A device for assessing microbial activity under ambient hydrostatic pressure: The in situ microbial incubator (ISMI).

Microbes in the dark ocean are exposed to hydrostatic pressure increasing with depth. Activity rate measurements and biomass production of dark ocean microbes are, however, almost exclusively performed under atmospheric pressure conditions due to technical constraints of sampling equipment maintaining in situ pressure conditions. To evaluate the microbial activity under in situ hydrostatic pressure, we designed and thoroughly tested an in situ microbial incubator (ISMI). The ISMI allows autonomously collecting and incubating seawater at depth, injection of substrate and fixation of the samples after a preprogramed incubation time. The performance of the ISMI was tested in a high-pressure tank and in several field campaigns under ambient hydrostatic pressure by measuring prokaryotic bulk 3H-leucine incorporation rates. Overall, prokaryotic leucine incorporation rates were lower at in situ pressure conditions than under to depressurized conditions reaching only about 50% of the heterotrophic microbial activity measured under depressurized conditions in bathypelagic waters in the North Atlantic Ocean off the northwestern Iberian Peninsula. Our results show that the ISMI is a valuable tool to reliably determine the metabolic activity of deep-sea microbes at in situ hydrostatic pressure conditions. Hence, we advocate that deep-sea biogeochemical and microbial rate measurements should be performed under in situ pressure conditions to obtain a more realistic view on deep-sea biotic processes.

Usefulness of 18F-FPP-RGD2 PET in pathophysiological evaluation of lung fibrosis using a bleomycin-induced rat model.

PURPOSE: Integrins αv are key molecules in the pathogenesis of fibrosis in multiple organs. To assess the potential utility of integrin αvß3 imaging for idiopathic pulmonary fibrosis (IPF), we evaluated an 18F-FPP-RGD2 PET probe in a rat model of bleomycin-induced lung fibrosis. METHODS: Pulmonary fibrosis was induced by single intratracheal instillation of bleomycin (3 mg/rat). Positron emission tomography (PET)/computerized tomography scans were performed 4 weeks after bleomycin administration using 18F-FPP-RGD2. Total distribution volume (VT) was estimated using one-tissue/two-compartment, two-tissue/three-compartment models, and Logan graphical analysis (Logan plot; t* = 30 min). Plasma-free fractions were estimated from images of the left ventricle. Correlation between Logan VT and lung pathology was assessed by Spearman's rank correlation. RESULTS: Histopathological evaluation demonstrated the development of fibrosis in IPF-model group. Integrin αv protein expression and lung radioactivity were higher in IPF-model group compared with control group. The lung radioactivity of 18F-FPP-RGD2 rapidly reached the peak after administration and then gradually decreased, whereas left ventricular radioactivity rapidly disappeared. Logan graphical analysis was found to be suitable for 18F-FPP-RGD2 kinetic analysis in the IPF-model lung. Logan VT values for 18F-FPP-RGD2 were significantly higher in IPF rats compared with control rats and strongly correlated with lung fibrosis, pathology, integrin αv protein expression, and oxygen partial pressure. CONCLUSION: Our findings demonstrate that the integrin αvß3 PET probe 18F-FPP-RGD2 can detect pathophysiological changes in lungs, including fibrosis accompanying upregulated integrin αv of IPF-model rats. These findings support the utility of 18F-FPP-RGD2 PET imaging for the pathophysiological evaluation of pulmonary fibrosis.

Role of Prostaglandin D2 and DP1 Receptor on Japanese Cedar Pollen-Induced Allergic Rhinitis in Mice.

Although we previously demonstrated the contribution of the DP1receptor in nasal obstruction using animals sensitized with ovalbumin in the presence of adjuvant, the contribution of the DP1receptor in sneezing is unclear. Here, we developed a mouse model of Japanese cedar (JC:Cryptomeria japonica) pollinosis to evaluate the symptoms of sneezing. To achieve this, we used JC pollen crude extract in the absence of adjuvant to sensitize mice to develop a model closer to the pathophysiology of human JC pollinosis. The immunologic and pharmacologic features of this model are highly similar to those observed in JC pollinosis in humans. Using this model, we found that DP1receptor antagonists suppressed JC pollen extract-induced sneezing and that a DP1receptor agonist induced sneezing. Moreover, JC pollen extract-induced sneezing was diminished in DP1receptor knockout mice. In conclusion, we developed a novel mouse model of allergic rhinitis that closely mimics human JC pollinosis. A strong contribution of DP1receptor signaling to sneezing was demonstrated using this model, suggesting that DP1receptor antagonists could suppress sneezing and nasal obstruction, and therefore these agents could be a new therapeutic option for allergic rhinitis.

