Safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies.

PURPOSE: Immune checkpoint inhibitors (ICIs) show promising clinical activity in advanced cancers. However, the safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies (ANA) are unclear. METHODS: 191 patients treated with nivolumab, pembrolizumab, atezolizumab, or durvalumab for unresectable advanced cancers between September 2014 and December 2018 were identified retrospectively. Patients were divided into positive (ANA titers ≥ 1:160) and negative ANA groups (ANA titers < 1:160). Development of immune-related adverse events (irAEs), the overall response rate (ORR), and disease control rate (DCR) were monitored. RESULTS: Positive ANA titers were seen in 9 out of 191 patients. Four patients in the positive ANA group and 69 patients in the negative group developed irAEs of any grade without a significant difference between the groups. The development of endocrine, pulmonary, and cutaneous irAEs was not significant, whereas positive ANA was significantly higher in patients who developed colitis (2/9) than in patients who did not (3/182, P = 0.0002). DCR in the positive and negative ANA group was 37.5% and 67.5%, respectively, and was not statistically significant, but had better efficacy in patients without ANA (P = 0.08). ANA-related autoimmune diseases such as SLE, Sjögren's syndrome, MCTD, scleroderma, dermatomyositis, and polymyositis was not induced in either group. However, one patient with preexisting dermatomyositis had a flare up after initiation of atezolizumab. CONCLUSION: Further studies to identify predictive factors for the development of irAEs are required to provide relevant patient care and maximize the therapeutic benefits of ICIs.

Myocardial late gadolinium enhancement: a head-to-head comparison of motion-corrected balanced steady-state free precession with segmented turbo fast low angle shot.

AIM: To evaluate the image quality and diagnostic agreement with a head-to-head comparison of late gadolinium enhancement (LGE) images acquired by the motion-corrected (MOCO) balanced steady-state free precession (bSSFP) phase sensitivity inversion recovery (PSIR) and conventional segmented fast low angle shot (FLASH) PSIR methods15,16 in a patient cohort with a wide spectrum of cardiovascular disease. MATERIALS AND METHODS: In 59 consecutive patients, signal-to-noise ratios (SNRs), contrast-to-noise ratios (CNRs) of the normal myocardium (NM), LGE, and blood pool (BP) were pair-wise compared between the two different sequences. A further semi-qualitative score system (graded 1 -4) was used to compare the overall image quality (OIQ). The diagnostic agreement of the two techniques were evaluated by both transmural severity and absolutely quantitative size of LGE. RESULTS: The SNRs of the NM, LGE, and BP of MOCO bSSFP were 4.8±3.4, 53.6±35.6 and 43.2±29.3, compared with 3.9±3.6 (p=0.126), 27.7±18.5 (p<0.001) and 24.3±13.4 (p<0.001) of FLASH LGE, respectively. The CNRs of LGE to NM, LGE to BP, and BP to NM were 48.3±33.1 versus 23.8±16.7 (p<0.001), 6.5±21.6 versus 3.8±10.8 (p<0.001), and 38.3±27.2 versus 20.3±10.7 (p=0.448), respectively. The OIQ of MOCO bSSFP was higher than that of segmented FLASH (median 4 versus median 3, p<0.001). For quantification of LGE size, there is good agreement and high correlation (r=0.992, p<0.001) between the two methods. CONCLUSIONS: MOCO bSSFP is a feasible, robust sequence for LGE imaging, especially for patients with arrhythmia and those incapable of breath-holding due to severe heart failure.

Intra- and inter-tester reliability and validity of normal finger size measurement using the Japanese ring gauge system.

This study was designed to investigate the reliability and validity of measurements of finger diameters with a ring gauge. A reliability study enrolled two independent samples (50 participants and seven examiners in Study I; 26 participants and 26 examiners in Study II). The sizes of each participant's little fingers were measured twice with a ring gauge by each examiner. To investigate the validity of the measurements, five hand therapists compared the finger size and hand volume of 30 participants with the ring gauge and with a figure-of-eight technique (Study III). The intra-class correlation coefficient for intra-observer reliability ranged from 0.97 to 0.99 in Study I, and 0.90 to 0.97 in Study II. The intra-class correlation coefficient for inter-observer reliability was 0.95 in Study I and 0.94 in Study II. The validity study showed a Pearson product moment correlation coefficient of 0.75. The ring gauge showed high reliability and validity for measurement of finger size. LEVEL OF EVIDENCE: III, diagnostic.

