A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody.

BACKGROUND: An important unmet need for new treatment options remains for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) previously treated with both platinum-based chemotherapy and anti-programmed cell death protein 1 (PD-1) antibody. Retrospective studies suggest that previous treatment with immune checkpoint inhibitor might augment the efficacy of subsequent chemotherapy. Here, we conducted a phase II trial aimed to evaluate the efficacy and safety of paclitaxel plus biweekly cetuximab for patients in this setting. PATIENTS AND METHODS: This was a single-arm, multicenter, phase II trial. Key eligibility criteria were R/M-HNSCC, and previous treatment with both platinum-based chemotherapy and PD-1 antibody. Paclitaxel plus biweekly cetuximab consisted of weekly paclitaxel 100 mg/m2 (days 1, 8, 15) and biweekly cetuximab 500 mg/m2 (days 1, 15) with a cycle of 28 days until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) (Common Terminology Criteria for Adverse Events version 5.0). RESULTS: Between August 2020 and August 2022, 35 patients were enrolled, of whom 33 were assessable for response. ORR was 69.6% (95% confidence interval 51.2% to 84.4%). With a median follow-up period for survivors of 16.6 months, median PFS and OS were 5.5 and 13.3 months, respectively. DCR was 93.7%. Twenty-three patients (65%) experienced grade 3 or 4 AEs, including neutropenia (34%), infection (14%), leukopenia (11%), mucositis (8%), and pneumonitis (8%). Eight patients discontinued study treatment due to treatment-related AEs, and no treatment-related death was observed. CONCLUSIONS: Paclitaxel plus biweekly cetuximab showed highly encouraging efficacy and manageable toxicities in R/M-HNSCC patients previously treated with both platinum-based chemotherapy and PD-1 antibody. This combination therapy warrants further investigation in this setting.

Measurements of neutrino oscillation parameters from the T2K experiment using 3.6×1021 protons on target.

The T2K experiment presents new measurements of neutrino oscillation parameters using 19.7(16.3)×1020 protons on target (POT) in (anti-)neutrino mode at the far detector (FD). Compared to the previous analysis, an additional 4.7×1020 POT neutrino data was collected at the FD. Significant improvements were made to the analysis methodology, with the near-detector analysis introducing new selections and using more than double the data. Additionally, this is the first T2K oscillation analysis to use NA61/SHINE data on a replica of the T2K target to tune the neutrino flux model, and the neutrino interaction model was improved to include new nuclear effects and calculations. Frequentist and Bayesian analyses are presented, including results on sin2θ13 and the impact of priors on the δCP measurement. Both analyses prefer the normal mass ordering and upper octant of sin2θ23 with a nearly maximally CP-violating phase. Assuming the normal ordering and using the constraint on sin2θ13 from reactors, sin2θ23=0.561-0.032+0.021 using Feldman-Cousins corrected intervals, and Δm322=2.494-0.058+0.041×10-3eV2 using constant Δχ2 intervals. The CP-violating phase is constrained to δCP=-1.97-0.70+0.97 using Feldman-Cousins corrected intervals, and δCP=0,π is excluded at more than 90% confidence level. A Jarlskog invariant of zero is excluded at more than 2σ credible level using a flat prior in δCP, and just below 2σ using a flat prior in sinδCP. When the external constraint on sin2θ13 is removed, sin2θ13=28.0-6.5+2.8×10-3, in agreement with measurements from reactor experiments. These results are consistent with previous T2K analyses.

A multi-centre, retrospective case series of oocyte cryopreservation in unmarried women diagnosed with haematological malignancies.

