[Relationship between Moral Concerns and Problem-Solving Behaviors for Outpatient Nurses Working in Palliative Care Accredited Educational Facilities].

The purpose of this study was to examine the moral concerns and problem-solving behavior for outpatient nurses in palliative cancer care. The target of this study was 284 outpatient nurses(22.9%)out of 1,241 respondents. As a result, it was concluded that outpatient nurses providing palliative cancer care have higher ethical concerns than nurses working in acute care hospitals. In addition, the more moral concerns there were, the more nurses manage their care according to patient's individual circumstances. In the future, it is necessary to provide education on the moral concerns of outpatient nurses and the problem-solving behavior for nurses so that patients in the final stages of life and their families can spend a better time.

Absence of copy number gain of EGFR: A possible predictive marker of long-term response to afatinib.

Treatment efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is diverse even in non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. Extraordinary long-term responses sustained over 3 years among NSCLC patients treated with afatinib, an EGFR-TKI, have been reported, but how to predict such long survivors has not been clarified. A multi-institutional prospective observational study, based on comprehensive genomic examination performed with next-generation sequencing of circulating tumor DNA (ctDNA), was conducted to identify potential predictive markers of long-term response to afatinib. Twenty-nine patients with advanced stage NSCLC and EGFR driver mutations detected by standard techniques were enrolled in the study. ctDNA from plasma collected before afatinib treatment was analyzed by Guardant360. ctDNA was detected in 25 of the 29 samples. Median progression-free survival was shorter in patients whose tumors had EGFR copy number gain (7.0 vs 23.0 months, p = 0.022). The impact of EGFR copy number on cell proliferation and the antitumor effect of afatinib were evaluated using genome-editing lung cancer cell lines. HCC827 with EGFR amplification was relatively resistant to afatinib at concentrations below 0.5 nM, but genome-edited derivatives of HCC827 with decreased EGFR copy number demonstrated growth inhibition with 0.1 nM afatinib. The absence of EGFR copy number gain detected in ctDNA may be a predictive marker of long-term response to afatinib. Comprehensive genomic analysis could lead to a more accurate prediction of EGFR-TKI efficacy.

Anti-cancer effect of afatinib, dual inhibitor of HER2 and EGFR, on novel mutation HER2 E401G in models of patient-derived cancer.

BACKGROUND: Precision medicine with gene panel testing based on next-generation sequencing for patients with cancer is being used increasingly in clinical practice. HER2, which encodes the human epidermal growth factor receptor 2 (HER2), is a potentially important driver gene. However, therapeutic strategies aimed at mutations in the HER2 extracellular domain have not been clarified. We therefore investigated the effect of EGFR co-targeted therapy with HER2 on patient-derived cancer models with the HER2 extracellular domain mutation E401G, based on our previous findings that this mutation has an epidermal growth factor receptor (EGFR)-mediated activation mechanism. METHODS: We generated a xenograft (PDX) and a cancer tissue-originated spheroid (CTOS) from a patient's cancer containing an amplified HER2 E401G mutation. With these platforms, we compared the efficacy of afatinib, a tyrosine kinase inhibitor having anti-HER2 and anti-EGFR activity, with two other therapeutic options: lapatinib, which has similar properties but weaker EGFR inhibition, and trastuzumab plus pertuzumab, for which evidence exists of treatment efficacy against cancers with wild-type HER2 amplification. Similar experiments were also performed with H2170, a cell line with wild-type HER2 amplification, to contrast the characteristics of these drug's efficacies against HER2 E401G. RESULTS: We confirmed that PDX and CTOS retained morphological and immunohistochemical characteristics and HER2 gene profiles of the original tumor. In both PDX and CTOS, afatinib reduced tumor size more than lapatinib or trastuzumab plus pertuzumab. In addition, afatinib treatment resulted in a statistically significant reduction in HER2 copy number at the end of treatment. On the other hand, in H2170 xenografts with wild-type HER2 amplification, trastuzumab plus pertuzumab was most effective. CONCLUSIONS: Afatinib, a dual inhibitor of HER2 and EGFR, showed a promising effect on cancers with amplified HER2 E401G, which have an EGFR-mediated activation mechanism. Analysis of the activation mechanisms of mutations and development of therapeutic strategies based on those mechanisms are critical in precision medicine for cancer patients.

