Morphological characterisation of glial and neuronal tau pathology in globular glial tauopathy (Types II and III).

AIMS: Globular glial tauopathy (GGT) is a new category within the 4-repeat tauopathies that is characterised neuropathologically by tau-positive globular glial inclusions (GGIs), namely, globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). Occurrence of tau-positive neuronal cytoplasmic inclusions (NCIs) is also a feature. GGT is classified into three pathological subtypes (Types I, II and III). We studied the tau pathology in 6 cases of GGT (Type II, n = 3; Type III, n = 3), with special reference to GAIs and NCIs. METHODS: Neuropathological examinations were conducted, along with immunohistochemistry, morphometry and three-dimensional imaging, and biochemical and genetic analysis of tau. RESULTS: The cortical GAIs in Type II and those in Type III were distinguishable from each other. In the motor cortex, GAIs were much more numerous in Type III than in Type II. Prominent occurrence of perikaryal globular structures was a feature of GAIs in Type III. By contrast, prominent occurrence of radiating process-like structures was a feature of GAIs in Type II. Overall, the GAIs were significantly smaller in Type III than in Type II. NCIs were divisible into three subgroups in terms of shape: diffuse granular, thick cord-like, and round/horseshoe-shaped structures. In all cases, NCIs were a feature of the upper and lower motor neurons. Interestingly, the round/horseshoe-shaped NCIs were observed only in Type III cases. CONCLUSIONS: These findings, which characterised GAIs and NCIs, indicated that Type II and Type III constitute two distinct pathological subtypes, and also further strengthen the concept of GGT as a distinct entity.

Effect of therapeutic plasma exchange on phenytoin plasma concentration in patients receiving intravenous fosphenytoin therapy.

We report for patients with encephalitis treated with plasma exchange (PE) and fosphenytoin. In patient 1, phenytoin levels decreased on the maintenance dose, and the phenytoin concentration was <10 µg/mL on day 12 of administration. In patient 2, the phenytoin levels was <10 µg/mL on day 4. Increasing the fosphenytoin dose pushed the phenytoin level into therapeutic range. There were no differences between the areas under the concentration-time curve of phenytoin with and without PE. We previously reported a decline in phenytoin levels after prolonged use of fosphenytoin. Therefore, dose adjustment of fosphenytoin in patients undergoing PE may be unnecessary.

Risk factors for decreased teicoplanin trough concentrations during initial dosing in critically ill patients.

Aim of the study: Here, we investigated the risk factors for decreased teicoplanin plasma trough concentrations relative to the initial dosing in critically ill patients. Patients and methods: Data obtained from 80 eligible critically ill patients who received intravenous teicoplanin were retrospectively analyzed. Risk factors for decreases in teicoplanin trough concentrations 72 h after administration of teicoplanin of more than 30% relative to predicted concentrations based on initial dosing setting were identified by logistic regression analysis. Results: Although prediction trough concentration and total dose of two days no significant differences were seen between the variation group and the non-variation group, actual trough concentration was significantly different between two groups (19.9±5.6 µg/ml vs 10.3±2.2 µg/ml, p < 0.001). In multivariate analysis, serum albumin ≤ 2.2 mg/dl (odds ratio [OR] = 3.003, 95% CI 1.072-8.408; p = 0.036) and SOFA score ≥ 9 (OR = 3.498, 95% CI 1.171-10.450; p = 0.025) were significant risk factors for decreased teicoplanin plasma trough concentrations. Conclusion: In critically ill patients, high SOFA score and low serum albumin were risk factors for decreased teicoplanin plasma trough concentration during initial dosing.

Numerical study on spindle positioning using phase field method.

A method of numerical simulation of cell division using phase fields is presented. The cell division plane is obtained as a result of the spindle position and orientation considered with the spatial distribution of the activated cortical force generators and the dividing cell shape. To exemplify the application of the proposed method, numerical simulations of the development of cysts and early embryos are performed. The numerical results demonstrate that the activated cortical force generators that are localized at the lateral cortices of the epithelial cells lead to the formation of a single central lumen. It is additionally shown that the linear distribution of the activated cortical force generators along the animal-vegetal axis of a spherical cell engenders a similar cell proliferation of the divided embryo generated by the 32 cell period in a sea cucumber.