The Role of ORAI1 in the Odontogenic Differentiation of Human Dental Pulp Stem Cells.

Pulp capping, or placing dental materials directly onto the vital pulp tissues of affected teeth, is a dental procedure that aims to regenerate reparative dentin. Several pulp capping materials are clinically being used, and calcium ion (Ca(2+)) released from these materials is known to mediate reparative dentin formation. ORAI1 is an essential pore subunit of store-operated Ca(2+) entry (SOCE), which is a major Ca(2+) influx pathway in most nonexcitable cells. Here, we evaluated the role of ORAI1 in mediating the odontogenic differentiation and mineralization of dental pulp stem cells (DPSCs). During the odontogenic differentiation of DPSCs, the expression of ORAI1 increased in a time-dependent manner. DPSCs knocked down with ORAI1 shRNA (DPSC/ORAI1sh) or overexpressed with dominant negative mutant ORAI1(E106Q) (DPSC/E106Q) exhibited the inhibition of Ca(2+) influx and suppression of odontogenic differentiation and mineralization as demonstrated by alkaline phosphatase (ALP) activity/staining as well as alizarin red S staining when compared with DPSCs of their respective control groups (DPSC/CTLsh and DPSC/CTL). The gene expression for odontogenic differentiation markers such as osteocalcin, bone sialoprotein, and dentin matrix protein 1 (DMP1) was also suppressed. When DPSC/CTL or DPSC/E106Q cells were subcutaneously transplanted into nude mice, DPSC/CTL cells induced mineralized tissue formation with significant increases in ALP and DMP1 staining in vivo, whereas DPSC/E106Q cells did not. Collectively, our data showed that ORAI1 plays critical roles in the odontogenic differentiation and mineralization of DPSCs by regulating Ca(2+) influx and that ORAI1 may be a therapeutic target to enhance reparative dentin formation.

Myocardial fat overgrowth in Proteus syndrome.

Proteus syndrome (PS) is a rare, mosaic disorder with asymmetric and distorting overgrowth of the skeletal system, skin, and adipose tissues. Cardiac abnormalities are rare in this syndrome and only two prior cases have been reported. Many patients with PS followed at our institution underwent transthoracic echocardiograms for preoperative evaluation or as work-up for associated pulmonary disease. Some were noted to have prominent, focal echodense areas in the myocardium. We further investigated cardiac findings in a cohort of children and adult patients with PS. Patients with abnormal echocardiograms were referred for cardiac magnetic resonance imaging, Holter monitoring, and exercise treadmill testing. Twenty children and adults with PS, age 24 months to 50 years old, underwent transthoracic echocardiograms. Seven patients (35%) had focal bright echodense areas within the myocardium suggesting fatty infiltration. The majority of patients had significant involvement of the interventricular septum. The cardiac characteristics of all patients with fatty infiltration on transthoracic echocardiograms were compared to Proteus patients without these findings. There were no significant differences in chamber sizes, mass, systolic or diastolic function. No increased risk of conduction defects or arrhythmias was found. This study shows that abnormal fat overgrowth is a common finding in the myocardium in patients with Proteus syndrome; however, it is not associated with functional derangements or arrhythmias. Further evaluation of a larger number of Proteus patients is needed in order to determine the frequency and prognosis of cardiac involvement. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Cord blood transplantation is associated with rapid B-cell neogenesis compared with BM transplantation.

Hematopoietic cell transplantation (HCT) is used for treatment of hematopoietic diseases. Assessment of T- and B-cell reconstitution after HCT is crucial because poor immune recovery has a major effect on the clinical course. In this study, we retrospectively analyzed T-cell receptor excision circles (TRECs) as well as signal and coding joint kappa-deleting recombination excision circles (sjKRECs and cjKRECs, respectively) as markers of newly produced lymphocytes in 133 patients (56 primary immunodeficient and 77 malignant cases, median (range): 12 (0-62) years old). We analyzed the kinetics of TREC and KREC recovery and determined the factors that contributed to better immune recovery. KRECs became positive earlier than TRECs and increased thereafter. Younger recipient age had a favorable effect on recovery of sjKRECs and cjKRECs. Compared with BM and peripheral blood, our data suggested that cord blood (CB) provided rapid B-cell recovery. CB also provided better B-cell neogenesis in adult HCT recipients. Chronic GVHD was associated with low TRECs, but not increased sjKRECs/cjKRECs. Finally, positive sjKRECs 1 month after HCT were associated with fewer infectious episodes. Monitoring of TRECs and KRECs may serve as a useful tool for assessment of immune reconstitution post HCT.