Deletion of Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization (HYBID) Results in Attenuation of Osteoarthritis in Mice.

Hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID) is involved in cartilage destruction via HA depolymerization in human knee osteoarthritis. However, the role of HYBID in the progression of osteoarthritis remain elusive. This study sought to examine whether genetic depletion of Hybid could suppress surgically induced osteoarthritis of mouse knee joints. In osteoarthritis induced by medial collateral ligament transection with meniscus removal, articular cartilage destruction and osteophyte formation at the medial femoral-tibial joint were significantly inhibited in Hybid-deficient (Hybid-/-) mice compared with wild-type mice. Hybid was highly produced by synovial cells and articular chondrocytes in the osteoarthritis joints of wild-type mice. IL-1ß, IL-6, and tumor necrosis factor-α were up-regulated in the osteoarthritis joint tissues of both wild-type and Hybid-/- mice. Vascular density at the synovial and periosteal junction was significantly reduced in Hybid-/- mice compared with wild-type mice. High-molecular-weight HA accumulated in osteoarthritis joint tissues of Hybid-/- mice. Injections of high-molecular-weight HA to knee joints attenuated the cartilage destruction and osteophyte formation in wild-type mouse osteoarthritis group. Inhibition of cartilage destruction and osteophyte formation in Hybid-/- mice was also observed in destabilization of the medial meniscus model. These data are the first to demonstrate that cartilage destruction and osteophyte formation are suppressed in Hybid-/- mice and suggest that Hybid-mediated HA depolymerization is implicated for the progression of mechanically-induced knee osteoarthritis.

A case of a renal abscess caused by Salmonella bareilly in a previously healthy boy.

BACKGROUND: Renal abscesses are relatively uncommon in children, and usually due to Gram-negative rods or Staphylococcus aureus, whereas abscesses caused by Salmonella are very rare. CASE PRESENTATION: We present the case of a previously healthy 10-year-old boy who had a renal abscess due to Salmonella bareilly. He responded well to treatment with antibiotics, and computed tomography (CT)-guided drainage of the abscess. His blood, urine and abscess aspirate cultures were sterile, but a broad-range 16S rDNA polymerase chain reaction (PCR) assay of the aspirate followed by analysis of four Salmonella genes (fliC, fliD, sopE2, and spaO) identified S. bareilly as the causative agent. CONCLUSION: To the best of our knowledge, this is the first report of renal abscess caused by S. bareilly.

Season- and facial site-specific skin changes due to long-term mask wearing during the COVID-19 pandemic.

BACKGROUND: As people have regularly worn facial masks due to the coronavirus disease 2019 (COVID-19) pandemic, mask-wear-related adverse effects on the skin have been recognized. The aim of this study was to explore skin changes, their seasonal variations in the general population caused by commonly used masks and a possible mechanism underlying negative effects of mask-wearing. MATERIALS AND METHODS: Eighteen Japanese females participated in the study during summer and winter in Japan. Skin characteristics were measured in the non-mask-wearing preauricular area and the mask-wearing cheek and perioral areas. RESULTS: Trans-epidermal water loss (TEWL) on the cheek area tended to be increased in winter, which was positively correlated with skin scaliness on the same area. Ceramide (CER) content and composition in the mask-covered stratum corneum (SC) were slightly changed between summer and winter, and CER [NP]/[NS] ratio was negatively correlated with the TEWL on the perioral skin in winter. Skin hydration and sebum secretion were higher on the cheek compared to the perioral area in summer. Skin redness was particularly high on the cheek in winter. CONCLUSION: Mask-wear-related skin changes were season- and facial site-specific, and alterations in SC CER may play a role in barrier-related skin problems caused by mask use.