Transcription factor DEC1 is required for maximal experimentally induced periodontal inflammation.

BACKGROUND AND OBJECTIVES: Disruption of transcriptional regulation is a confounding factor associated with a wide range of human inflammatory diseases. To investigate mechanistic links between transcription factor DEC1 and pathways underlying inflammation, wild-type and DEC1 knockout (KO) C57BL/6 mice were treated with Porphyromonas gingivalis (or carboxymethyl cellulose as a control) to induce periodontal inflammation. It provoked an inflammatory response within the oral environment, which showed robust variation in alveolar bone resorption and expression of inflammatory cytokines. MATERIAL AND METHODS: Male DEC1KO mice and their wild-type littermates were used for the experimental periodontitis model. Measurement of alveolar bone resorption, micro-computed tomography, isolation of gingival mononuclear cells (GMCs), flow cytometry and immunohistochemical analysis were used in this study. Human gingival fibroblast cells (HGF-1) were used for DEC1 over-expression and short interference RNA (siRNA) studies and quantitative real-time polymerase chain reaction and western blot analysis were performed. RESULTS: Micro-computed tomography analysis demonstrated that P. gingivalis caused a decrease in bone area of wild-type mice compared with DEC1KO mice. Expression of inflammatory and immune markers in GMCs was significantly decreased in DEC1KO mice after treatment with P. gingivalis. Conversely, interleukin (IL)-4 and IL-10 mRNAs were significantly increased in GMCs isolated from DEC1KO mice. The results show that treatment of DEC1KO mice with P. gingivalis decreased the numbers of CD11b+ F4/80+ and CD4+ RANKL+ T cells. Moreover, expression of CD4, F4/80, RANKL and cathepsin K in inflammatory cell infiltrates was significantly reduced in DEC1KO mice treated with P. gingivalis compared with controls. Furthermore, over-expression of DEC1 in HGF-1 cells increased the expression of IL-1ß and tumor necrosis factor-α mRNAs and their expression levels reached a maximum in response to treatment with lipopolysaccharide. Inhibition of DEC1 by short interference RNA interference suppressed the P. gingivalis-derived lipopolysaccharide-induced expression of IL-1ß, tumor necrosis factor-α and toll-like receptor4. CONCLUSION: These results suggest that transcription factor DEC1 can modulate P. gingivalis-induced periodontitis in the oral mucosa.

A new application of the phase-field method for understanding the mechanisms of nuclear architecture reorganization.

Specific features of nuclear architecture are important for the functional organization of the nucleus, and chromatin consists of two forms, heterochromatin and euchromatin. Conventional nuclear architecture is observed when heterochromatin is enriched at nuclear periphery, and it represents the primary structure in the majority of eukaryotic cells, including the rod cells of diurnal mammals. In contrast to this, inverted nuclear architecture is observed when the heterochromatin is distributed at the center of the nucleus, which occurs in the rod cells of nocturnal mammals. The inverted architecture found in the rod cells of the adult mouse is formed through the reorganization of conventional architecture during terminal differentiation. Although a previous experimental approach has demonstrated the relationship between these two nuclear architecture types at the molecular level, the mechanisms underlying long-range reorganization processes remain unknown. The details of nuclear structures and their spatial and temporal dynamics remain to be elucidated. Therefore, a comprehensive approach, using mathematical modeling, is required, in order to address these questions. Here, we propose a new mathematical approach to the understanding of nuclear architecture dynamics using the phase-field method. We successfully recreated the process of nuclear architecture reorganization, and showed that it is robustly induced by physical features, independent of a specific genotype. Our study demonstrates the potential of phase-field method application in the life science fields.

Short communication: Detection of stx2 and elt genes in bovine milk by using a multiplex PCR system.