STUDY QUESTION: Is oocyte cryopreservation an applicable option for fertility preservation in unmarried patients with haematological malignancies? SUMMARY ANSWER: Oocyte cryopreservation via the vitrification method is accessible and may be considered an option for fertility preservation in unmarried patients with haematological malignancies. WHAT IS KNOWN ALREADY: Haematological malignancies are most commonly observed amongst adolescent and young adult women. Although the survival rate and life expectancy of those with haematological malignancies have improved, chemotherapy and radiotherapy may impair their reproductive potential. Oocyte cryopreservation is thus an ideal option to preserve their fertility. STUDY DESIGN SIZE DURATION: This study retrospectively evaluated 193 unmarried patients (age: 26.2 ± 0.4 years) with haematological malignancies, who consulted for oocyte cryopreservation across 20 different fertility centres in Japan between February 2007 and January 2015. The primary outcome measures were the oocyte retrievals and oocyte cryopreservation outcomes. The secondary outcome measures were the outcomes following oocyte warming for IVF. PARTICIPANTS/MATERIALS SETTING METHODS: The patients had commenced ovarian stimulation cycles via antagonist, agonist, natural and minimal methods for oocyte retrievals, defined according to the treatment strategy of each respective fertility centre. A vitrification method using the Cryotop safety kit was used for oocyte cryopreservation. ICSIs were used for insemination of warmed oocytes. The endometrial preparation method for embryo transfer was hormonal replacement therapy, except in the case of a patient who underwent a spontaneous ovulatory cycle. MAIN RESULTS AND THE ROLE OF CHANCE: Among 193 patients, acute myeloid leukaemia (n = 45, 23.3%) was most common, followed by acute lymphoid leukaemia (n = 38, 19.7%) and Hodgkin's lymphoma (n = 30, 15.5%). In total, 162 patients (83.9%) underwent oocyte retrieval, and oocytes were successfully cryopreserved for 155 patients (80.3%). The mean number of oocyte retrieval cycles and cryopreserved oocytes were 1.7 ± 0.2 and 6.3 ± 0.4, respectively. As of December 2019, 14 patients (9.2%) had requested oocyte warming for IVF. The survival rate of oocytes after vitrification-warming was 85.2% (75/88). The rates of fertilisation and embryo development were 80.0% (60/75) and 46.7% (28/60), respectively. Ten patients (71.4%) had successful embryo transfers, and seven live births (50.0%) were achieved. LIMITATIONS REASONS FOR CAUTION: This study was limited by its retrospective nature. Additionally, there remains an insufficient number of cases regarding the warming of vitrified oocytes to reliably conclude whether oocyte cryopreservation is effective for patients with haematological malignancies. Further long-term follow-up study is required. WIDER IMPLICATIONS OF THE FINDINGS: Oocyte retrieval and oocyte cryopreservation were accessible for patients with haematological malignancies; however, the number of oocyte retrievals may have been limited due to the initiation of cancer treatments. Acceptable embryonic and pregnancy outcomes could be achieved following oocyte warming; therefore, our results suggest that oocyte cryopreservation can be considered an option for fertility preservation in patients with haematological malignancies. STUDY FUNDING/COMPETING INTERESTS: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

"Bridging, brokering, and buffering": a theoretical exploration of school leaders' engagement with local school wellness policy implementation.

BACKGROUND: The Healthy, Hunger-Free Kids Act of 2010 (P.L. 111-296) prompted the expansion of federal requirements for local school wellness policies, which aim to improve health promoting practices across school districts in the USA. This qualitative study examined how school district superintendents-as key school leaders who are often listed as the district accountability figure for wellness policies applicable to kindergarten through 12th grade-engaged with wellness policy implementation. The inquiry was guided by evidence-informed implementation and leadership frameworks, including the Consolidated Framework for Implementation Research (CFIR) and "bridging, buffering, and brokering" strategies from education leadership theory. METHODS: We conducted focus groups and interviews with superintendents (n = 39) from 23 states. Interviews were recorded and professionally transcribed; transcripts were team-coded in Atlas.ti v8 using an iteratively revised coding guide that was informed by CFIR, pilot testing, and during weekly analyst meetings. Principles of constant comparative analysis were employed to develop themes. RESULTS: Most superintendents' reported positive perspectives and personal motivations to engage with wellness policy implementation. Within the CFIR process domain, superintendents demonstrated adaptive leadership traits and employed a combination of "bridging, buffering, and brokering" strategies to lead implementation activities. Rather than focus on personal traits, an emphasis on specific strategies highlights actions that may be applied. CONCLUSIONS: The findings offer practical strategies to support superintendents with implementation, as well as a formative contribution to the dearth of theoretical frameworks in school wellness literature, particularly by advancing the specific understanding of leadership roles within a broader implementation framework. The application of education theory allowed for a deeper inquiry into the potential ways that leaders' strategies and engagement influences implementation more broadly.

Search for Electron Antineutrino Appearance in a Long-Baseline Muon Antineutrino Beam.

