Impact of concurrent antibody-drug conjugates and radiotherapy on symptomatic radiation necrosis in breast cancer patients with brain metastases: a multicenter retrospective study.

AIM: We aimed to investigate the impact of concurrent antibody-drug conjugates (ADC) and radiotherapy on symptomatic radiation necrosis (SRN) in breast cancer patients with brain metastases (BM). METHODS: This multicenter retrospective study uses four institutional data. Eligibility criteria were histologically proven breast cancer, diagnosed BM with gadolinium-enhanced MRI, a Karnofsky performance status of 60 or higher, and radiotherapy for all BM lesions between 2017 and 2022. Patients with leptomeningeal dissemination were excluded. Concurrent ADC was defined as using ADC within four weeks before or after radiotherapy. The cumulative incidence of SRN until December 2023 with death as a competing event was compared between the groups with and without concurrent ADC. Multivariable analysis was performed using the Fine-Gray model. RESULTS: Among the 168 patients enrolled, 48 (29%) received ADC, and 19 (11%) had concurrent ADC. Of all, 36% were HER2-positive, 62% had symptomatic BM, and 33% had previous BM radiation histories. In a median follow-up of 31 months, 18 SRNs (11%) were registered (11 in grade 2 and 7 in grade 3). The groups with and without concurrent ADC had 5 SRNs in 19 patients and 13 SRNs in 149, and the two-year cumulative incidence of SRN was 27% vs. 7% (P = 0.014). Concurrent ADC was associated with a higher risk of SRN on multivariable analysis (subdistribution hazard ratio, 3.0 [95% confidence interval: 1.1-8.3], P = 0.030). CONCLUSIONS: This study suggests that concurrent ADC and radiotherapy are associated with a higher risk of SRN in HER2-positive breast cancer patients.

Association of the Number of Teeth With Physical Function and Length of Hospital Stay After Hip Fracture Surgery: A Prospective Observational Study at a Tertiary Hospital in Japan.

OBJECTIVES: Although lower-extremity muscle strength is associated with physical function, there are challenges in assessing the muscle strength of patients after hip surgery due to pain or limited cognitive function. The number of teeth is a characteristic that can be easily examined. Although the relationship between the number of teeth and physical function has been reported in recent years, there are no reports examining the relationship with prognosis in patients with hip fractures. Therefore, this study aimed to investigate the relationship between the number of teeth and physical function and length of hospital stay after hip fracture surgery and to evaluate the predictive efficacy of the number of teeth on postoperative prognosis. METHODS: This prospective cohort study was conducted in a tertiary clinical care facility. Patients aged ≥65 years who underwent hip surgery were included. A total of 101 patients (mean age: 85.1±8.0 years) were included. The factor analyzed was the number of teeth at admission. Patients were divided into two groups according to the number of teeth: those with ≥20 and those with ≤19 teeth. The outcomes were knee extension muscle strength-to-weight ratio at two weeks postoperatively and the length of hospital stay. A multiple regression analysis was performed to determine the association between the two groups. RESULTS: Of 101 patients, 79 (78.2%) had ≤19 teeth, whereas 22 (21.8%) had ≥20 teeth. The mean muscle strength-to-weight ratio and length of hospital stay were 0.26±0.11 kgf/kg and 57.5±31.4 days, respectively. Multiple regression analysis revealed that the number of teeth was significantly associated with the muscle strength-to-weight ratio (ß=-0.26, p=0.04) but not with the duration of hospitalization (ß=0.17, p=0.09). CONCLUSIONS: We suggest that assessment of the number of teeth at admission may be a useful predictor of patient physical function.

Correlations between intraplan and postplan parameters in I-125 permanent prostate brachytherapy using loose seeds or linked seeds.

