An animal model of posttraumatic stress disorder in rats using a shuttle box]

We administered inescapable footshocks (IS) to male Wistar rats in a shuttle box, and after 2 weeks, an avoidance/escape task was performed in the same box. The rats exposed to IS 2 weeks beforehand exhibited PTSD-like bi-directional changes similar to symptoms of "avoidance/ numbing" and "hyperarousal". That is, in the relatively calm period just before the avoidance/escape task, spontaneous locomotor activities decreased. On the other hand, in the stressful situation after starting the task, not only responses to external stimuli but also locomotor activities increased. Thus, the paradigm we have used until now could serve as a useful PTSD model because of its "face validity". To demonstrate the greater validity, we administered paroxetine (PRX), which is effective for PTSD, to rats to examine its chronic effect on our model. We also substituted F344 rats, which are vulnerable to various stressors, for the Wistar rats to investigate the difference between the strains. Two weeks of PRX treatment significantly reduced hyperarousal-like behavior, and its ameliorating effect on avoidance/numbing-like behavior was also significant. F344 showed more significant 'bi-directional changes' than Wistar rats. These findings demonstrate that our paradigm is sufficiently valid for an animal model of PTSD, especially in "predictive validity" and "construct validity."     

The intraoperative gap difference (flexion gap minus extension gap) is altered by insertion of the trial femoral component

A Tensor/Balancer device has been recently developed in order to assess soft tissue balancing in total knee arthroplasty (TKA) under more physiological conditions. This device allows us to measure the joint gap with a trial femoral component in place with the patella reduced. The purpose of this study was to clarify whether the placement of the component changes the intraoperative gap difference (flexion gap distance minus extension gap distance). We prospectively investigated the extension (0°) and flexion (90°) gaps in 73 posterior-stabilized TKAs under 30 lb of joint distraction force. Then, we compared the gap difference with and without the trial femoral component in place. Our results showed that the intraoperative gap difference with the trial femoral component in place was larger than the intraoperative gap difference without the trial component (p=0.00003; with the trial component: mean 4.7 mm (standard deviation (SD): 3.0mm); without the trial component: mean 2.7 mm (SD: 3.3mm)). We consider that the change in gap difference with or without femoral component was caused by a relative difference in the elasticity and/or tightness of the soft tissue in extension versus flexion. Surgeons should be aware of this effect of the femoral component when considering intraoperative soft tissue balancing which leads to postoperative stability of the knee joint consequently.     

Prophylactic intraaortic balloon pumping preserves left ventricular systolic function in acute anterior myocardial infarction without cardiogenic shock

OBJECTIVES: Left ventricular function and prognosis were evaluated in patients with acute myocardial infarction who underwent primary percutaneous coronary intervention supported by intraaortic balloon pumping. METHODS: Fifty-eight consecutive patients with first acute myocardial infarction were treated between July 1999 and April 2006. Twenty-five had cardiogenic shock on admission, whereas 33 did not. Patients with anterior acute myocardial infarction without cardiogenic shock were divided into the prophylactic intraaortic balloon pumping group (Group 1; n=17) and the rescue intraaortic balloon pumping group (Group 2; n=9). RESULTS: Thirty-day in-hospital mortality was 52% in cardiogenic shock patients, and 3% in non-shock patients. Baseline characteristics of non-shock anterior acute myocardial infarction were similar including Thrombolysis in Myocardial Infarction (TIMI) risk scores (5.1 and 5.0) in the two groups. However, average left ventricular ejection fraction in the convalescent stage was superior in Group 1 (48.7% vs. 37.8%, p = 0.03). Thirty-day in-hospital mortality was 0% in Group 1 and 11% in Group 2 (p = 0.34). Cox's hazard ratio in Group 2 to Group 1 was 2.38 (95% confidence intrerval; 0.84-11.1, p = 0.09) in terms of the subsequent major cardiac events. CONCLUSIONS: Prophylactic use of intraaortic balloon pumping starting prior to primary percutaneous coronary intervention preserves the convalescent left ventricular systolic function in patients with high risk for anticipated cardiac events after anterior acute myocardial infarction without cardiogenic shock.     