Changes in Internal Cerebral Vein Pulsation and Intraventricular Hemorrhage in Extremely Preterm Infants.

OBJECTIVES: This study aimed to investigate the relationship between internal cerebral vein (ICV) pulsation and intraventricular hemorrhage (IVH) and to identify the cut-off values that predict IVH. We hypothesized that the severity of ICV flow pulsations was related to IVH severity. STUDY DESIGN: In this prospective observational study, ICV flow was measured in 61 extremely preterm infants using ultrasonography at every 12 hours until 96 hours after birth and on days 7, 14, and 28. The ICV pulsation index (ICVPI = minimum/maximum ICV speed) was calculated and compared among the groups determined by Papile's IVH classification. The ICVPI cut-off values for IVH were determined by receiver operating characteristic curve analysis. RESULTS: Compared with those in the no IVH (NIVH) group (n = 51), the ICVPI median values in the severe IVH (SIVH; grades 3 and 4) group (n = 5) were lower at 25 to 96 hours and on day 7, whereas those in the mild IVH (MIVH; grades 1 and 2) group (n = 5) were lower at 37 to 60 hours. All SIVH events were initially detected within 60 hours after birth. The ICVPI cut-off values for SIVH were 0.92 at 13 to 24 hours, 0.42 at 25 to 36 hours, 0.58 at 37 to 48 hours, and 0.55 at 49 to 60 hours. Infants whose ICVPI values were below the cut-off value ≥3 times between 13 and 60 hours had a significantly higher SIVH incidence than those whose ICVPI values were below the cut-off value ≤2 times (57.1 vs. 1.9%, p < 0.001). CONCLUSION: Our results indicate that SIVH had sustained pronounced internal cerebral vein pulsations and that the ICVPI values may help predict SIVH. Further research on strategies to decrease venous pressure for IVH prevention is needed. KEY POINTS: · IVH preterm infants had sustained ICV pulsations.. · ICV flow in SIVH pulsated stronger.. · ICVPI fluctuation implies postnatal adaptation.. · We newly defined ICVPI to predict SIVH..

HYBID (alias KIAA1199/CEMIP) and hyaluronan synthase coordinately regulate hyaluronan metabolism in histamine-stimulated skin fibroblasts.

The immune-regulatory compound histamine is involved in the metabolism of the essential skin component hyaluronan (HA). We previously reported that histamine up-regulates the expression of HYBID (hyaluronan-binding protein involved in hyaluronan depolymerization, also called CEMIP or KIAA1199), which plays a key role in HA degradation. However, no information is available about histamine's effects on HA synthase (HAS) expression, the molecular sizes of HA species produced, and histamine receptors and their signaling pathways in skin fibroblasts. Moreover, histamine's effects on photoaged skin remain elusive. Here, we show that histamine increases HA degradation by up-regulating HYBID and down-regulating HAS2 in human skin fibroblasts in a dose- and time-dependent manner and thereby decreases the total amounts and sizes of newly produced HA. Histamine H1 blocker abrogated the histamine effects on HYBID up-regulation, HAS2 suppression, and HA degradation. Histamine H1 agonist exhibited effects on HA levels, composition, and breakdown similar to those of histamine. Of note, blockade of protein kinase Cδ or PI3K-Akt signaling abolished histamine-mediated HYBID stimulation and HAS2 suppression, respectively. Immunohistochemical experiments revealed a significant ∼2-fold increase in tryptase-positive mast cells in photoaged skin, where HYBID and HAS2 expression levels were increased and decreased, respectively, compared with photoprotected skin. These results indicate that histamine controls HA metabolism by up-regulating HYBID and down-regulating HAS2 via distinct signaling pathways downstream of histamine receptor H1. They further suggest that histamine may contribute to photoaged skin damage by skewing HA metabolism toward degradation.

Implication of HYBID (Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization) in Hyaluronan Degradation by Synovial Fibroblasts in Patients with Knee Osteoarthritis.