Spontaneous complete regression of pancreaticoduodenal artery aneurysms with celiac artery occlusion after aorto-splenic bypass without additional treatment: a case report.

BACKGROUND: Pancreaticoduodenal artery aneurysm (PDAA) is a rare, but fatal disease. However, the association between aneurysm size and the risk of rupture remains unclear. There are many options for therapeutic strategies that should be discussed well because the treatment options are often complicated and highly invasive. However, it remains unclear whether additional endovascular therapy is essential for all patients undergoing bypass surgery. Here, we present a case of triple PDAAs with celiac axis occlusion and spontaneous complete regression of inferior PDAAs (IPDAA) after aneurysmectomy of superior PDAA (SPDAA) and aorto-splenic bypass. CASE PRESENTATION: A 68-year-old woman presented with one SPDAA and two IPDAAs caused by celiac axis occlusion. Aneurysmectomy for IPDAAs was difficult because of their anatomical location and shape. Therefore, we planned a two-stage hybrid therapy. The patient underwent aorto-splenic bypass and resection of the SPDAA. Follow-up CT was performed to evaluate the IPDAAs before planned endovascular embolization. Spontaneous regression of the IPDAAs and normalized PDA arcade decreased the blood flow in the PDA arcade. The patient is doing well without graft occlusion, and the IPDAAs have completely regressed 7 years after surgery. CONCLUSION: Normalization of hyperinflow to the PDA arcade can lead to the regression of PDAA. Potentially, additional endovascular therapy may not be required in all cases when dilation of the PDA improves. However, more cases must be accumulated to establish criteria for predicting the risks of short- and long-term PDAA ruptures.

Distal Bypass Improves Skin Perfusion Pressure at the Whole Foot Regardless of Angiosomes in Patients with Chronic Limb-Threatening Ischemia.

Objectives: Distal bypass surgery's effect on tissue blood pressure beyond a focal angiosome remains debated. This study assessed tissue blood pressure in both direct revascularized angiosome (DRA) and indirect revascularized angiosome (IRA) after bypass surgery, utilizing repeated skin perfusion pressure (SPP) measurements. Methods: Twenty-nine limbs in 27 chronic limb-threatening ischemia (CLTI) patients (22 males and five females, age: 70.2 ± 9.3 years) who received distal bypass surgery were enrolled. SPP measurements were conducted for the DRA and IRA at 10 time intervals, encompassing both preoperative and postoperative periods of every 3-5 days until 30 days. Results: In total, 486 SPP measurements were collected from 58 measurement sites, and the transition of the SPP at the DRA was 35.4-62.5-59.5-70.2-58.2-62.2-63.1-63.6-63.8-73.4 mmHg and IRA was 29.4-53.4-53.7-58.8-51.3-63.1-47.9-62.1-57.6-61.0 mmHg. No significant differences were observed between SPP at the DRA and IRA. Fifteen wounds on the DRA (63%) and five on the IRA (100%) healed. Conclusion: Distal bypass improves SPP in both direct and IRAs of CLTI patients. These data indicated distal bypass improves tissue blood flow at entire foot regardless of angiosomes.

Duration of last depressive episode may influence serum BDNF levels in remitted patients with major depression.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) may have an important role in the pathophysiology of depression. Previous studies indicate that serum BDNF levels were lower in patients with depression and increased after treatment with antidepressants. However, results of studies on serum BDNF levels in remitted patients with depression have been inconsistent. The purpose of the present study was to determine which factors influence the alteration of serum BDNF levels in depression in the remitted state. METHODS: Serum BDNF levels were evaluated in 75 remitted inpatients with major depressive disorder (MDD) and 108 controls. Multiple regression analyses were conducted using serum BDNF levels as the dependent variable; and the number of episodes, Hamilton Rating Scale for Depression score at admission, or duration of last depressive episode as independent variables. RESULTS: Serum BDNF levels were lower in remitted patients with MDD than in controls (P < .001). Multiple regression analysis showed a significant effect between the duration of the last depressive episode and serum BDNF levels (P < .022). CONCLUSIONS: Serum BDNF levels in remitted patients with MDD did not recover to the level of healthy controls, and lower serum BDNF levels were influenced by a longer duration of last depressive episode. It is possible that persistent hippocampal reduction in remitted depression may be caused by lower BDNF levels associated with a longer duration of the last depressive episode.