Electron antineutrino appearance is measured by the T2K experiment in an accelerator-produced antineutrino beam, using additional neutrino beam operation to constrain parameters of the Pontecorvo-Maki-Nakagawa-Sakata (PMNS) mixing matrix. T2K observes 15 candidate electron antineutrino events with a background expectation of 9.3 events. Including information from the kinematic distribution of observed events, the hypothesis of no electron antineutrino appearance is disfavored with a significance of 2.40σ and no discrepancy between data and PMNS predictions is found. A complementary analysis that introduces an additional free parameter which allows non-PMNS values of electron neutrino and antineutrino appearance also finds no discrepancy between data and PMNS predictions.

Characterization of Carotid Plaque Components by Quantitative Susceptibility Mapping.

BACKGROUND AND PURPOSE: Intraplaque hemorrhage in the carotid artery is related to an increased risk of cerebrovascular ischemic events. We aimed to investigate whether quantitative susceptibility mapping can characterize carotid artery plaque components and quantify the severity of intraplaque hemorrhage. MATERIALS AND METHODS: For this ex vivo quantitative susceptibility mapping study, 9 carotid endarterectomy specimens were imaged on a 3T MR imaging scanner using a 3D multi-echo gradient-echo sequence and a microscopy coil. The samples were examined histologically using immunostains, including glycophorin A and Prussian blue. The areas of erythrocytes, iron deposits, calcification, and fibrous matrices observed on stained sections were compared with quantitative susceptibility mapping findings and their mean susceptibility values. RESULTS: Intraplaque hemorrhage and iron deposits were observed only in areas hyperintense on quantitative susceptibility mapping; calcifications and fibrous matrices were prevalent in hypointense areas. The mean susceptibility values for necrotic cores with intraplaque hemorrhage but no iron deposits, cores with iron deposits but no intraplaque hemorrhage, cores without either intraplaque hemorrhage or iron deposits, and cores with calcification were 188 ± 51, 129 ± 49, -11 ± 17, and -158 ± 78 parts per billion, respectively. There was a significant difference in the mean susceptibility values among the 4 histologic components (P < .01). The mean susceptibility values of the whole plaque positively correlated with the percentage area positive for glycophorin A (r = 0.65, P < .001) and Prussian blue (r = 0.47, P < .001). CONCLUSIONS: Our findings suggest that quantitative susceptibility mapping can characterize the composition of carotid plaques and quantify the degree of intraplaque hemorrhage and iron deposits.

When is a randomised controlled trial health equity relevant? Development and validation of a conceptual framework.

BACKGROUND: Randomised controlled trials can provide evidence relevant to assessing the equity impact of an intervention, but such information is often poorly reported. We describe a conceptual framework to identify health equity-relevant randomised trials with the aim of improving the design and reporting of such trials. METHODS: An interdisciplinary and international research team engaged in an iterative consensus building process to develop and refine the conceptual framework via face-to-face meetings, teleconferences and email correspondence, including findings from a validation exercise whereby two independent reviewers used the emerging framework to classify a sample of randomised trials. RESULTS: A randomised trial can usefully be classified as 'health equity relevant' if it assesses the effects of an intervention on the health or its determinants of either individuals or a population who experience ill health due to disadvantage defined across one or more social determinants of health. Health equity-relevant randomised trials can either exclusively focus on a single population or collect data potentially useful for assessing differential effects of the intervention across multiple populations experiencing different levels or types of social disadvantage. Trials that are not classified as 'health equity relevant' may nevertheless provide information that is indirectly relevant to assessing equity impact, including information about individual level variation unrelated to social disadvantage and potentially useful in secondary modelling studies. CONCLUSION: The conceptual framework may be used to design and report randomised trials. The framework could also be used for other study designs to contribute to the evidence base for improved health equity.

Microvascular proliferation of brain metastases mimics glioblastomas in squash cytology.