The purpose of this study was to determine the most appropriate seed arrangement by comparing two different methods (linked seeds and loose seeds). A total of sixty-one patients (28 linked seed brachytherapy cases and 33 loose seed brachytherapy cases) with clinically localized prostate cancer were treated with I-125 permanent prostate brachytherapy. Modified peripheral loading was the method used for seed placement. The parameters evaluated were as follows: prostate D90, V100, and V150; urethral D90, D10, and D5; and rectal V100 (RV100) and D2 (RD2). Coefficient parameters (r and r2) were assessed by regression analysis. Prostate V150, urethral D90, urethral D10, urethral D5, and RD2 showed significant correlations between both methods in all patients. Urethral D90, urethral D10, urethral D5, and RD2 showed significant correlations in patients who received linked seed brachytherapy. Prostate V150, urethral D90, urethral D10, urethral D5, RV100, and RD2 showed significant correlations in patients who received loose seed brachytherapy. Urethral D90, urethral D10, urethral D5, and RD2 showed significant correlations in the linked seed and loose seed brachytherapy analyses. In contrast, prostate D90 and prostate V100 showed no correlation. Parameters of normal organ damage showed good correlations between intraplan and postplan parameters. These parameters may be useful to determine normal organ damage during guided brachytherapy with two different methods (linked seeds and loose seeds).

Benefits of mindfulness in academic settings: trait mindfulness has incremental validity over motivational factors in predicting academic affect, cognition, and behavior.

BACKGROUND: Achievement motivation research has established that motivational factors predict academic affect, cognition, and behavior. Recent studies have shown that trait mindfulness might also predict these academic outcomes. However, it remains unclear whether trait mindfulness has incremental validity over motivational factors. We hypothesized that trait mindfulness would explain unique variance in academic outcomes beyond motivational factors, because mindfulness that is characterized by the being mode of mind (i.e., a present-focused, non-striving, and accepting mind mode) would contribute to academic outcomes through unique and effective self-regulatory processes (i.e., bottom-up self-regulation of learning and present-focused, acceptance-based self-regulation of academic stress), which differ from those (i.e., top-down self-regulation of learning and future-focused, change-oriented self-regulation of academic stress) promoted by motivational factors that are characterized by the doing mode of mind (i.e., a goal-oriented, striving, and change-seeking mind mode). We tested the hypothesis by examining four established motivational factors (competence perception, implicit theory of intelligence, achievement goals, and autonomous and controlled academic reasons) and five outcome variables (test anxiety, enjoyment of learning, study strategy, mind-wandering, and help-seeking avoidance) that had been investigated in both the trait mindfulness and achievement motivation literatures. METHODS: One hundred and seventy-five students (104 females) were recruited from undergraduate psychology and cultural studies classes at two universities in Japan. Trait mindfulness was assessed using the Five Facet Mindfulness Questionnaire. The other study variables were assessed using established measures as well. We conducted hierarchical multiple regression analyses to test the hypothesis. RESULTS: Trait mindfulness predicted four of the five outcome variables (i.e., test anxiety, enjoyment of learning, mind-wandering, and help-seeking avoidance) after controlling for the motivational factors. The acting-with-awareness facet predicted three outcome variables, whereas the other facets predicted one outcome each. CONCLUSIONS: This study supports the incremental validity of trait mindfulness relative to motivational factors, suggesting that not only the doing mode of mind but also the being mode is beneficial for academic learning.

Clinicopathological and prognostic significance of immunophenotypic characterization of endocervical adenocarcinoma using CLDN18, CDH17, and PAX8 in association with HPV status.