Effectiveness of Glecaprevir/Pibrentasvir for Hepatitis C: Real-World Experience and Clinical Features of Retreatment Cases.

Glecaprevir/pibrentasvir (G/P) are direct-acting antivirals (DAAs) that achieve a high sustained virological response (SVR) rate for hepatitis C virus (HCV) infection. We investigated G/P effectiveness for HCV patients based on real-world experience and the clinical features of retreatment cases. HCV patients (n = 182) were compared for clinical features and outcomes between first treatment (n = 159) and retreatment (n = 23) G/P groups. Overall, 77 patients (42.3%) were male, the median age was 68 years, and 86/66/1/4 cases had genotype 1/2/1+2/3, respectively. An SVR was achieved in 97.8% (178/182) of cases by intention-to-treat analysis and 99.4% (178/179) of cases by per-protocol analysis. There were no remarkable differences between the first treatment and retreatment groups for male (42.8% vs. 39.1%, p = 0.70), median age (68 vs. 68 years, p = 0.36), prior hepatocellular carcinoma (5.8% vs. 8.7%, p = 0.59), or the fibrosis markers AST-to-platelet ratio index (APRI) (0.5 vs. 0.5, p = 0.80) and fibrosis-4 (FIB-4) index (2.2 vs. 2.6, p = 0.59). The retreatment group had a significantly more frequent history of interferon treatment (12.3% vs. 52.2%, p < 0.01) and the Y93H mutation (25.0% vs. 64.7%, p = 0.02). The number of retreatment patients who had experienced 3, 2, and 1 DAA treatment failures was 1, 3, and 19, respectively, all of whom ultimately achieved an SVR by G/P treatment. In conclusion, G/P was effective and safe for both HCV first treatment and retreatment cases despite the retreatment group having specific resistance mutations for other prior DAAs. As G/P treatment failure has been reported for P32 deletions, clinicians should consider resistance mutations during DAA selection.

Evaluation of a poly(L-lactic acid) stent for sutureless vascular anastomosis.

We have developed a sutureless anastomosis device consisting of a biodegradable stent and stainless steel band for end-to-end anastomosis. The aim of this acute phase study was to evaluate the feasibility of a sutureless anastomotic procedure with a bioabsorbable stent during a 4-week period in a swine model. The porcine infrarenal aorta was replaced with an expanded polytetrafluoroethylene graft. A proximal anastomosis was completed using a sutureless anastomotic procedure employing a bioabsorbable stent made of poly(L-lactic acid) (PLLA) and a stainless steel plate. A distal anastomosis completed by manual suturing served as a control. At 4 weeks after surgery, angiography was performed. The animals were then killed, and the specimens were evaluated histologically. The sutureless anastomotic procedure required significantly less time than the suturing technique. Angiograms showed patency of the grafts, and no signs of either stenosis or leakage. Both pressure-proof and tensile tests confirmed the adequate mechanical strength of the anastomoses. Sutureless anastomosis with a PLLA stent appears to be feasible, at least within an observation period of 4 weeks. This simple procedure shortened the time of surgery and would contribute to reducing the risks of operation-related complications.

Serum amyloid beta protein in young and elderly depression: a pilot study.