OBJECTIVE: Although microvascular proliferation is a key feature in the diagnosis of high-grade glioma, the characteristics of metastatic tumour vessels in smear preparations have not been documented. In this study, the vascular changes in metastatic brain tumours, using squash cytology to examine the vascular patterns in brain metastases, were reviewed. METHODS: One hundred and forty-three squash smears of brain tissue, including 25 normal or reactive tissue, 23 malignant lymphomas, 8 grade I glioma (pilocytic astrocytoma), 23 grade II glioma (diffuse astrocytoma and oligodendroglioma), 42 grade IV glioma (glioblastoma), and 22 metastasis, were assessed. Two vascular patterns were assessed: thick and branching, and glomeruloid. The vessel density, nuclear layer and the number of vessel branches were compared. Furthermore, tumour vessels of brain metastases were analysed by histology and for immunohistochemical expression of CD34, α-smooth muscle actin (SMA) and high-molecular-weight caldesmon (h-CD). RESULTS: Among 22 metastatic tumours, thick and branching vessels were found in 17 (77%) and glomeruloid vessels in 13 (59%). These incidences of microvascular proliferation patterns were similar to those of glioblastomas or pilocytic astrocytomas. Vessel density, nuclear layer and vessel wall branches were significantly higher in metastatic tumours than malignant lymphomas, grade II gliomas or normal brain tissues. Glomeruloid vessels consisted of CD34-positive cells and α-SMA-positive cells, and α-SMA-positive cells had a low h-CD expression. These immunohistochemical patterns were similar to those of high-grade gliomas. CONCLUSIONS: The vascular features of metastatic brain tumours are similar to those of glioblastomas, suggesting that these microvascular proliferations contribute to the progression of metastatic tumours.

Oxyntomodulin analog and exendin-4 derivative lower plasma glucose in cattle.

The present study was undertaken with the aim of examining whether and how exendin-4 (1-3) fragment, ie, Ex-4 (1-3) fragment, contributes to the regulation of glucose. An analog of oxyntomodulin (OXM) ([Gly2, Glu3]-OXM), a glucagon analog ([Gly2, Glu3]-glucagon), and two derivatives of Ex-4 (glucandin and [Gly2, Glu3]-glucandin) were synthesized by substituting with Gly2, Glu3 at the N-terminuses of OXM and glucagon and/or by attaching Ex-4 (30-39) amide at the C-terminus of glucagon. Effects of these peptides on plasma insulin and glucose concentrations were investigated in cattle by conducting 3 in vivo experiments. In all 3 experiments, 0.1% BSA saline was injected as a control. In experiment 1, glucandin (amino acid sequence was glucagon [1-29]-Ex-4 [30-39] amide) and [Gly2, Glu3]-glucandin were injected at the dose rates of 5 µg/kg BW in 4-mo-old Holstein steers. Results showed that glucoregulatory effects of glucandin were similar to those of glucagon. [Gly2, Glu3]-glucandin stimulated insulin secretion at 2 to 10 min and lowered glucose concentrations at 15 to 75 min. Experiment 2 was carried out to better understand the glucose-lowering potency of [Gly2, Glu3]-glucandin, in comparison with Ex-4 and glucagon-like peptide-1 (GLP-1), using 4.5-mo-old Holstein steers. [Gly2, Glu3]-glucandin was injected at dose rates of 0.3 µg/kg BW, 1.0 µg/kg BW, 3.2 µg/kg BW, and 6.4 µg/kg BW. Ex-4 and GLP-1 were injected at dose rates of 0.3 µg/kg BW. Results showed that the insulinotropic and glucose-lowering effects of [Gly2, Glu3]-glucandin were not as potent as for Ex-4 and GLP-1, and the minimum effective dose of [Gly2, Glu3]-glucandin to regulate plasma glucose concentrations was 3.2 µg/kg BW. In experiment 3, [Gly2, Glu3]-OXM and [Gly2, Glu3]-glucagon were injected at dose rates of 5 µg/kg BW in 5-mo-old Holstein steers. Both [Gly2, Glu3]-OXM and [Gly2, Glu3]-glucagon increased insulin concentration. [Gly2, Glu3]-OXM potently lowered plasma glucose, but [Gly2, Glu3]-glucagon did not change it. In summary, our findings clearly demonstrate that Ex-4 (1-3) fragment contributes to the regulation of glucose. [Gly2, Glu3]-OXM and [Gly2, Glu3]-glucandin are insulinotropic and glucose-lowering peptides. It was of interest that the substitution of the first 3 amino acids of OXM with Ex-4 (1-3) could reverse the upregulation of glucose by OXM into downregulation of glucose. In lowering glycemia, [Gly2, Glu3]-OXM seemed almost as effective as Ex-4, and [Gly2, Glu3]-glucandin was less profound than Ex-4. These findings contributed new insights into the hormonal regulation of glucose in ruminants. The action of [Gly2, Glu3]-OXM and [Gly2, Glu3]-glucandin might provide an advantage in glycemic control of insulin resistance in cattle and humans.

Immunocytochemistry for Claudin-18 and Maspin in biliary brushing cytology increases the accuracy of diagnosing pancreatobiliary malignancies.

