymectomy via a median sternotomy. The histopathological diagnosis was a lipofibroadenoma of the thymus. The findings resembled fibroadenoma of the breast. Lymphocytes were scarce within the tumor with abundant interstitial stroma, and the tumor epithelial cells displayed restiform and dendritic structures. The epithelial cells were mostly negative for Ki-67 immunohistochemical staining. A very small amount of calcification was detected within the tumor using alizarin red staining. Based on the histopathological findings, it was considered to be a benign tumor with little growth potential, and which had been present for a long period of time.

[Bloody sputum caused by hemorrhage around staple-lines 5 years after surgery; report of a case].

23 year-old non-smoking male who had underwent bilateral video-assisted thoracoscopic surgery (VATS) bullectomy for spontaneous pneumothorax using surgical stapler (Endo GIA, Tyco Healthcare) 5 years before, referred to our hospital due to hemoptysis. Chest computed tomography (CT) revealed infiltrative shadow surrounding stapled-line at right pulmonary apex. Aspiration-shadows were scattered in right lung parenchyma. Bronchoscopy revealed bloody clot extended from right B1 to main bronchi. These findings suggested that the cause of bloody sputum was bleeding from the tissue around staples used in VATS bullectomy. On admission he treated with hemostatic agents, and bloody sputum and abnormal CT shadows disappeared. Metallic surgical staplers may cause airway bleeding after surgery in its chronic stage, although complications due to them are rare.

Phase transformation of plasma-sprayed hydroxyapatite coating with preferred crystalline orientation.

Highly oriented hydroxyapatite coatings (HACs) were obtained on titanium substrates through a radio-frequency thermal plasma spraying (TPS) method. XRD patterns showed that the HACs had crystallites with [001] preferred orientation vertical to the coating's surface. XRD results also indicated that tetracalcium phosphate crystallites in the as-sprayed HAC were oriented in the (100) direction. XRD peaks corresponding to tetracalcium phosphate, tricalcium phosphate and calcium oxide were absent after heat and hydrothermal treatment. The orientation degree of the HAC was influenced little by such post-heat treatments. Considering the crystallographic relationship between the tetracalcium phosphate in the as-sprayed HAC and the HA crystallites formed in the heat-treated HAC, these XRD results indicate that the tetracalcium phosphate in the as-prepared coatings transformed topotaxially into HA during the post-heat treatment. TEM and SEM analyses of the highly oriented HAC were conducted. The characteristic lamellar structure of TPS deposits was observed in cross-sections of the HAC. A prismatic texture was also observed in magnified SEM images. TEM observation showed that 200-800-nm-wide prismatic crystallites were formed in HA splats, and their longitudinal axis was oriented vertically to the coating's surface. SAD patterns showed that the longitudinal axis of the prismatic crystallites corresponded to the [001] zone axis of the HA crystal.

New method for evaluation of lung lymph flow rate with intact lymphatics in anaesthetized sheep.

AIM: Lung lymph has commonly been studied using a lymph fistula created by tube cannulation into the efferent duct of the caudal mediastinal node in sheep. In this method, the tail region of the caudal mediastinal node is resected and the diaphragm is cauterized to exclude systemic lymph contamination, and cannulation is performed into one of the multiple efferent ducts originating from the caudal mediastinal node. Moreover, the pumping activity of lymphatics might be diminished by cannulation. Therefore, the purpose of the study was to evaluate the flow rate of lung lymph with maintenance of intact lymphatic networks around the caudal mediastinal node to the thoracic duct in sheep. METHODS: An ultrasound transit-time flow meter was used to measure lung lymph flow. The thoracic duct was clamped just above the diaphragm and the flow probe was attached to the thoracic duct just after the last junction with an efferent duct from the caudal mediastinal node. The lung lymph flow rate was measured at baseline and under conditions of lung-oedema formation. RESULTS: The baseline lung lymph flow rate in our model was three- to sixfold greater than values obtained with the cannulation method. With oedema-formation, the lung lymph flow rate was the same as that measured using cannulation. CONCLUSION: The lung lymph flow was unexpectedly large under the conditions of the study, and our data suggest that the drainage effect of lymphatics is significant as a safety factor against pulmonary oedema formation.

Cyclic performance of carbon-coated TiO2 for photocatalytic activity of methylene blue decomposition.

Carbon-coated TiO2 powders were prepared from the mixtures of anatase (ST-01) and carbon precursor poly(vinyl alcohol) in different ratios by carbonization at 900 degrees C in a flow of either Ar or N2. Carbon-coated TiQ2 thus prepared was either fixed on an adhesive tape or formed into a film by using the organic binder poly(tetrafluoroethylene) and used for photodecomposition of methylene blue in water repeatedly. On the samples fixed on adhesive tapes, the rate constant was reproduced with about 10-20% scattering during repeated uses in a fresh methylene blue solution up to 7 times. On the samples formed into films by using the organic binder, the rate constant was reproduced after the 3rd or 4th cycle. The mutual relations in rate constant were almost the same among three different conditions for the determination, suspending the sample particles, fixed on an adhesive tape and formed into a film. The rate constant for the photodecomposition was found to give a maximum on the sample containing about 9 mass% carbon.

A case of alpha-fetoprotein-producing adenocarcinoma of the endometrium with a hepatoid component as a potential source for alpha-fetoprotein in a postmenopausal woman.

Although case reports of alpha-fetoprotein (AFP)-producing adenocarcinoma other than hepatocellular carcinoma have gradually increased in number, AFP-producing adenocarcinoma of the endometrium is very rare. The patients universally complain of abnormal vaginal bleeding. The patient presented with complaints of epigastric discomfort. No vaginal bleeding was observed. Serum AFP concentration was 453 ng/mL, and lens culinaris agglutinin-reactive AFP percentage of total AFP was increased to 67%. Radiologic imaging and endoscopy did not provide evidence of any primary carcinoma in the liver and gastrointestinal tract. To investigate the unknown origin of high AFP, Pap smear of the endometrium followed by fractional curettage was performed and revealed adenocarcinoma of the endometrium. Radical hysterectomy with pelvic lymph node dissection and partial omentectomy was performed. Histologic study showed a mixture of major AFP-negative endometrioid adenocarcinoma and minor medullary proliferation of the AFP-positive hepatoid adenocarcinoma cells with eosinophilic cytoplasm and hyaline globules. After the surgery followed by four courses of weekly carboplatin and paclitaxel administration, serum levels of AFP dropped into normal range. The possible existence of AFP-producing adenocarcinoma of the endometrium should be considered in a postmenopausal woman even if there is no vaginal bleeding, when AFP-producing tumor is clinically suspected and the imaging studies fail to confirm the diagnosis.