In 2020, the WHO published a new system for classifying invasive endocervical adenocarcinoma based on histological features and high-risk human papillomavirus (HPV) infection. However, immunophenotypes of each histological subtype require further investigation. We immunohistochemically analyzed 66 invasive endocervical adenocarcinomas using three cell-lineage-specific markers: claudin 18 (CLDN18) for gastric, cadherin 17 (CDH17) for intestinal, and PAX8 for Müllerian epithelial cells. We identified five immunophenotypes of endocervical adenocarcinoma: gastric (21%); intestinal (14%); gastrointestinal (11%); Müllerian (35%); and not otherwise specified (NOS) (20%). Adenocarcinomas with gastric immunophenotype, characterized by aging (p = 0.0050), infrequent HPV infection (p < 0.0001), concurrent lobular endocervical glandular hyperplasia (p = 0.0060), lymphovascular invasion (p = 0.0073), advanced clinical stage (p = 0.0001), and the poorest progression-free (p < 0.0001) and overall (p = 0.0023) survivals, were morphologically compatible with gastric-type adenocarcinoma of the WHO 2020 classification. Conversely, most adenocarcinomas with Müllerian (91%) and intestinal (89%) immunophenotypes were HPV associated and morphologically compatible with usual- or intestinal-type adenocarcinomas of the WHO 2020 classification. The morphology of adenocarcinomas with gastrointestinal immunophenotype was intermediate or mixed between those of gastric and intestinal immunophenotypes; 57% were HPV associated. Adenocarcinomas with NOS immunophenotype were mainly HPV associated (85%) and histologically poorly differentiated. Multivariate analysis revealed that gastric (p = 0.008), intestinal + gastrointestinal (p = 0.0103), and NOS (p = 0.009) immunophenotypes were independent predictors of progression-free survival. Immunophenotypes characterized by CLDN18, CDH17, and PAX8 exhibited clinicopathological relevance and may improve the diagnostic accuracy and prognostic value of conventional histological classification.

Superiority of sucrase-isomaltase to CD10 for immunohistochemical detection of intestinal absorptive cell phenotype in differentiated-type gastric adenocarcinoma.

Gastric adenocarcinoma (GAC) can be divided immunophenotypically into gastric, intestinal, or mixed gastric and intestinal phenotypes. Cadherin 17 (CDH17) and CD10 have been used as comprehensive markers for intestinal epithelial cells and for small intestinal absorptive cells in GACs, respectively. Sucrase-isomaltase (SI) and CD10 are expressed in small intestinal absorptive cells and SI is more frequently expressed than CD10 in gastric intestinal metaplasia (IM). The aim of this study was to evaluate the potential of SI as a marker for intestinal absorptive cells compared to CD10 in differentiated-type (DT) GACs. We compared the immunohistochemical expression of CDH17, SI, and CD10 in IMs and tissue microarrays of 40 samples of DTGACs. In IMs and DTGACs, CDH17 showed a diffuse lateral cytoplasmic membrane staining both in columnar and goblet cells. SI and CD10 were expressed on the luminal surfaces of the columnar cells. In IMs, SI was positive both in both complete-type IMs and in incomplete-type IMs. CD10 was positive only in complete-type IMs. In DTGACs, CDH17, SI, and CD 10 were positive in 37 (92.5%), 22 (55%), and 11 (27.5%) cases, respectively. In SI-positive cases, the degrees of expression of SI were equal to (7 cases) or less than (15 cases) those of CDH17; the degrees of expression of SI were equal to (5 cases), more than (16 cases), or less than (1 case) those of CD10. In conclusion, SI is a more sensitive immunohistochemical marker for intestinal absorptive cells than CD10 in DTGACs.

Predictors of Secondary Bladder Cancer in Patients with Prostate Cancer Treated with Brachytherapy: A Single-institution Study of a Japanese Cohort.