OBJECTIVE: Biliary brush cytology is an important diagnostic tool in the evaluation of pancreatobiliary malignancies. However, it is difficult to distinguish between malignant and benign cells. The present study evaluated the utility of immunocytochemical expression of Claudin-18 and Maspin in brushing cytology specimens of pancreatobiliary lesions in the diagnosis of pancreatobiliary malignancies. METHODS: The study retrospectively assessed biliary and pancreatic duct brushing cytology specimens of 43 patients whose pancreatobiliary lesions were histologically diagnosed at the University of Miyazaki Hospital. Scanty cellularity slides and cases with no histological confirmation were excluded. Alcohol-fixed and Papanicolaou-stained slides were immunostained with monoclonal antibodies to Claudin-18 and Maspin. RESULTS: Of the 43 patients, 35 (81.4%) were finally histologically diagnosed with invasive adenocarcinomas. The sensitivity of routine cytology for the detection of malignancy was 63%, and the specificity was 100%. The sensitivity of cytology in combination with immunocytochemical expression of Claudin-18 (89%) or Claudin-18 and/or Maspin (97%) was significantly higher than that of cytology alone (P < 0.01). CONCLUSION: Immunocytochemical staining for Claudin-18 and Maspin improved the diagnostic sensitivity for pancreatobiliary adenocarcinomas.

Survey of patient exposure from general radiography and mammography in Japan in 2014.

With the objective of reducing patient exposure to radiation, we conducted a questionnaire survey regarding radiographic conditions in 2014. Here we report estimates of dose exposure in general radiography and mammography through an investigation and comparison of present patient exposure conditions. Questionnaires were sent to 3000 facilities nationwide in Japan. Surveys asked questions on a total of 16 items related to general radiography, including the chest, abdomen, and breast. Output data from x-ray tubes measured in the Chubu area of Japan were used as the mean in these estimates. The index of patient exposure was adopted as the entrance skin dose (ESD) for general radiography and as the mean glandular dose (MGD) for mammography. The response rate for this survey was 21.9%. Our results showed that doses received through the use of flat-panel detector (FPD) devices were lower than those received through computed radiography devices, except for the ankle joint (e.g. in chest examination, the dose from FPD and CR was 0.24 mGy, 0.31 mGy on the average, respectively). These results suggest that more widespread use of FPD devices could lead to decreases in the ESD and MGD, thereby reducing patient exposure.

Human papilloma virus detection in oropharyngeal cancer with gargle samples.

Human papilloma virus detection in oropharyngeal cancer with gargle samples. OBJECTIVE: human papilloma virus (HPV) is a major risk factor for oropharyngeal squamous cell carcinoma (OPSCC) and knowledge of a patient's HPV status is clinically important in terms of treatment and prognosis. The practicality of using oral gargle samples to reliably detect HPV in patients with OPSCC remains unclear. Therefore, we evaluated the feasibility of HPV detection in gargle samples of OPSCC patients using an HPV-dedicated nucleic acid amplification test (cobas 4800 HPV Test; Roche Diagnostics K.K.). METHODOLOGY: 15 patients with histologically proven OPSCC were evaluated from May 2014 to March 2015. Swab sam- ples served as positive controls and were tested using both the Hybrid Capture II HPV Test (HC-II; Digene Corporation) and the cobas 4800 HPV Test. Oral gargle samples were tested using the cobas 4800 HPV Test. Five of the 15 patients were confirmed to be HPV-positive by a combination of p16 immunohistochemistry, HPV-DNA in situ hybridization and nucleic acid amplification. RESULTS: the sensitivity and specificity of the gargling method were 60% and 100%, respectively. No false-positives were obtained. Detection of HPV in two very small tumours rising from the base of the tongue was difficult and these cases were overlooked as HPV-negative. CONCLUSIONS: use of the gargling method to determine HPV positivity in OPSCC patients appears feasible, except in patients with very small tumours. Real-time polymerase chain reaction using gargle samples may have greater clinical efficacy than the swabbing method.

Survey of volume CT dose index in Japan in 2014.