Gender differences of suicide in Japan, 1947-2010.

BACKGROUND: The effects of socio-economic factors on suicide were gender-dependent. Japanese suicide mortality gender ratio (male: female) had gradually increased during the twentieth century. METHODS: With the data covering 1947-2010 collected from Japanese official websites, we conducted non-parametric rank test, curve estimations, spearman ranking correlation and quantile regression in succession with Stata version 12.0. RESULTS: The suicide mortality rate in male with a "U" shape had been always higher than that in female with a "J" shape. The male suicide mortality peaked around in 1955 (38.5 per 100,000 populations), dropped quickly afterwards until the 1970s; it increased in the 1980s with another peak in 2003 (33.2 per 100,000 populations). For female, an overall decreasing trend was seen with a peak during the 1950s (23.5 per 100,000 populations in 1958). It dropped gradually afterwards with small variations in 1970s and 80s, and was stabilized after 1995 (9.3 per 100,000 populations). The unemployment rate could be used as a single positive predictor of suicide mortality for men (p<0.01), while the total fertility rate (TFR) (p<0.01) and divorce rate (p<0.01) were significantly associated positively and negatively with women's suicide, respectively. LIMITATIONS: The impact of mental disorders was not analyzed and age-specific analysis was not conducted. CONCLUSION: The findings of these gender differences in, and the associated factors with, suicide in Japan, warranted further studies including delineation of the implications of differential economic pressure between genders, as well as child-rearing pressure and marriage satisfaction.

Serum vitamin D and parathyroid hormone in relation to cardiac structure and function: the ICELAND-MI substudy of AGES-Reykjavik.

CONTEXT: Emerging evidence suggests that vitamin D and PTH may play a role in the development of cardiac diseases. OBJECTIVE: We investigated whether 25-hydroxyvitamin D (25OHD) and PTH concentrations are cross-sectionally associated with cardiac structure and function using magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: ICELAND-MI is a substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study, an older-aged community-dwelling cohort with oversampling of participants with diabetes (29%) and measurements between 2004 and 2007. Serum 25OHD concentrations were measured using an immunoassay (n = 992). Intact PTH concentrations were measured using a 2-site immunoassay (n = 203). We included 969 participants for this cross-sectional analysis (mean age 76 ± 5.3 years, 51% female). Mean 25OHD was 54.2 ± 25.5 nmol/L and the median PTH was 4.5 pmol/L (range 1.5-18). MAIN OUTCOMES: MRI to measure cardiac structure and function was the main outcome. RESULTS: The lowest 25OHD category (<25 nmol/L) compared with the highest category (≥75 nmol/L) was associated with a smaller left and right atrial area in unadjusted analyses; however, the associations became nonsignificant after adjustment for covariates. The highest PTH quartile compared with the lowest quartile was significantly associated with a 7.3 g (95% confidence interval 0.8, 13.8) greater left ventricular (LV) mass and a 5.1% (-9.1, -1.1) lower LV ejection fraction compared with the lowest PTH quartile in the fully adjusted model. CONCLUSIONS: Serum 25OHD concentrations were not associated with MRI measures in an older white population. Higher PTH concentrations were associated with greater LV mass and lower systolic function and may point to a potential role for PTH as a determinant of cardiac remodeling.

Efficacy of music therapy in treatment for the patients with Alzheimer's disease.

We report that music therapy is effective in the treatment of Alzheimer's disease. We found that the secretion of 17ß-estradiol and testosterone, hormones that are supposed to have preventive effects on Alzheimer's disease, is significantly increased by music therapy. During the sessions, patients with Alzheimer's disease were allowed to listen to music and songs with verbal contact from the therapist. It was found that problematic behaviors such as poriomania (fugue) had decreased. Music therapy has the potential as an alternative treatment for adverse hormone replacement therapy.