The aim of this study was to detect 2 important toxin genes from diarrheagenic Escherichia coli (DEC) in bovine milk using a new multiplex PCR. To standardize the multiplex PCR, the stx2 and elt genes were investigated for the detection of Shiga toxin-producing Escherichia coli (STEC) and enterotoxigenic E. coli (ETEC), respectively. The DNA template was prepared with a thermal procedure (boiling) and a commercial kit. Samples consisted of UHT and pasteurized milk, both skimmed, and STEC and ETEC were tested in concentrations between 101 and 109 cfu/mL. With the thermal procedure, the multiplex PCR system detected both pathotypes of E. coli at 109 cfu/mL in UHT and pasteurized milk. When the commercial kit was used for template preparation, STEC and ETEC could be detected at concentrations as low as 104 cfu/mL in UHT and pasteurized milk. Negative controls (Listeria monocytogenes, Salmonella Typhimurium, Salmonella Enteritidis, and Escherichia coli strain APEC 13) were not amplified with the multiplex PCR. These results indicate that the multiplex PCR was a rapid (less than 6 h) and efficient method to detect STEC and ETEC in milk using different methods for DNA preparation; however, the commercial kit was more sensitive than the thermal procedure.

Effects of Acute Aerobic Exercise on Arterial Stiffness Before and After Glucose Ingestion.

The purpose of present study was to compare the acute effects of moderate-intensity aerobic exercise (65% peak oxygen uptake, 30 min) on arterial stiffness before and after glucose ingestion. 11 healthy young males completed 4 trials in random order. They started aerobic exercise at 90 min before (-90 min-EX), 60 min before (-60 min-EX), 30 min after (30 min-EX), and 60 min after (60 min-EX) the 75-g oral glucose tolerance test (OGTT). Aortic (carotid-femoral) and leg (femoral-ankle) pulse wave velocity (PWV), brachial and ankle blood pressure (BP), blood glucose (BG) and insulin levels were measured at 90 min (baseline) and 30 min before and at 30, 60 and 120 min after the 75-g OGTT. Aortic PWV and brachial systolic BP did not change from baseline after the 75-g OGTT in all trials. Leg PWV and ankle systolic BP increased from baseline after the 75-g OGTT in the -90, 30 and 60 min-EX, but not in the -60 min-EX. Levels of BG and insulin increased from baseline after the 75-g OGTT in all trials. These results suggest that the aerobic exercise most effectively suppresses the increase in peripheral arterial stiffness after glucose ingestion when implemented before glucose ingestion.

Novel multiplex PCR for detection of diarrheagenic Escherichia coli strains isolated from stool and water samples.

Diarrhea is considered the second most common cause of infant mortality worldwide. The disease can be caused by many different pathogens, including diarrheagenic Escherichia coli (DEC), which includes the pathotypes enterotoxigenic E. coli (ETEC), enteroinvasive E. coli (EIEC), enteroaggregative E. coli (EAEC), Shiga toxin-producing E. coli (STEC), and enteropathogenic E. coli (EPEC). To develop a multiplex PCR system for the safe and accurate identification of the five main pathotypes of DEC, seven pairs of primers were determined for the following genes: aaiC, escV, bfpA, ipaH, elt, stx1, and stx2. To validate the system, 413 isolates from different sources (water and both animal and human stool) were analyzed that had been characterized previously. The sensitivity data were grouped by pathotype, in which 92.7% of the atypical EPEC were correlated, as were 92.8% of the STEC, 91.35% of the EAEC, and 100% of the typical EPEC, ETEC, and EIEC. These findings indicate that it is possible to detect the major five pathotypes of DEC from different sources, which can aid in determining the epidemiology of diarrhea with a low cost, high sensitivity and specificity, and the easy and safe viewing of the resulting PCR products.

Risk factors for the failure of treatment of Pseudomonas aeruginosa bacteremia in critically ill patients.