PURPOSE: The incidence of secondary bladder cancer after treatment for localized prostate cancer (PCa) remains unclear. In this study, PCa cases treated with brachytherapy (BT) were evaluated to assess the incidence of a second malignancy of bladder cancer in a Japanese cohort. MATERIALS AND METHODS: Overall, 969 patients treated with BT at our hospital between July 2006 and January 2019 were included in the study cohort. The incidence and predictors of secondary bladder cancer were also assessed. RESULTS: The incidence of secondary bladder cancer was 1.5% (n = 14). Of the seven factors (age, pretreatment PSA, Gleason score, cTNM stage, prostate volume, total activity, and combined external beam), prostate volume and total activity showed significant differences between the cohorts with and without secondary bladder cancer (P = .03 and P = .001, respectively). Upon comparison of the seven parameters for the 969 patients treated with BT, we found that only the total activity factor was affected by the incidence of secondary bladder cancer in the multivariate analysis (P = .007). CONCLUSION: The incidence of secondary bladder cancer was evaluated after BT for PCa. Total activity was associated with the incidence of secondary bladder cancer in Japanese patients who received BT.

Periprosthetic Fracture Resembling Atypical Femoral Fracture After Fixation With Retrograde Intramedullary Nail in Elderly Women: A Report of Two Cases.

BACKGROUND/AIM: The number of individuals diagnosed with and requiring medical treatment for osteoporosis continues to increase due to global population aging and the high awareness of osteoporosis. Bone-modifying agents (BMAs) including bisphosphonate and denosumab are widely used for osteoporosis, and atypical femoral fracture (AFF) is also gaining attention as a severe potential side effect of long-term BMA treatment. The definition of AFF excludes periprosthetic femoral fracture; here, we describe two cases of a periprosthetic femoral fracture that resembled AFF. CASE REPORT: The fractures occurred at the proximal tip of the retrograde femoral nail after an internal fixation for a distal femoral shaft fracture in elderly Japanese women. Each woman had been treated with bisphosphonate therapy for >2 years and had continued the bisphosphonate after undergoing surgery for a distal femoral shaft fracture. Each patient had noticed thigh pain before falling down, and plain radiographs showed a short oblique or transverse fracture with medial spike and localized periosteal reaction of the lateral cortex in each case. The fractures were re-fixed with an antegrade intramedullary nail, and bone union was achieved at >1 year after the second operation. Although these two cases were classified as periprosthetic fractures, they fulfilled the characteristics of AFF. CONCLUSION: Physicians should conduct a thorough interview of patients with a history of BMA treatment in order to correctly diagnose periprosthetic fractures that resemble AFFs, and they should be aware that symptomatic fractures can be prevented by prophylactic fixation. The discontinuance of BMA therapy and the introduction of another drug such as teriparatide may lead to faster healing of surgically treated AFFs.

'Acute Masquelet technique' for reconstructing bone defects of an open lower limb fracture.

INTRODUCTION: The reconstruction of bone defects of open lower leg fractures is challenging, and there is no established treatment strategy to date, especially in the acute phase. We report herein an 'acute Masquelet technique' for reconstructing bone defects of open lower limb fractures as the primary treatment in the acute phase. PATIENTS AND METHODS: We retrospectively analyzed the outcomes of seven lower limbs of the seven Japanese patients (five males, two females, aged 24-76 years [mean 53 years]) who underwent the acute Masquelet technique for open fractures with bone defects. We evaluated postsurgical complications including deep infection, absorption of grafted bone, and the final result of the bone union. RESULTS: Deep infection occurred in one of the seven limbs (14%). There was no case with absorption of grafted bone in our series. We have treated two patients who needed additional surgery for delayed bone union. Bone union was eventually obtained in all seven limbs. All of the patients became pain-free and could walk without a cane. CONCLUSION: The 'acute Masquelet technique' was quite useful for reconstructing bone defects of open lower limb fractures as the primary treatment in the acute phase. We believe that this is one of the options that might be successful in the treatment of open lower limb fractures.

Correlation analysis of the proportion of monocytic myeloid-derived suppressor cells in colorectal cancer patients.