BACKGROUND: Depression may increase the risk of developing Alzheimer's disease (AD). Recent large cohort studies have also shown that a low plasma amyloid beta (Abeta)-42 level combined with a high Abeta40 level increases the risk of developing AD, suggesting plasma Abeta42/40 ratio as useful for identifying risk of developing mild cognitive impairment and AD. Although several studies have examined Abeta levels in the peripheral blood of elderly individuals with depression, results have been inconsistent. Furthermore, no results have been described for younger depression. METHODS: Serum Abeta40, Abeta42 level and Abeta40/42 ratio were evaluated using enzyme-linked immunosorbent assay in 60 patients with major depressive disorder (MDD) and 60 healthy controls. The results were analyzed in two age groups (young, <60 years; elderly, >or=60 years). RESULTS: Serum Abeta40 level was significantly higher in young MDD patients compared to young controls (P < 0.001), but it was not significantly deferent in the elderly group. Serum Abeta42 level did not differ significantly in both young and elderly groups. Abeta40/42 ratio was significantly higher in both young (P < 0.001) and elderly (P < 0.001) patients with MDD compared to controls. CONCLUSIONS: Serum Abeta40/42 ratio was significantly higher in MDD patients than in controls, and this difference was seen for both elderly and young subjects. This may suggest that even young subjects with MDD undergo pathological changes in the very early stage of amyloid deposition.

[Noticeable clinical response to S-1/CDDP combination therapy for Virchow node recurrence after surgery for advanced gastric carcinoma with marked involvement of the esophagus - report of a case].

We have recently experienced a case in which S-1/CDDP combination therapy proved remarkably efficacious for a rapid, extensive lymph node recurrence with metastasis into a Virchow node that had developed after resection of advanced gastric carcinoma accompanied with a marked invasion of the esophagus. The patient, a woman aged 73, underwent a total gastrectomy upon left thoracolaparotomy for a gastric carcinoma at the cardia with a 5-cm involvement of the esophagus. On day 65 post-operation, a diagnosis of Virchow node and para-aortic lymph node recurrence was made on the basis of CT scan findings. Of tumor markers checked, CEA and CA19-9 were noted to be increased to as high as 37.55 ng/mL and 3,235 U/mL, respectively. The patient received three courses of S-1/CDDP combination therapy, with a consequent noticeable contraction of the Virchow node and enlarged para-aortic lymph node. Further, she was given two courses of S-1 therapy, which resulted in normalization of tumor markers. The patient has since been on continued chemotherapy without any sign of recurrence.

Executive dysfunction in medicated, remitted state of major depression.

BACKGROUND: Past neuropsychological studies on depression have documented executive dysfunction and it has been reported that some dysfunction persists even after depressive symptoms disappear. Studies have shown a correlation between cerebrovascular lesions and executive dysfunction in depression among the elderly. The aim of the present study was to focus on executive functions in remitted major depressive disorder (MDD) patients, and to investigate whether remitted young and elderly patients show different patterns of executive dysfunction, and to ascertain the relationships with vascular lesions. METHODS: Subjects were 79 inpatients with MDD and 85 healthy controls. Each subject received Wisconsin Card Sorting Test (WCST), Stroop test, and Verbal Fluency Test (VFT) in a remitted state. Both the MDD and control groups were divided into young and elderly groups, and the performances between 4 groups were compared. RESULTS: For Stroop test, the scores of the MDD group were significantly lower than controls. In addition, as for VFT, the scores for the elderly MDD group were significantly lower than the other groups. Multiple regression analysis showed that VFT scores were affected by the presence of vascular lesions. CONCLUSIONS: The results of the present study demonstrated that executive dysfunction remained even in a remitted state in MDD patients, but the patterns of impairment were different between young and elderly patients. The results also suggested that vascular lesions affect executive dysfunction, particularly in elderly depressive patients.

Effects of a Dictamnus dasycarpus T. extract on allergic models in mice.

The anti-allergic effect of a 70% ethanol extract from Dictamnus dasycarpus Turcz (DDT) was studied in mice. DDT at doses of 200 and 500 mg/kg inhibited the systemic anaphylactic shock induced by compound 48/80 in a dose-dependent manner. It also inhibited dose-dependently the scratching behavior induced by compound 48/80, histamine and serotonin. An increase in the vascular permeability induced by compound 48/80, histamine and serotonin was also inhibited by DDT. In an in vitro study, DDT inhibited the histamine released from rat peritoneal mast cells induced by compound 48/80. It seems likely from these findings that DDT was effective in antagonizing certain pharmacological effects induced by compound 48/80 that occurred via both histamine and serotonin released from mast cells. In conclusion, DDT may be effective in the relief of symptoms of allergic atopic dermatitis and other allergy-related diseases.