Cell migration-inducing hyaluronidase 1 (CEMIP), also known as hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), plays a role in HA degradation. CEMIP2, also known as transmembrane protein 2 (TMEM2), possessing a sequence similarity with HYBID, is reported as a hyaluronidase in mice. However, the expression of these molecules in osteoarthritic synovium and their involvement in HA degradation in synovial fluid (SF) from patients with knee osteoarthritis remain elusive. This study examined their expression in synovial tissue and the relationship with molecular weight of HA in SF in knee osteoarthritis patients. Quantification of mRNA demonstrated that HYBID expression is significantly (5.5-fold) higher in osteoarthritic synovium than in normal control synovium, whereas TMEM2 expression level is similar between the two groups. By immunohistochemistry, HYBID was localized mainly to CD68-negative and fibroblast-specific protein 1-positive synovial lining cells and sublining fibroblasts in osteoarthritic synovium. The mRNA expression levels of HYBID, but not TMEM2, in osteoarthritic synovium positively correlated with distribution of lower-molecular-weight HA with below 1000 kDa in SF. HA-degrading activity in osteoarthritic synovial fibroblasts was abrogated by siRNA-mediated knockdown of HYBID. Among the 12 factors examined, IL-6 significantly up-regulated the HYBID expression and HA-degrading activity in osteoarthritic synovial fibroblasts. These data suggest that HYBID overexpressed by IL-6-stimulated synovial fibroblasts is implicated in HA degradation in osteoarthritic synovium.

Tree hazards compounded by successive climate extremes after masting in a small endemic tree, Distylium lepidotum, on subtropical islands in Japan.

Ongoing global warming increases the frequency and severity of tropical typhoons and prolonged drought, leading to forest degradation. Simultaneous and/or successive masting events and climatic extremes may thus occur frequently in the near future. If these climatic extremes occur immediately after mass seed reproduction, their effects on individual trees are expected to be very severe because mass reproduction decreases carbohydrate reserves. While the effects of either a single climate extreme or masting alone on tree resilience/growth have received past research attention, understanding the cumulative effects of such multiple events remains challenging and is crucial for predicting future forest changes. Here, we report tree hazards compound by two successive climate extremes, a tropical typhoon and prolonged drought, after mass reproduction in an endemic tree species (Distylium lepidotum Nakai) on oceanic islands. Across individual trees, the starch stored within the sapwood of branchlets significantly decreased with reproductive efforts (fruit mass/shoot mass ratio). Typhoon damage significantly decreased not only the total leaf area of apical shoots but also the maximum photosynthetic rates. During the 5-month period after the typhoon, the mortality of large branchlets (8-10-mm diameter) increased with decreasing stored starch when the typhoon hit. During the prolonged summer drought in the next year, the recovery of total leaf area, stored starch, and hydraulic conductivity was negatively correlated with the stored starch at the typhoon. These data indicate that the level of stored starch within branchlets is the driving factor determining tree regrowth or dieback, and the restoration of carbohydrates after mass reproduction is synergistically delayed by such climate extremes. Stored carbohydrates are the major cumulative factor affecting individual tree resilience, resulting in their historical effects. Because of highly variable carbohydrate levels among individual trees, the resultant impacts of such successive events on forest dieback will be fundamentally different among trees.

Evaluating the safety of dienogest in women with adenomyosis: A retrospective analysis.