Eosinophil trans-basement membrane migration induced by interleukin-8 and neutrophils

Neutrophilic inflammation observed with severe asthma is often associated with interleukin-8 (IL-8). Neutrophils can secrete a variety of mediators that may augment the migration of eosinophils. We have reported a positive correlation between the concentrations of neutrophils and eosinophils in sputum from subjects with severe asthma, suggesting a possible role of neutrophils in regulating eosinophilic inflammation. The aim of this study was to investigate whether neutrophils stimulated with IL-8 modify the trans-basement membrane migration (TBM) of eosinophils. Eosinophils and neutrophils were isolated from peripheral blood drawn from healthy donors or subjects with mild asthma. The TBM of eosinophils in response to IL-8 was evaluated in the presence or absence of neutrophils using the chambers with a Matrigel-coated transwell insert. Neither IL-8 alone nor the presence of neutrophils alone induced the TBM of eosinophils. However, when eosinophils were coincubated with neutrophils and stimulated with IL-8, the TBM of eosinophils was significantly augmented. This augmented TBM of eosinophils was inhibited by a matrix metalloproteinase-9 inhibitor, a leukotriene B4 receptor antagonist, platelet-activating factor antagonists, or an anti-TNF-alpha monoclonal antibodies. These results suggest that neutrophils migrated in response to IL-8 may lead eosinophils to accumulate in the airways of asthma and possibly aggravate this disease.     

Overcoming graft rejection in heavily transfused and allo-immunised patients with bone marrow failure syndromes using fludarabine-based haematopoietic cell transplantation

Allogeneic haematopoietic cell transplantation (HCT) can cure a variety of non-malignant haematological disorders. Although transplant outcomes for selected patients with severe aplastic anaemia (SAA) and paroxysmal nocturnal haemoglobinuria (PNH) have improved, older age, allo-immunisation from transfusions, prior immunosuppressive therapy and a prolonged time from diagnosis to transplantation are associated with worse outcome. Because of its potent immunosuppressive effects, we investigated a fludarabine-based non-myeloablative conditioning regimen in patients with transfusion-dependent non-malignant haematological disorders at increased risk for graft rejection with conventional transplant conditioning. Twenty-six patients with transfusion dependent/anti-thymocyte globulin (ATG)-refractory SAA, PNH or pure red cell aplasia underwent HCT from a human leucocyte antigen (HLA)-compatible relative. Transplant conditioning consisted of cyclophosphamide (120 mg/kg) and fludarabine (125 mg/m2) with or without ATG. Ciclosporine, alone or combined with mycophenolate mofetil or methotrexate, was used as graft-versus-host disease (GVHD) prophylaxis. All patients achieved durable engraftment and transfusion-independence. Twenty-four of 26 patients are alive at a median of 21 months following transplantation. Although a high cumulative incidence of acute (65% grades II-IV, 54% grades III-IV) and chronic GVHD (56%) was observed, only one patient died from transplant-related causes (cumulative incidence 7%). These data show that HCT following fludarabine-based non-myeloablative conditioning results in durable engraftment and excellent survival in SAA and PNH patients at high risk for graft rejection.     