Pseudomonas aeruginosa bacteremia is associated with high morbidity and mortality in critically ill patients. In this study, we assessed risk factors for clinical failure of first definitive therapy for P. aeruginosa bacteremia in critically ill patients. All patients with P. aeruginosa bacteremia who entered the intensive care unit in Gifu University Hospital from January 2006 to December 2015 were retrospectively identified from electronic records. Risk factors associated with clinical failure of the first definitive therapy for P. aeruginosa bacteremia were analyzed by logistic regression analysis. A total of 28 patients were enrolled in the analysis. On multivariate analysis, severe burns (odds ratio [OR] = 70.9, 95% CI 2.9-1720.3; p = 0.009) and SOFA score ≥ 10 (OR = 28.5, 95% CI 1.1-754.3; p = 0.045) were significant factors in the clinical failure of first definitive therapy for P. aeruginosa bacteremia. The clinical success rate of first definitive therapy was significantly reduced in patients with these risk factors compared with those without them (p < 0.001). Severe burns and a SOFA score (≥ 10) were significant risk factors associated with the clinical failure of first definitive therapy for P. aeruginosa bacteremia in critically ill patients. We therefore recommend the use of therapeutic drug monitoring to optimize antibiotic dosing in these critically ill patients.

A simplified chart for determining the initial loading dose of teicoplanin in critically ill patients.

AIM OF THE STUDY: A simplified chart to determine the initial loading dose of teicoplanin (TEIC chart) for achieving the target trough concentration was developed. The aim of the present study was to evaluate the usefulness of this chart in critically ill patients. PATIENTS AND METHODS: The initial loading dose and maintenance dose to achieve a target trough concentration ≥10 µg/mL on day 4 was determined using the teicoplanin TDM software and presented in a TEIC chart. The dosage of teicoplanin, including the loading dose for the first 2 days and the maintenance dose thereafter, was selected from the chart (chart method, N = 41) or calculated using TDM software (software method, N = 39). RESULTS: The performance rate of initial loading of teicoplanin increased from 83.0% to 100% after the TEIC chart was introduced (P = 0.016). The TEIC chart significantly reduced the time required for determining the initial loading dose compared with the use of software (1.9±0.6 min vs. 29.7±13.8 min, P < 0.001). No significant differences were observed in the rates of achieving a target level ≥10 µg/mL (P = 0.766). CONCLUSION: The TEIC chart enables a simple, rapid, and reliable determination of teicoplanin dosage.

Non-anaplastic peripheral T cell lymphoma in children and adolescents-an international review of 143 cases.

Peripheral T cell lymphomas (PTCL) are rare in children and adolescents, and data about outcome and treatment results are scarce. The present study is a joint, international, retrospective analysis of 143 reported cases of non-anaplastic PTCL in patients <19 years of age, with a focus on treatment and outcome features. One hundred forty-three patients, between 0.3 and 18.7 years old, diagnosed between 2000 and 2015 were included in the study. PTCL not otherwise specified was the largest subgroup, followed by extranodal NK/T cell lymphoma, hepatosplenic T cell lymphoma (HS TCL), and subcutaneous panniculitis-like T cell lymphoma (SP TCL). Probability of overall survival (pOS) at 5 years for the whole group was 0.56 ± 0.05, and probability of event-free survival was (pEFS) 0.45 ± 0.05. Patients with SP TCL had a good outcome with 5-year pOS of 0.78 ± 0.1 while patients with HS TCL were reported with 5-year pOS of only 0.13 ± 0.12. Twenty-five percent of the patients were reported to have a pre-existing condition, and this group had a dismal outcome with 5-year pOS of 0.29 ± 0.09. The distribution of non-anaplastic PTCL subtypes in pediatric and adolescent patients differs from what is reported in adult patients. Overall outcome depends on the subtype with some doing better than others. Pre-existing conditions are frequent and associated with poor outcomes. There is a clear need for subtype-based treatment recommendations for children and adolescents with PTCL.

Prolonged occupational activity and 6-year changes in postural sway in elderly women.