Implementation of municipal mobility support services for older people who have stopped driving in Japan.

OBJECTIVES: In a motorized society, increasing numbers of drivers and their family members will have to face the issue of driving cessation late in life due to dementia or age-related conditions. Mobility support for driving retirees should be considered from a public health perspective. Compared with alternative forms of transportation, relying on family members and friends, municipality-provided mobility support services would be more reliable and practical. The present study aimed to explore the provision of mobility support measures at the community level. STUDY DESIGN: A cross-sectional study of all municipal governments in Japan. METHODS: A nationwide survey was conducted using a postal self-administered questionnaire to explore the allocation of municipality-provided mobility support measures for two target groups: (1) healthy older residents and (2) older residents with dementia. The possible sociodemographic characteristics of municipalities affecting the implementation of such measures were examined. RESULTS: Data from 1027 (56.8%) municipal governments were analysed. The present study demonstrated that mobility support measures for older residents, particularly dementia sufferers, were not sufficiently developed in municipalities. Moreover, the analyses showed that the following three characteristics of municipalities were related to the implementation of mobility support measures for healthy older residents: longer roads, low percentage of older residents per unit of road length, and low population density. CONCLUSIONS: These findings provide insight into the possible incentives for implementing mobility support for healthy older residents, and indicate the prospective mobility needs of driving retirees, including dementia sufferers.

Prolactin-releasing peptide enhances synaptic transmission in rat thalamus.

Prolactin-releasing peptide (PrRP) is an RF-amide peptide that is believed to be the physiological ligand for the G-protein coupled receptor GPR10. This receptor is highly expressed in the GABAergic principal neurons of the reticular thalamic nucleus (RTN), but the cellular and physiological effects of receptor activation on thalamic function are not yet clear. The present study examined the effects of PrRP on excitatory and inhibitory synaptic transmission in the RTN and the ventrobasal complex (VB) of the thalamus. In RTN neurons, PrRP enhanced excitatory synaptic transmission by selectively increasing the amplitude of the NMDA receptor-mediated excitatory postsynaptic current (EPSC; NMDA-EPSC). AMPA receptor mediated current were not affected. A mutated form of PrRP with negligible affinity to GPR10 was ineffective, and no enhancement of NMDA-EPSCs was observed in the ventrobasal thalamus, which does not express GPR10. The effect was distinct from that of neuropeptide FF (NPFF), which enhanced both AMPA and NMDA receptor mediated responses and probably acted though a presynaptic NPFF receptor. Taken together, these results suggest that PrRP selectively modulates NMDA receptor-mediated synaptic transmission in RTN neurons through postsynaptic GPR10 receptors. This effect appears to involve an unconventional mechanism because it was not blocked by intracellularly applied GDPßS. PrRP also increased by 50-75% the amplitude of GABAA receptor-mediated inhibitory postsynaptic current (IPSCs) in both ventrobasal nucleus and RTN neurons. The former represents inhibitory input from RTN neurons to thalamocortical relay cells and the latter a local inhibition produced by RTN axon collaterals. Miniature IPSC analysis revealed that PrRP enhanced release of GABA and thus acted presynaptically. In conclusion, PrRP increases both excitatory and inhibitory synaptic transmission in the thalamus via distinct mechanisms, and the receptors responsible for these actions are in all cases present in the principal neuron of the RTN.

Quality of life after esophagectomy and endoscopic therapy for Barrett's esophagus with dysplasia.

Esophagectomy (EG) and endoscopic therapy (ET) can eradicate Barrett's esophagus with early neoplasia. Their relative effect on quality of life is unknown. The 36-item Short Form Health Survey (SF-36) and Gastrointestinal Quality of Life Index (GIQLI) questionnaires were sent to all patients who underwent either EG or ET at our institution over the last 9 years. Groups were stratified by age and American Society of Anesthesia (ASA) class. Surveys were sent to 77 patients and completed by 14 EG (50%) and by 28 ET patients (57%). The average time between treatment and survey was 4 years in the ET group and 5 years in the EG group. There were no significant differences in SF-36 scores between EG and ET patients except for superior physical functioning among EG patients 65 and older QOL scores among EG and ET groups were not significantly different than sex age-matched controls. GIQLI scores were similar between ET and EG patients of all ages (P= 0.60). GIQLI scores were higher among younger ET patients than young EG patients (P= 0.049). GIQLI scores also tended to be higher among ASA 1 and 2 ET patients than ASA 1 and 2 EG patients, but this did not reach statistical significance (P= 0.09). EG and ET for early Barrett's neoplasia appear to have similar impact on QOL 1 year or more after treatment compared with age-matched controls. Negative QOL impact appears to be greater for younger patients undergoing EG than for ET.