OBJECTIVE: The aims of this study are to propose a new set of Japanese diagnostic reference levels (DRLs) for 2014 and to study the impact of tube voltage and the type of reconstruction algorithm on patient doses. The volume CT dose index (CTDI(vol)) for adult and paediatric patients is assessed and compared with the results of a 2011 national survey and data from other countries. METHODS: Scanning procedures for the head (non-helical and helical), chest and upper abdomen were examined for adults and 5-year-old children. A questionnaire concerning the following items was sent to 3000 facilities: tube voltage, use of reconstruction algorithms and displayed CTDI(vol). RESULTS: The mean CTDI(vol) values for paediatric examinations using voltages ranging from 80 to 100 kV were significantly lower than those for paediatric examinations using 120 kV. For adult examinations, the use of iterative reconstruction algorithms significantly reduced the mean CTDI(vol) values compared with the use of filtered back projection. Paediatric chest and abdominal scans showed slightly higher mean CTDI(vol) values in 2014 than in 2011. The proposed DRLs for adult head and abdominal scans were higher than those reported in other countries. CONCLUSION: The results imply that further optimization of CT examination protocols is required for adult head and abdominal scans as well as paediatric chest and abdominal scans. ADVANCES IN KNOWLEDGE: Low-tube-voltage CT may be useful for reducing radiation doses in paediatric patients. The mean CTDI(vol) values for paediatric scans showed little difference that could be attributed to the choice of reconstruction algorithm.

Osteoprotegerin is secreted into the coronary circulation: a possible association with the renin-angiotensin system and cardiac hypertrophy.

The circulating osteoprotegerin (OPG) level reflects a series of cardiovascular diseases; however, the source(s) of circulating OPG remain(s) to be determined. This study explored whether OPG is released in the coronary circulation and whether it is associated with cardiac structure and function. Fifty-six patients (67±10 years old, male 57%, hypertension 73%, coronary artery disease 50%) were enrolled, and blood samples were collected simultaneously from the orifice of the left coronary artery (CA) and the coronary sinus (CS) after angiography. The concentration of OPG was higher in the CS than in the CA (7.7±4.1 vs. 6.7±3.6 pmol/l, p<0.001). The trans-cardiac OPG concentration was significantly (p=0.019) decreased in patients who have been prescribed either an angiotensin converting enzyme inhibitor or an angiotensin II type 1 receptor blocker (ACEI/ARB). In patients subgroup who did not take an ACEI/ARB (n=27), the trans-cardiac OPG level was positively correlated with age (r=0.396, p=0.041) and relative wall thickness of left ventricle (r=0.534, p=0.004). In multivariate linear regression analysis, relative wall thickness remained to be the independent variable for the trans-cardiac OPG level (p=0.004). Moreover, trans-cardiac OPG was significantly (p=0.021) increased in patients with relative wall thickness greater than 0.45 but it did not differ if the left ventricular mass index was increased (≥116 for males, or ≥ 104 for females, g/m(2)) or not (p=0.627). This study suggests that OPG is secreted into the coronary circulation and is associated with concentric remodeling/hypertrophy of LV, possibly in interactions with the renin-angiotensin system.

Results of a 2011 national questionnaire for investigation of mean glandular dose from mammography in Japan.

Diagnostic reference levels (DRLs) for mammography have yet to be created in Japan. A national questionnaire investigation into radiographic conditions in Japan was carried out for the purpose of creating DRLs. Items investigated included the following: tube voltage; tube current; current-time product; source-image distance; craniocaudal view; automatic exposure control (AEC) settings; name of mammography unit; image receptor system (computed radiography (CR), flat panel detector (FPD), or film/screen (F/S)); and supported or unsupported monitor diagnosis (including monitor resolution). Estimation of the mean glandular dose (MGD) for mammography was performed and compared with previous investigations. The MGD was 1.58(0.48) mGy, which did not significantly differ from a 2007 investigation. In relation to image receptors, although no difference in average MGD values was observed between CR and FPD systems, F/S systems had a significantly decreased value compared to both CR and FPDs. Concerning digital systems (FPDs), the MGD value of the direct conversion system was significantly higher than the indirect conversion system. No significant difference in MGD value was evident concerning type of monitor diagnosis for either the CR or the FPD digital systems; however, hard copies were used more often in CR. No significant difference in the MGD value was found in relation to monitor resolution. This report suggests ways to lower the doses patients undergoing mammography receive in Japan, and serves as reference data for 4.2 cm compressed breast tissue of 50% composition DRLs. Furthermore, our findings suggest that further optimisation of FPD settings can promote a reduction in the MGD value.