Monocytic myeloid-derived suppressor cells (mMDSCs) are a class of immunosuppressive immune cells with prognostic value in many solid tumors. It is reported that the proportion of mMDSCs in the peripheral blood can be a predictive marker for response to cancer immunotherapy. In this study, we performed a correlation analysis of the proportion of mMDSCs in freshly-drawn peripheral blood, levels of plasma proteins, and demographic factors in colorectal cancer (CRC) patients, to find factors that could be used to predict mMDSC proportions. Freshly-drawn mMDSCs were measured using flow cytometry on peripheral blood mononuclear cells (PBMCs) from healthy donors (n = 24) and CRC patients (n = 78). The plasma concentrations of 29 different cytokines, chemokines, growth factors, and enzymes were measured using a multiplex assay or enzyme-linked immunosorbent assay. Correlation analysis to find mMDSC-associated factors was conducted using univariate and multivariate models. In univariate correlation analysis, there were no plasma proteins that were associated with mMDSC proportions in CRC patients. In multivariate analysis, considering all variables including age, sex, and plasma proteins, levels of inducible nitric acid synthase (iNOS) (p = 0.013) and platelet-derived growth factor (PDGF)-BB (p = 0.035) were associated with mMDSC proportion in PBMCs (mMDSC proportion [%] = 0.2929 - 0.2389 * PDGF-BB + 0.3582 * iNOS) (p < 0.005, r = 0.32). Measuring the plasma concentrations of iNOS and PDGF-BB may be useful in predicting the proportion of mMDSCs in CRC patients' peripheral blood. Further research is required to establish and validate these predictive factors. Data registration Patient data were registered in an anonymization system at Tsukuba Clinical Research & Development Organization (T-CReDO).

Advanced cadaver-based educational seminar for trauma surgery using saturated salt solution-embalmed cadavers.

AIM: Senior surgeons in Japan who participated in "cadaver-based educational seminar for trauma surgery (CESTS)" subsequently stated their interest in seminars for more difficult procedures. Therefore, we held a 1-day advanced-CESTS with saturated salt solution (SSS)-embalmed cadavers and assessed its effectiveness for surgical skills training (SST). METHODS: Data were collected from three seminars carried out from September 2015 to January 2018, including a 10-point self-assessment of confidence levels (SACL) questionnaire on nine advanced surgical skills, and evaluation of seminar content before, just after, and half a year after the seminar. Participants assessed the suitability of the two embalming methods (formalin solution [FAS] and SSS) for SST, just after the seminar. Statistical analysis resulted in P < 0.0167 comparing SACL results from seminar evaluations at the three time points and P < 0.05 comparing FAS to SSS. RESULTS: Forty-three participants carried out surgical procedures of the lung, liver, abdominal aorta, and pelvis and extremity. The SACL scores increased in all skills between before and just after the seminar, but were decreased by half a year after. However, SACL scores of each skill did not change significantly, except for external fixation for pelvic fracture at just after and half a year after. The SSS-embalmed cadavers were evaluated as being more suitable than FAS-embalmed cadavers for each procedure. CONCLUSIONS: Advanced-CESTS using SSS-embalmed cadavers increased the participants' self-confidence just after the seminar, which was maintained after half a year in each skill, except external fixation for pelvic fracture. Therefore, SSS-embalmed cadavers are useful for SST, particularly for surgical repairs.

Phase II study of ceritinib in alectinib-pretreated patients with anaplastic lymphoma kinase-rearranged metastatic non-small-cell lung cancer in Japan: ASCEND-9.