AIM: Dienogest (DNG) is highly effective for relieving pain caused by endometriosis and adenomyosis. However, women with severe uterine swelling due to adenomyosis who take DNG usually experience metrorrhagia. This study aimed to examine the safety of DNG usage in women with adenomyosis. METHODS: This study included 20 women who were prescribed DNG for adenomyosis in our hospital from January 2016 to December 2016. We retrospectively analyzed women's clinical background characteristics (age, the use of the gonadotropin-releasing hormone agonist as pre-treatment of DNG, the uterus size [major axis, minor axis, maximum thickness in the myometrium, and length of the uterine body] by transvaginal ultrasonography [TVUS], hemoglobin level, and the presence of metrorrhagia during treatment). These variables were compared between the DNG continuation and discontinuation groups using the Mann-Whitney U test. RESULTS: Thirteen women continued DNG, and seven discontinued DNG within 12 months because of metrorrhagia. The uterine size was significantly larger in the discontinuation group than in the continuation group. All uterine measurements had high Spearman rank correlation coefficients (ρ > 0.8, P < 0.05). In six of seven cases in the discontinuation group, adenomyosis was in the anterior wall. Measuring the uterus size and locating adenomyosis by TVUS are simple methods of predicting DNG discontinuation. CONCLUSION: We consider that DNG can be safely administered in women with adenomyosis if the uterine size is <6 cm in the minor axis and the main lesion of adenomyosis is located in the posterior uterine wall.

A rare case of Trichosporon mycotoxinivorans and Cryptococcus neoformans co-infection in lung.

A 70-year-old woman with liver cirrhosis caused by primary biliary cirrhosis and rheumatoid arthritis was found to have multiple pulmonary nodular shadows in the right middle and lower lung fields on chest radiography. The multiple pulmonary nodules and masses rapidly increased over 2 months. Trichosporon mycotoxinivorans and Cryptococcus neoformans were identified in brushing specimens, bronchial lavage, and transbronchial lung biopsy specimens. The patient was diagnosed as having a co-infection of the lung with T. mycotoxinivorans and C. neoformans, and was treated with fluconazole. Although the pulmonary shadows were under control with treatment, she died 5 months later due to liver failure. We report herein a rare case of co-infection of the lung with T. mycotoxinivorans and C. neoformans.

Impaired expression of innate immunity-related genes in IgG4-related disease: A possible mechanism in the pathogenesis of IgG4-RD.

Background: IgG4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. The pathogenesis of this disease is not clear. Transcriptome analysis was performed to identify genes over- and under-expressed in patients with IgG4-RD.Method: DNA microarray analysis was performed using RNA from peripheral blood mononuclear cells of two patients with IgG4-RD and four healthy individuals. Genes showing a greater than threefold change in expression in IgG4-RD patients following steroid therapy were identified. Four genes related to innate immunity such as transcobalamin I (TCN1), secretory leukocyte peptidase inhibitor (SLPI), bactericidal/permeability-increasing protein (BPI) and lactotransferrin (LTF) were assessed by real-time PCR in 15 IgG4-RD patients and 13 healthy individuals.Result: DNA microarray analysis identified 30 genes showing a greater than threefold change in expression in IgG4-RD patients following steroid therapy. Real-time RT-PCR showed that the levels of mRNAs encoding TCNI and SLPI, except for BPI and LTF, were significantly lower in patients with IgG4-RD than in healthy people. The levels of all four mRNAs in patients with IgG4-RD were significantly increased after steroid treatment.Conclusion: These results indicate that reduction in expression of innate immunity-related genes may participate in the pathogenesis of IgG4-RD that steroid treatment may rectify impaired innate immunity as well as acquired immunity.

Activated vitamin D3 formulations can be safely used as concomitant medication for prevention of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis.

AIM: Denosumab prevents osteoporosis by potently inhibiting bone resorption, but requires oral therapy with calcium and vitamin D preparations to prevent the side effects of hypocalcemia. Generally, a combination drug containing calcium, natural vitamin D, and magnesium is used. However, if activated vitamin D has been used before the initiation of denosumab therapy, continued use of activated vitamin D is not uncommon. This study aimed to evaluate the combination vitamin D preparation, alfacalcidol, and eldecalcitol on the therapeutic effect on denosumab therapy, the preventive effect on hypocalcemia, and the effect on renal function, to determine the optimal choice of concomitant medication. METHODS: This is a retrospective and single-center study. Among 39 patients who had used denosumab (60 mg dose) for at least 12 months between November 2013 and October 2015, those who used the combination medication concomitantly as the standard treatment, those who used alfacalcidol concomitantly, and those who used eldecalcitol concomitantly were compared. RESULTS: Denosumab therapy markedly increased lumbar spine and femoral neck bone densities at 12 months in the three groups, showing no particular difference in the rate of increase of bone density. The three groups had marked decreases in bone metabolism markers, but had no intergroup differences. No hypocalcemia, hypercalcemia, or obvious renal dysfunction occurred over 12 months. CONCLUSION: This study indicates that the use of activated vitamin D preparations, as concomitant medications with denosumab therapy, is appropriate considering the therapeutic efficacy of denosumab, prevention of hypocalcemia, and influence on renal function.