Divergence of repetitive DNA sequences in the heterochromatin of medaka fishes: Molecular cytogenetic characterization of constitutive heterochromatin in two medaka species: Oryzias hubbsi and O. celebensis (Adrianichthyidae, Beloniformes).

The large biarmed chromosomes of Oryzias celebensis [2n = 36, fundamental arm number (FN) = 48] are considered to have resulted from fusions of acrocentric chromosomes in the ancestral karyotype of Oryzias, which is retained in O. hubbsi (2n = 48, FN = 48). To understand the molecular evolution of heterochromatin associated with karyotype reorganization in medaka fishes, we cloned 3 and 6 novel families of heterochromatin-related repetitive DNA sequences from O. hubbsi and O. celebensis, respectively, and characterized them using molecular cytogenetics. Two AT-rich repetitive sequences isolated from the genomic DNA of O. hubbsi, a 164-bp satellite DNA (OHU-RsaI-Scen) and a 177-bp telomere-specific repeat (OHU-RsaI-Stelo), were shown to be major components of the constitutive heterochromatin of centromeres and telomeres, respectively. A GC-rich 326-bp sequence, named OHU-AluI-M1, was colocalized with the 18S-28S ribosomal RNA gene cluster to a single autosomal pair of chromosomes and the W chromosome. In O. celebensis, 2 major satellite DNA sequences (the AT-rich 157-bp OCE-AluI-Scen sequence and the 186-bp OCE-HinfI-Scen sequence) were identified in the centromeric regions of almost all chromosomes. The 197-bp OCE-HinfI-S6 sequence was located in the centromeric and distal and/or interstitial heterochromatin of almost all chromosomes, and the 191-bp OCE-HinfI-S8 sequence was located in 6 pairs of chromosomes. Constitutive heterochromatin on the short arm of large submetacentric chromosome 5 was composed of at least 3 different repetitive sequences: the 171-bp OCE-AluI-S18 sequence, the 197-bp OCE-HinfI-S6 sequence and the 172-bp OCE-HinfI-S11 sequence. All families of repeated sequences showed no nucleotide sequence similarity with each other and high species-specificity among 7 different species. These results suggest that the heterochromatin of O. hubbsi and O. celebensis consists of various types of repetitive sequence and that the sequences evolved independently and were then amplified site-specifically in each lineage after karyotype reorganization occurred in the ancestral karyotype.

Role of occlusion in masseter muscle acetylcholine receptor clustering.

Nicotinic acetylcholine receptor (nAChR) clustering is a key event in the synaptogenesis of the neuromuscular junction (NMJ) for the efficient transmission of neural signals from motor neurons to skeletal muscle. The microphthalmic mouse (mi/mi) with a mutation in the mitf gene cannot perform occlusion, because its teeth do not erupt. The present study attempted to elucidate the contribution of occlusion to the clustering of nAChR in the NMJ of the masseter, with mi/mi as a model system. In mice at 1 week of age, no significant change in the fragmentation or volume of the nAChR cluster was observed in either the masseter or gastrocnemius between breast-fed +/+ and mi/mi. In mice at 4 and 12 weeks of age, after the occlusion emerged in the +/+, excessive fragmentation and volume decline in the nAChR cluster were observed in the masseter of mi/mi fed a powdered diet compared with +/+ fed a pellet or powdered diet, whereas, in the gastrocnemius, no such differences were observed between the 2 strains. These results indicate abnormal formation of the nAChR cluster in the NMJ of the masseter of mi/mi, suggesting that occlusion is essential for the normal progress of nAChR clustering in the NMJ of the masseter.

Oxyntomodulin attenuates exendin-4-induced hypoglycemia in cattle.