Development of new atopic dermatitis models characterized by not only itching but also inflammatory skin in mice.

The present study was performed to develop a new atopic dermatitis model characterized by not only itching but also inflammatory skin using BALB/c mice. From 18 days after the first systemic immunization, daily epicutaneous application of ovalbumin was performed for 2 weeks. Antigen challenge (ovalbumin) resulted in a significant increase of scratching behavior from day 23 to day 32. Moreover, skin symptoms such as erythema/hemorrhage, edema, excoriation/erosion and dryness/desquamation were also observed from day 19 to day 32. The frequency of scratching in the first stage (from day 24 to day 26 after the systemic first immunization) was decreased by chlorpheniramine and epinastine; however, in the last stage (from day 27 to day 30 after the systemic first immunization), both drugs showed no inhibition of scratching behavior. Therefore, an endogenous mediator other than histamine may be responsible for provoking the itching sensation in the last stage. Naloxone dose-dependently reduced the frequency of scratching in the last stage. Moreover, repeated local application of dexametasone significantly inhibited both scratching behavior and skin symptoms from day 24 to day 30. From these findings, it may be concluded that this model is essentially similar to atopic dermatitis in humans and could be used to elucidate the pathogenic mechanisms of atopic dermatitis and to develop appropriate new drugs for therapy.

Increased plasma glutamate by antipsychotic medication and its relationship to glutaminase 1 and 2 genotypes in schizophrenia -- Juntendo University Schizophrenia Projects (JUSP).

Disturbed glutamatergic neurotransmission has become recognized as a key component in the pathophysiology of schizophrenia. The change in serum/plasma glutamate with the use of antipsychotic medication has been studied and may be a possible clinical marker. In the present study, we examined plasma glutamate concentration, including a comprehensive investigation of its involvement with clinical course of schizophrenia and a genomic analysis. We performed a case-control genetic association analysis of the glutaminase 1 (GLS) and 2 (GLS2) genes. In addition, the difference in plasma glutamate concentration between the "acute stage" and "remission stage", and the effect of genotypes of SNPs within the two genes were assessed. The genetic association analysis of the GLS and GLS2 genes showed no association with schizophrenia. Plasma glutamate was increased with antipsychotic medication at "remission stage". Although GLS and GLS2 are not likely genetic risk factors for schizophrenia, changes in plasma glutamate concentration might be connected with clinical course of schizophrenia.

Participation in cysteinyl leukotrienes and thromboxane A2 in nasal congestion model in Brown Norway rats.

The aim of this study was to investigate the involvement of chemical mediators in a nasal congestion model in Brown Norway (BN) rats. For the above purpose, we studied the effects of pranlukast and zafirlukast (cysteinyl leukotriene (cys-LT) receptor antagonists), seratrodast and ramatroban (thromboxane A(2) (TXA(2)) receptor antagonists) on nasal congestion and sneezing induced by toluene 2, 4-diisocyanate (TDI). All of these drugs suppressed the increase of enhanced pause (Penh), the index of nasal congestion, in both early and late phase responses; however, pranlukast, zafirlukast and seratrodast failed to suppress immediate sneezing caused by TDI challenge. These results indicate that cys-LTs and TXA(2) are responsible for the development of both early and late phase nasal congestion. Moreover, these chemical mediators contribute very little to immediate sneezing in a BN rat model of allergic rhinitis.

Comparative study of cognitive impairment between medicated and medication-free patients with remitted major depression: class-specific influence by tricyclic antidepressants and newer antidepressants.

Patients with major depressive disorder (MDD) are known to present with cognitive deficits; however, the presence of these deficits in the remitted state have been inconsistent. One of the most important factors potentially contributing to inconsistencies between studies may be the influence of medications. To explore the influence of antidepressants on cognitive performance in remitted MDD, we evaluated memory and executive functions using Wechsler Memory Scale-Revised and Stroop Color and Word Test, and compared performance among 50 medicated (29 treated with tricyclic antidepressants [TCA], 21 treated with selective serotonin reuptake inhibitors or serotonin noradrenalin reuptake inhibitors) and 19 medication-free MDD patients and 31 controls. The results showed that all 3 MDD groups had significantly lower performance for verbal memory compared with controls. Both medicated groups showed significantly lower performance for visual memory compared with controls; however, the medication-free group did not differ from controls. For the executive function, only the TCA group showed a significantly lower performance compared with controls. These results suggest that cognitive impairment remained even in remitted patients with MDD, however, part of this impairment may be influenced by class-specific antidepressant side effects.