Prey evolution on the time scale of predator-prey dynamics revealed by allele-specific quantitative PCR

Using rotifer-algal microcosms, we tracked rapid evolution resulting from temporally changing natural selection in ecological predator-prey dynamics. We previously demonstrated that predator-prey oscillations in rotifer-algal laboratory microcosms are qualitatively altered by the presence of genetic variation within the prey. In that study, changes in algal gene frequencies were inferred from their effects on population dynamics but not observed directly. Here, we document rapid prey evolution in this system by directly observing changes in Chlorella vulgaris genotype frequencies as the abundances of these algae and their consumer, Brachionus calyciflorus, change through time. We isolated a group of algal clones that we could distinguish by using microsatellite-DNA markers, and developed an allele-specific quantitative PCR technique (AsQ-PCR) to quantify the frequencies of pairs of clones in mixed culture. We showed that two of these genotypes exhibited a fitness tradeoff in which one was more resistant to predation (more digestion-resistant), and the other had faster population growth under limiting nitrogen concentrations. A fully specified mathematical model for the rotifer-algal population and evolutionary dynamics predicted that these two clones would undergo a single oscillation in clonal frequencies followed by asymptotic fixation of the more resistant clone, rather than the recurrent oscillations previously observed with other algal clones. We used AsQ-PCR to confirm this prediction: the superior competitor dominated initially, but as rotifer densities increased, the more predator-resistant clone predominated.     

Involvement of the Autonomic Nervous System in Diurnal Variation of Corrected QT Intervals in Common Marmosets

Our previous study has shown that the corrected QT (QTc) interval of the electrocardiogram is longer during the dark period than during the light period in telemetered common marmosets. In the present study, we investigated the involvement of sympathetic and parasympathetic nervous activities in the changes of QTc interval associated with the light–dark cycle. Telemetry transmitters were implanted in six common marmosets to continuously record the electrocardiogram. The QT intervals obtained were corrected for the RR interval by applying individual probabilistic QT-rate correction formulae. Power spectral analysis of heart rate variability was performed to quantify each autonomic nervous function. Changes in QTc intervals and autonomic nervous tones were associated with the light–dark cycle. Parasympathetic nervous activity and QTc intervals significantly increased by approximately 10 ms during the dark period. Atropine, a muscarinic receptor antagonist, suppressed the increased parasympathetic tone and QTc prolongation during the dark period. In contrast, propranolol, a β-adrenoceptor antagonist, decreased the sympathetic activity and increased QTc intervals during the light period. These results suggest that the parasympathetic nerve functions prolong QTc intervals during the dark period, while the sympathetic nerve functions shorten them during the light period in common marmosets.     

Comparison of chemotherapeutic efficacy between LCNEC diagnosed using large specimens and possible LCNEC diagnosed using small biopsy specimens

Background

It is often difficult to diagnose large cell neuroendocrine carcinomas (LCNEC) of the lung using small biopsy specimens. Some recent studies attempted to diagnose LCNEC using biopsy specimens; in 2011, the International Association for the Study of Lung Cancer pathological panels suggested possible LCNEC as a diagnosis for LCNEC by using biopsy specimens. Here, we compared the chemotherapeutic efficacy in possible LCNEC and LCNEC diagnosed using surgically resected specimens.

Methods

We retrospectively reviewed patients who received platinum-based chemotherapy as first-line chemotherapy at our institution during September 2002–September 2011. Further, we compared the clinical characteristics, chemotherapeutic responses, and survival outcomes of patients diagnosed as having “LCNEC definite” with those diagnosed as having “possible LCNEC.”

Results

We selected 34 patients of whom 10 were diagnosed with LCNEC using surgically resected specimens and 24 patients with possible LCNEC were diagnosed using small biopsy specimens. In both groups, almost all patients were men and were smokers. Small-cell carcinoma-based chemotherapy, such as platinum plus irinotecan or platinum plus etoposide, was used for treating 60 % LCNEC patients (6/10) and 67 % possible LCNEC patients. In the LCNEC and possible LCNEC groups, respectively, the response rate was 70 and 54 % (p = 0.39), median progression-free survival was 2.9 and 4.4 months (p = 0.20), and median survival time was 12.8 and 9.1 months (p = 0.50).

Conclusion

No statistically significant differences were found in chemotherapeutic responses and survival outcomes between the 2 groups, which suggests that chemotherapeutic efficacy is similar in both possible LCNEC and LCNEC.