Oxyntomodulin (OXM), glucagon, glucagon-like peptide-1 (GLP-1), and exendin-4 (Ex-4) are peptide hormones that regulate glucose homeostasis in monogastric and ruminant animals. Recently, we reported that the insulin-releasing effects of OXM and glucagon in cattle are mediated through both GLP-1 and glucagon receptors. The purpose of this study was to examine the mechanisms of the glucoregulatory actions induced by Ex-4, GLP-1, OXM, and glucagon and the interrelationships among these hormones in cattle. Two experiments were performed in Holstein cattle. In Experiment 1, we initially assessed the effects of intravenous (iv) bolus injection of 0, 0.25, 1, and 2 µg/kg body weight (BW) of Ex-4, GLP-1, and OXM on insulin and glucose concentrations in 3-mo-old intact male Holstein calves. In Experiment 2, we studied insulin and glucose responses to iv coinjection of 0.25 µg of Ex-4 or GLP-1/kg BW with 2 µg of OXM or glucagon/kg BW in 4-mo-old Holstein steers. Administration of peptides and blood sampling were done via a jugular catheter. Plasma was separated and the concentrations of peptides and glucose in plasma were analyzed using radioimmunoassay and enzymatic methods, respectively. Results showed that the potent glucoregulatory action of Ex-4 in 4-mo-old steers was delayed and attenuated when Ex-4 was coinjected with OXM. The decline in plasma glucose concentrations began at 5 min in the Ex-4-injected group (P < 0.05) vs 15 min in the Ex-4 + OXM-injected group (P < 0.05). Plasma concentrations of glucose at 30 min were reduced 26% from basal concentrations in the Ex-4-injected group and 13% in the Ex-4 + OXM-injected group (P < 0.001). Results also showed that the glucose concentrations initially increased in the Ex-4 + glucagon-treated group, but declined to a relatively hypoglycemic condition by 90 to 120 min. In contrast, the glucose concentrations at specific time points between the GLP-1 + OXM-injected group and the OXM-injected group did not differ. Similarly, the glucose concentrations in the GLP-1 + glucagon-injected group did not differ from those in the glucagon-injected group. Because OXM and glucagon mediate glucose concentrations via the glucagon receptor, it is suggested that the potent glucose-lowering action of Ex-4 might include the glucagon receptor antagonistic action of Ex-4.

Associations of intrauterine growth restriction with placental pathological factors, maternal factors and fetal factors; clinicopathological findings of 257 Japanese cases.

Intrauterine growth restriction (IUGR) is the leading cause of fetal mortality and morbidity. As an etiology, each of placental findings, maternal factors and fetal factors has been reported to be associated with IUGR, although a comprehensive approach to examine all of these parameters as a cause of IUGR has not been reported. In the present study, therefore, we comprehensively examined the placental findings and maternal and fetal factors in the cases of IUGR (n=257, mean maternal age, 30 years; gestational weeks, 34 weeks) and normal growth pregnancies (n=258, mean maternal age, 30 years; gestational weeks, 33 weeks), and determined risk factors for IUGR. The prevalence of pregnancy hypertension (PHT) (19% vs. 8%, P<0.01), smoking habit (3% vs. 0.7%, P<0.05) and fetal anomaly (3.5% vs. 0.8%, P<0.05) were higher in IUGR cases than normal growth pregnancies. Pathologically, the prevalence of infarction (33% vs. 14%, P<0.05), fetal vessel thrombosis (22% vs. 6%, P<0.001) and chronic villitis (11% vs. 3%, P<0.001) were higher in IUGR cases than those in normal growth pregnancies. A multivariable regression analysis revealed that maternal factors (PHT), fetal factors (anomaly), and placental findings (infarction, fetal vessel thrombosis, and chronic villitis) are independently associated with increased risk of IUGR (all P<0.01).

Clinical significance of CADM1/TSLC1/IgSF4 expression in adult T-cell leukemia/lymphoma.

Cell adhesion molecule 1 (CADM1/TSLC1) was recently identified as a novel cell surface marker for adult T-cell leukemia/lymphoma (ATLL). In this study, we developed various antibodies as diagnostic tools to identify CADM1-positive ATLL leukemia cells. In flow cytometric analysis, the percentages of CD4(+)CADM1(+) double-positive cells correlated well with both the percentages of CD4(+)CD25(+) cells and with abnormal lymphocytes in the peripheral blood of patients with various types of ATLL. Moreover, the degree of CD4(+)CADM1(+) cells over 1% significantly correlated with the copy number of the human T-lymphotropic virus type 1 (HTLV-1) provirus in the peripheral blood of HTLV-1 carriers and ATLL patients. We also identified a soluble form of CADM1 in the peripheral blood of ATLL patients, and the expression levels of this form were correlated with the levels of soluble interleukin 2 receptor alpha. Moreover, lymphomas derived from ATLL were strongly and specifically stained with a CADM1 antibody. Thus, detection of CD4(+)CADM1(+) cells in the peripheral blood, measurement of serum levels of soluble CADM1 and immunohistochemical detection of CADM1 in lymphomas would be a useful set of markers for disease progression in ATLL and may aid in both the early diagnosis and measurement of treatment efficacy for ATLL.