Remarkable alkaline stability of an engineered protein A as immunoglobulin affinity ligand: C domain having only one amino acid substitution.

Protein A affinity chromatography is the standard purification process for the capture of therapeutic antibodies. The individual IgG-binding domains of protein A (E, D, A, B, C) have highly homologous amino acid sequences. From a previous report, it has been assumed that the C domain has superior resistance to alkaline conditions compared to the other domains. We investigated several properties of the C domain as an IgG-Fc capture ligand. Based on cleavage site analysis of a recombinant protein A using a protein sequencer, the C domain was found to be the only domain to have neither of the potential alkaline cleavage sites. Circular dichroism (CD) analysis also indicated that the C domain has good physicochemical stability. Additionally, we evaluated the amino acid substitutions at the Gly-29 position of the C domain, as the Z domain (an artificial B domain) acquired alkaline resistance through a G29A mutation. The G29A mutation proved to increase the alkaline resistance of the C domain, based on BIACORE analysis, although the improvement was significantly smaller than that observed for the B domain. Interestingly, a number of other amino acid mutations at the same position increased alkaline resistance more than did the G29A mutation. This result supports the notion that even a single mutation on the originally alkali-stable C domain would improve its alkaline stability. An engineered protein A based on this C domain is expected to show remarkable performance as an affinity ligand for immunoglobulin.

Heterogeneity of elderly depression: increased risk of Alzheimer's disease and Aß protein metabolism.

Epidemiological studies have proposed that depression may increase the risk for Alzheimer's disease (AD), even in patients with early-onset depression. Although metabolism of amyloid ß protein (Aß) in elderly depression received attention in terms of their correlation, there is a serious heterogeneity in elderly depression in terms of age at onset of depression. Moreover, it is unknown whether early-onset major depressive disorder (MDD) has a long-term effect on the involvement of Aß metabolism and later development of AD. Thus, we evaluated serum Aß40 and Aß42 levels, the Aß40/Aß42 ratio in 89 elderly (≥60 years of age) inpatients with MDD and 81 age-matched healthy controls, and compared them among patients with early-onset (<60 years) and late-onset (≥60years) MDD and controls. The results showed that the serum Aß40/Aß42 ratio was significantly higher in patients with both early- and late-onset MDD than in controls (early-onset, p=0.010; late-onset, p=0.043), and it is of great interest that the serum Aß40/Aß42 ratio was negatively correlated with the age at MDD onset (R=-0.201, p=0.032). These results suggest that an earlier onset of MDD may have a more serious abnormality in Aß metabolism, possibly explaining a biological mechanism underlying the link between depression and AD.

Time course for memory dysfunction in early-life and late-life major depression: a longitudinal study from the Juntendo University Mood Disorder Project.

BACKGROUND: Previous studies have demonstrated that patients with depression also have memory dysfunctions during depressive episodes. These dysfunctions partially remain immediately after remission from a depressive state; however, it is unclear whether these residual memory dysfunctions may disappear through long-term remission from depression. The present study compared patients during early-life (age<60) and late-life (age ≥ 60) depression while in their remitted stage with healthy controls to elucidate the impact of a long-term course on memory. METHODS: Logical memory from the Wechsler Memory Scale-Revised was administered to 67 patients with major depressive disorder (MDD) (47 patients with early-life depression and residual 20 patients with late-life depression) and 50 healthy controls. MDD patients received memory assessments at the time of their initial remission and at a follow-up three years after remission. RESULTS: At the time of initial remission, scores for logical memory were significantly lower in both patient groups compared to matched controls. At follow-up, memory dysfunction for early-life MDD patients disappeared, whereas scores in the late-life MDD group remained significantly lower than those of matched controls. LIMITATIONS: All patients in the present study were on antidepressant medications. CONCLUSIONS: Our findings suggested that the progress of memory performance in late-life MDD patients may be different from early-life MDD patients.