Clinical experience of ceritinib in patients who progressed on alectinib is limited. In this prospective phase II study, we evaluated the activity of ceritinib in alectinib-pretreated patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic (stage IIIB/IV) non-small-cell lung cancer (NSCLC) in Japan. All patients were required to have ≥1 measurable lesion per RECIST, 1.1, and a World Health Organization Performance Status (WHO PS) of 0-1. Prior crizotinib and/or up to 1 chemotherapy regimen was allowed. Primary endpoint was investigator-assessed overall response rate (ORR) per RECIST 1.1. Ceritinib was given at a dose of 750 mg/day fasted. A total of 20 patients were enrolled from August 2015 to March 2017. All patients received prior alectinib (100%), 13 (65.0%) patients received prior platinum-based chemotherapy, and 4 (20%) patients received prior crizotinib. Median duration of exposure and the follow-up time with ceritinib were 3.7 months (range: 0.4-15.1) and 11.6 months (range: 4.8-23.0), respectively. Investigator-assessed ORR was 25% (95% CI: 8.7-49.1). Key secondary endpoints, all investigator assessed, included disease control rate (70.0%; 95% CI: 45.7-88.1), time to response (median, 1.8 months; range: 1.8-2.0), and duration of response (median, 6.3 months; 95% CI: 3.5-9.2). Median progression-free survival was 3.7 months (95% CI: 1.9-5.3). The most common adverse events reported were diarrhea (85.0%), nausea (80.0%), and vomiting (65.0%). Based on our findings, ceritinib could be considered as one of the treatment options for patients with ALK-positive NSCLC who progressed on alectinib. (Trial registration no. NCT02450903).

Apolipoproteins C-II and C-III as nutritional markers unaffected by inflammation.

BACKGROUND: Rapid turnover proteins (RTPs), such as transthyretin (TTR), retinol binding protein (RBP), and transferrin (Tf), provide an accurate assessment of nutritional status but are susceptible to inflammation. Lipid-related markers, which have short half-lives in serum, may be better suited for nutritional assessment. We sought to identify sensitive nutritional markers unaffected by inflammation. METHODS: Fasting serum samples were collected from 30 malnourished inpatients and 25 healthy volunteers. Malnourished inpatients were divided into 2 groups: a low-C-reactive protein (CRP) group (CRP < 20 mg/l, n = 15) and a high-CRP group (CRP ≥ 20 mg/l, n = 15). Lipid-related markers, traditional nutritional markers, RTPs, micronutrients, and ketone bodies were measured and compared among the groups. RESULTS: Apolipoprotein (Apo)C-II and ApoC-III concentrations were lower in malnourished inpatients than in the control group. There was no significant difference in ApoC-II and ApoC-III between the low- and high-CRP groups. Carnitine transporters and ketone bodies did not show a significant difference among the three groups. Albumin, TTR, RBP, and Tf concentrations were lowest in the high-CRP group, intermediate in the low-CRP group, and highest in the control group. CONCLUSIONS: These results indicate that ApoC-II and ApoC-III are appropriate nutritional biomarkers unaffected by inflammation.

Phase 3 study of ceritinib vs chemotherapy in ALK-rearranged NSCLC patients previously treated with chemotherapy and crizotinib (ASCEND-5): Japanese subset.

BACKGROUND: In the global, Phase 3, ASCEND-5 study, ceritinib improved progression-free survival (PFS) vs chemotherapy in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) who had previously progressed on crizotinib and platinum-based chemotherapy. Here, we report efficacy and safety in a subset of Japanese patients from the ASCEND-5 study. METHODS: Patients with advanced ALK-rearranged NSCLC received oral ceritinib 750 mg/day or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator's choice], every 21 days). RESULTS: Among the 231 patients, 29 were Japanese, of which, 11 were treated with ceritinib and 18 were treated with chemotherapy (5 with pemetrexed and 13 with docetaxel). All the patients received prior crizotinib and one or two lines of prior chemotherapy for advanced disease. Median follow-up time was 16.6 months for ceritinib arm and 16.4 months for chemotherapy arm in the overall population. The median PFS by blinded independent review committee was 9.8 months (95% CI, 4.3-14.0) in ceritinib arm vs 1.6 months (95% CI, 1.4-3.0) in chemotherapy arm. Grade 3 or 4 adverse events, suspected to be study drug related, were reported in 36.4% of ceritinib arm and 72.2% of chemotherapy arm, respectively. No Grade 3 or 4 events of diarrhea, nausea and vomiting were reported in both the treatment arms. Adverse events leading to study drug discontinuation were reported in one patient in each arm: Grade 3 central-nervous system metastases in ceritinib-treated patient and Grade 3 febrile neutropenia in chemotherapy-treated patient. CONCLUSIONS: Consistent with overall population, ceritinib demonstrated better efficacy compared with the standard second-line chemotherapy in Japanese patients with crizotinib-resistant ALK+ NSCLC. CLINICALTRIALS.GOV IDENTIFIER: NCT01828112.

HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node.

KEY POINTS: The contribution of HCN4 pacemaker channels in the autonomic regulation of the sino-atrial node (SAN) has been a matter of debate. The transgenic overexpression of HCN4 did not induce tachycardia, but reduced heart rate variability, while the conditional knockdown of HCN4 gave rise to sinus arrhythmia. The response of the SAN to ß-adrenergic stimulation was not affected by overexpression or knockdown of HCN4 channels. When HCN4 channels were knocked down, the parasympathetic response examined by cervical vagus nerve stimulation (CVNS) was enhanced; the CVNS induced complete sinus pause. The overexpression of HCN4 attenuated bradycardia induced by CVNS only during ß-adrenergic stimulation. We concluded that HCN4 pacemaker channels stabilize the spontaneous firing by attenuating the parasympathetic response of the SAN. ABSTRACT: The heart rate is dynamically controlled by the sympathetic and parasympathetic nervous systems that regulate the sinoatrial node (SAN). HCN4 pacemaker channels are the well-known causative molecule of congenital sick sinus syndrome. Although HCN4 channels are activated by cAMP, the sympathetic response of the SAN was preserved in patients carrying loss-of-function mutations of the HCN4 gene. In order to clarify the contribution of HCN4 channels in the autonomic regulation of the SAN, we developed novel gain-of-function mutant mice in which the expression level of HCN4 channels could be reversibly changed from zero to ∼3 times that in wild-type mice, using tetracycline transactivator and the tetracycline responsive element. We recorded telemetric ECGs in freely moving conscious mice and analysed the heart rate variability. We also evaluated the response of the SAN to cervical vagus nerve stimulation (CVNS). The conditional overexpression of HCN4 did not induce tachycardia, but reduced heart rate variability. The HCN4 overexpression also attenuated bradycardia induced by the CVNS only during the ß-adrenergic stimulation. In contrast, the knockdown of HCN4 gave rise to sinus arrhythmia, and enhanced the parasympathetic response; complete sinus pause was induced by the CVNS. In vitro, we compared the effects of acetylcholine on the spontaneous action potentials of single pacemaker cells, and found that similar phenotypic changes were induced by genetic manipulation of HCN4 expression both in the presence and absence of ß-adrenergic stimulation. Our study suggests that HCN4 channels attenuate the vagal response of the SAN, and thereby stabilize the spontaneous firing of the SAN.

Effectiveness of cadaver-based educational seminar for trauma surgery: skills retention after half-year follow-up.

Aim: In Japan, trauma surgery training remains insufficient, and on-the-job training has become increasingly difficult because of the decreasing number of severe trauma patients and the development of non-operative management. Therefore, we assessed whether a 1-day cadaver-based seminar is effective for trauma surgery training. Methods: Data were collected from 11 seminars carried out from January 2013 to March 2014, including a 10-point self-assessment of confidence levels (SACL) for 21 surgical skills and an evaluation of the contents before, just after, and a half-year after the seminar. Statistical analysis was undertaken using the paired t-test at P < 0.0167. Results: A total of 135 participants were divided into three groups based on experience and clinical careers. The SACL improved in all skills between before and just after the seminar, however, they decreased between just after and a half-year after the seminar. The SACL did not change significantly in all skills between just after and a half-year after the seminar in highly experienced and experienced group members belonging to an emergency center. Conclusions: A cadaver-based seminar provided more self-confidence just after the seminar for participants at all experience levels. This effect was not maintained after a half-year, except in participants who can practice the skills at an emergency center. Practicing and participating in the seminar repeatedly is suggested to be effective for skills retention in trauma surgery.