OBJECTIVES: Prolonged occupational work such as farm work has been reported to adversely affect mobility in elderly women. The purpose of this study was to investigate possible relationships between prolonged occupational work and 6-year changes in postural sway in elderly women. METHODS: Subjects were 392 women aged ≥ 69 years who participated in a 6-year follow-up examination of the Muramatsu Cohort Study. Handgrip strength and postural sway, measured as gravity-center velocity (cm/s), were evaluated at baseline and 6-year follow-up. Interviews were conducted to determine the time spent on moderate occupational activity (3-5 metabolic equivalents) such as farm work. Activity levels were defined as: 1, no-activity; 2, 'short' (>0, ≤ 17.75 h/wk); and 3, 'long' ( ≥ 17.75 h/wk). RESULTS: At baseline, mean values for age, handgrip strength, and postural sway were 73.3 years (SD 3.7), 20.3 kg (SD 4.1), and 2.0 cm/s (SD 0.8), respectively, and 32.5% of participants engaged in occupational activity. The change in postural sway was significantly greater in the long-activity group (median, 35.0 h/wk) than the no-activity group (0.56 vs. 0.27 cm/s, P=0.021). CONCLUSIONS: Prolonged occupational work may be detrimental to the control of body balance. Accordingly, elderly individuals are not recommended to engage in prolonged occupational activity.

Spin-chirality-driven ferroelectricity on a perfect triangular lattice antiferromagnet.

Magnetic field (B) variation of the electrical polarization P(c) (∥c) of the perfect triangular lattice antiferromagnet RbFe(MoO(4))(2) is examined up to the saturation point of the magnetization for B⊥c. P(c) is observed only in phases for which chirality is predicted in the in-plane magnetic structures. No strong anomaly is observed in P(c) at the field at which the spin modulation along the c axis, and hence the spin helicity, exhibits a discontinuity to the commensurate state. These results indicate that the ferroelectricity in this compound originates predominantly from the spin chirality, the explanation of which would require a new mechanism for magnetoferroelectricity. The obtained field-temperature phase diagram of ferroelectricity agree well with those theoretically predicted for the spin chirality of a Heisenberg spin triangular lattice antiferromagnet.

Controllable Rashba spin-orbit interaction in artificially engineered superlattices involving the heavy-fermion superconductor CeCoIn5.

By using a molecular beam epitaxy technique, we fabricate a new type of superconducting superlattices with controlled atomic layer thicknesses of alternating blocks between the heavy-fermion superconductor CeCoIn5, which exhibits a strong Pauli pair-breaking effect, and nonmagnetic metal YbCoIn5. The introduction of the thickness modulation of YbCoIn5 block layers breaks the inversion symmetry centered at the superconducting block of CeCoIn5. This configuration leads to dramatic changes in the temperature and angular dependence of the upper critical field, which can be understood by considering the effect of the Rashba spin-orbit interaction arising from the inversion symmetry breaking and the associated weakening of the Pauli pair-breaking effect. Since the degree of thickness modulation is a design feature of this type of superlattices, the Rashba interaction and the nature of pair breaking are largely tunable in these modulated superlattices with strong spin-orbit coupling.

Salvage radiation therapy and chemoradiation therapy for postoperative locoregional recurrence of esophageal cancer.

The purpose of this retrospective study was to assess the efficacy of salvage radiation therapy (RT) or chemoradiation therapy (CRT) for locoregional recurrence (LR) of esophageal cancer after curative surgery. Forty-two patients who received salvage RT or CRT for LR of esophageal cancer after curative surgery between November 2000 and May 2012 were reviewed. The intended RT regimen was 60 Gy in 30 fractions combined with concurrent platinum-based chemotherapy. Median follow-up periods were 17.9 months for all evaluable patients and 28.2 months for patients still alive (19 patients) at analysis time. The 1-, 2-, and 3-year survival rates were 81.2 ± 6.4%, 51.3 ± 8.6%, and 41.1 ± 8.7%, respectively, with a median survival time of 24.3 ± 4.1 months. Out of 41 evaluable patients, 16 patients (39%) were alive beyond 2 years from salvage therapy. However, univariate analyses for overall survival showed no significant prognostic factor. Grade 3 or higher leukocytopenia was observed in 46% of the patients. Salvage RT or CRT for LR after surgery for esophageal cancer was safe and effective. These therapies may offer long-term survival to some patients. RT or CRT should be considered for LR.

Myelopathy due to lumbar disc herniation in the presence of a tethered cord.