Advances in clinical applications of cardiovascular magnetic resonance imaging.

Cardiovascular magnetic resonance (CMR) is an evolving technology with growing indications within the clinical cardiology setting. This review article summarises the current clinical applications of CMR. The focus is on the use of CMR in the diagnosis of coronary artery disease with summaries of validation literature in CMR viability, myocardial perfusion, and dobutamine CMR. Practical uses of CMR in non-coronary diseases are also discussed.

Association between lifestyle activity and depressed mood among home-dwelling older people: a community-based study in Japan.

In the community-based cross-sectional study, we investigated patterns of lifestyle activities among older people and examined the association between specific types of lifestyle activity and depressed mood status. The participants were 656 men and women aged 65 or older in 2004 who lived in a rural town in Japan, neither institutionalized nor hospitalized and who did not have symptoms of dementia. We found that less interaction with neighbors, society and friends was highly associated with depressed mood for men. Additionally, although they were physically active in gardening/farming, it did not necessarily mean that they were mentally healthy if they did not have close ties with friends, family and children/grandchildren. For women, it seemed important to engage in several types of activities relating to society, leisure and children/grandchildren to be in less depressed mood. Even if they were socially inactive, if they had frequent contact with family and children/grandchildren or going out for pleasure they were less likely to be depressed. Distinguishing gender differences in lifestyle activity patterns and the association of activities with depressed mood will help to guide the development of depression intervention programs.

Direct-write patterning of indium-tin-oxide film by high pulse repetition frequency femtosecond laser ablation.

Ablation of indium oxide doped with tin oxide (ITO) from glass substrates is described. Laser pulse energy and focus spot size were varied in single-pulse, single-spot ablation tests and for ablation of linear features with scanned multiple pulses. The single-pulse ablation threshold of ITO was smaller than that of the glass substrate so the entire thickness of ITO could be removed in a single pulse or with overlying multiple pulses without the possibility of substrate ablation. Linear features could be created at much higher scanning speeds using a high repetition frequency (100 kHz) Yb fiber amplified laser as compared to a lower repetition frequency (2 kHz) laser. An analysis showed that incubation effects lowered ITO ablation thresholds when pulse frequency was high relative to scanning speed, contributing to large feasible scanning speeds for high pulse frequency lasers.

Pharmacology of ampakine modulators: from AMPA receptors to synapses and behavior.

Ampakines are drugs structurally derived from aniracetam that potentiate currents mediated by AMPA type glutamate receptors. These drugs slow deactivation and attenuate desensitization of AMPA receptor currents, increase synaptic responses and enhance long-term potentiation. This review focuses mainly on recent physiological studies and on evidence for two distinct subfamilies. Type I compounds like CX546 are very effective in prolonging synaptic responses while type II compounds like CX516 mainly increase response amplitude. Type I and II drugs do not compete in binding assays and thus presumably act through separate sites. Their differences are likely to have consequences also for synaptic plasticity and behavior. Thus, while all ampakines facilitated long-term potentiation, only CX546 enhanced long-term depression. Further discussed are studies showing that ampakine effects vary substantially between neurons, with increases in EPSCs being larger in CA1 pyramidal cells than in thalamus and in hippocampal interneurons. In behavioral tests, ampakines facilitate learning in many paradigms including odor discrimination, spatial mazes, and conditioning, and they improved short-term memory in a non-matching-to-sample task. Positive results were also obtained in various psychological tests with human subjects. The drugs were effective in correcting behaviors in various animal models of schizophrenia and depression. Lastly, evidence is discussed that ampakines have few adverse effects at therapeutically relevant concentrations and that they protect neurons against neurotoxic insults, in part by mobilizing growth factors like BDNF. Type II drugs like CX516 in particular appear to be inherently safe since their ability to prolong responses is kinetically limited.