Fractional laser-assisted percutaneous drug delivery via temperature-responsive liposomes.

Liposomes are used for transdermal delivery of drugs and vaccines. Our objective was to develop temperature-responsive (TR) liposomes to achieve temperature-dependent, controlled release of an encapsulated drug, and use fractional laser irradiation to enhance transdermal permeability of these liposomes. TR-liposomes prepared using a thermosensitive polymer derived from poly-N-isopropylacrylamide, N,N-dimethylacrylamide, egg phosphatidylcholine, and dioleoylphosphatidylethanolamine, delivered fluorescein isothiocyanate-conjugated ovalbumin (OVA-FITC) as a model drug. Effect of temperature on liposome size and drug release rate was estimated at two temperatures. Transdermal permeation through hairless mouse skin, with and without CO2 fractional laser irradiation, and penetration into Yucatan micro-pig skin were investigated using Franz cell and fluorescence microscopy. Dynamic light scattering showed that mean liposome diameter nearly doubled from 190 to 325 nm between 37 and 50 °C. The rate and amount of OVA-FITC released from TR-liposomes were higher at 45 °C that those at 37 °C. Transdermal permeation of OVA-FITC across non-irradiated skin from both TR- and unmodified liposomes was minimal at 37 °C, but increased at 45 °C. Laser irradiation significantly increased transdermal permeation of both liposome groups at both temperatures. Fluorescence microscopy of frozen biopsy specimens showed deeper penetration of FITC from unmodified liposomes compared to that from polymer-modified liposomes. Rhodamine accumulation was not observed with polymer-modified liposomes at either temperature. Temperature-dependent controlled release of an encapsulated drug was achieved using the TR-liposomes. However, TR-liposomes showed lower skin permeability despite higher hydrophobicity. Fractional laser irradiation significantly increased the transdermal permeation. Additional studies are required to control liposome size and optimize transdermal permeation properties.

Elderly-onset hereditary pulmonary alveolar proteinosis and its cytokine profile.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by surfactant accumulation, and is caused by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. Abnormalities in CSF2 receptor alpha (CSF2RA) were reported to cause pediatric hereditary PAP. We report here the first case of CSF2RA-mutated, elderly-onset hereditary (h) PAP. CASE PRESENTATION: The patient developed dyspnea on exertion, and was diagnosed with PAP at the age of 77 years, based on findings from chest computed tomography scan and bronchoalveolar lavage. She tested negative for GM-CSF autoantibodies, with no underlying disease. Her serum GM-CSF level was elevated (91.3 pg/mL), indicating GM-CSF signaling impairment and genetic defects in the GM-CSF receptor. GM-CSF-stimulated phosphorylation in signal transducer and activator of transcription 5 (STAT5) was not observed, and GM-CSF-Rα expression was defective in her blood cells. Genetic screening revealed a homozygous, single-base C > T mutation at nt 508-a nonsense mutation that yields a stop codon (Q170X)-in exon 7 of CSF2RA. High-resolution analysis of single nucleotide polymorphism array confirmed a 22.8-Mb loss of heterozygosity region in Xp22.33p22.11, encompassing the CSF2RA gene. She was successfully treated with whole lung lavage (WLL), which reduced the serum levels of interleukin (IL)-2, IL-5, and IL-17, although IL-3 and M-CSF levels remained high. CONCLUSIONS: This is the first known report of elderly-onset hPAP associated with a CSF2RA mutation, which caused defective GM-CSF-Rα expression and impaired signaling. The analyses of serum cytokine levels during WLL suggested that GM-CSF signaling might be compensated by other signaling pathways, leading to elderly-onset PAP.