STUDY DESIGN: Single case report. OBJECTIVES: To present a case of lumbar disc herniation causing compression of a tethered cord that was successfully treated with lumbar decompression and fusion. BACKGROUND: A tethered cord is a rare pathology associated with a congenital spinal malformation, spinal dysraphism. Furthermore, myelopathy due to lumbar disc herniation in the presence of a tethered cord is extremely rare. METHODS: Single case report. RESULTS: A 43-year-old male with a history of spina bifida presented to our clinic for an evaluation of a progressive spastic gait disturbance and numbness in the lower limbs. A neurological examination revealed muscle weakness and pyramidal tract signs in the lower limbs. Magnetic resonance imaging of the lumbar spine showed disc herniation at L2-3 causing compression of a low-lying cord. Surgical intervention, including herniotomy via a posterolateral approach and instrumented posterolateral fusion, was performed, and a good outcome was achieved 1 year after the surgery. CONCLUSION: The potential for lumbar disc herniation in the presence of a tethered cord should be taken into account in the differential diagnosis of spinal pathologies causing spastic gait disturbances. Furthermore, posterior decompression and fusion is a useful treatment option in such cases.

Prognostic factors for cervical spondylotic amyotrophy: are signs of spinal cord involvement associated with the neurological prognosis?

OBJECTIVES: The purpose of this study was to clarify the prognostic factors for cervical spondylotic amyotrophy (CSA). METHODS: The authors retrospectively reviewed the medical records of 47 consecutive patients with CSA in whom the presence/absence of the pyramidal tract sign was noted. We analyzed whether the age, sex, presence of diabetes mellitus, medication (vitamin B12), type of the most atrophic and impaired muscle, the muscle strength at the presentation, the presence of the pyramidal tract sign, magnetic resonance imaging (MRI) findings, including the presence and number of T2 high signal intensity areas (T2 HIA) in the spinal cord and the conversion to surgery were associated with the recovery of muscle strength in the patients. In addition, we also investigated whether the duration of symptoms before surgery and the type of surgery were associated with the recovery of muscle strength in patients who required conversion to surgical treatment. RESULTS: The presence of T2 HIA on MRI (P=0.002), the number of T2 HIA on MRI (P=0.002) and conversion to surgery (P=0.015) were found to be significantly associated with a poorer recovery at the observational final follow-up. Further, the presence of the pyramidal tract sign (P=0.043) was significantly associated with a poor recovery at the final follow-up after surgery. CONCLUSION: The presence of a high signal intensity change on T2-weighted MRI and the pyramidal tract sign can be used as prognostic factors for patients with CSA.

Recruitment of trimeric proliferating cell nuclear antigen by G1-phase cyclin-dependent kinases following DNA damage with platinum-based antitumour agents.

BACKGROUND: In cycling tumour cells, the binary cyclin-dependent kinase Cdk4/cyclin D or Cdk2/cyclin E complex is inhibited by p21 following DNA damage to induce G1 cell-cycle arrest. However, it is not known whether other proteins are also recruited within Cdk complexes, or their role, and this was investigated. METHODS: Ovarian A2780 tumour cells were exposed to the platinum-based antitumour agent 1R,2R-diaminocyclohexane(trans-diacetato)(dichloro)platinum(IV) (DAP), which preferentially induces G1 arrest in a p21-dependent manner. The Cdk complexes were analysed by gel filtration chromatography, immunoblot and mass spectrometry. RESULTS: The active forms of Cdk4 and Cdk2 complexes in control tumour cells have a molecular size of ~140 kDa, which increased to ~290 kDa when inhibited following G1 checkpoint activation by DAP. Proteomic analysis identified Cdk, cyclin, p21 and proliferating cell nuclear antigen (PCNA) in the inhibited complex, and biochemical studies provided unequivocal evidence that the increase in ~150 kDa of the inhibited complex is consistent with p21-dependent recruitment of PCNA as a trimer, likely bound to three molecules of p21. Although p21 alone was sufficient to inhibit the Cdk complex, PCNA was critical for stabilising p21. CONCLUSION: G1 Cdk complexes inhibited by p21 also recruit PCNA, which inhibits degradation and, thereby, prolongs activity of p21 within the complex.