Stability of benzylpenicillin potassium and ampicillin in an elastomeric infusion pump.

Some infectious diseases, such as infective endocarditis, osteomyelitis, and abscesses, require treatment with long-term intravenous antimicrobial treatment. Therefore, the patient is required to stay in the hospital to receive therapy, which lowers their quality of life. Establishing an outpatient parenteral antimicrobial therapy (OPAT) by continuous infusion pump is desired in Japan to overcome these issues. However, the 24-h stability of antimicrobial agents dissolved in infusion solutions is unclear. Thus, we investigated the stability of antimicrobial agents in five different infusion solutions in a clinical setting. Benzylpenicillin potassium (PCG) and ampicillin (ABPC) were dissolved separately in five different infusion solutions and kept at 25 or 31.1 °C for 24 h. The residual ratios were determined by high-performance liquid chromatography (HPLC). Dissolved PCG in acetate ringer solution remained stable for 24 h at temperatures of 25 and 31.1 °C (101.7 ± 1.4% and 92.9 ± 1.3%, respectively). In addition, the PCG solution did not adsorb onto the elastomeric infusion pump after 24 h at 31.1 °C. PCG dissolved in acetate ringer solution was also stable for 10 days after being kept in an elastomeric infusion pump at 4 °C (99.7 ± 0.5%). ABPC was unstable in all of the tested infusion solutions and temperatures. Based on our results, PCG in acetate ringer solution can be used in OPAT with continuous infusion pumps.

Eldecalcitol increases bone mass in patients with Turner syndrome who have insufficient bone mass acquisition after estrogen replacement therapy.

Most patients with Turner syndrome (TS) exhibit amenorrhea due to premature ovarian failure. Therefore, estrogen replacement therapy (ERT) is required; however, even after undergoing ERT, it is not rare for bone mass acquisition to be insufficient. This study was conducted in two stages, involving a cross-sectional and a prospective interventional study. We recruited 52 TS patients undergoing ERT due to amenorrhea (categorized into low (LB group; n = 23), and normal (NB group; n = 29) bone mass groups) and 7 TS patients who maintained ovarian function (spontaneous menstrual cycle group (MC group)) as controls. We compared bone associated markers between the three groups (LB, NB, and MC). Furthermore, the LB group had concomitant treatment with eldecalcitol (ELD) and ERT for 12 months. The bone mineral density (BMD) of the lumber spine (L2-4) and the bone metabolism markers were then compared before and after the treatment. The bone metabolism markers were significantly higher in the LB group than the NB and MC groups. Furthermore, with the concomitant use of ELD and ERT in the LB group, BMD increased significantly (pre-treatment 0.710 ± 0.056 g/cm2 vs. 0.736 ± 0.062 g/cm2 after 12 months; p < 0.001). TS patients with insufficient bone mass acquisition even after ERT were characterized by a higher turnover in bone metabolism. Therefore, the concomitant use of ELD was considered an effective adjuvant therapy for increasing bone mass.

Alzheimer's disease severity and its association with patient and caregiver quality of life in Japan: results of a community-based survey.

BACKGROUND: Alzheimer's disease (AD) dementia, a progressive neurodegenerative disease, exerts significant burden upon patients, caregivers, and healthcare systems globally. The current study investigated the associations between AD dementia patient disease severity and health-related quality of life (HRQoL) of both patients (proxy report) and their caregivers living in Japan, as well as caregiving-related comorbidities such as depression. METHODS: This cross-sectional study used self-reported data from caregivers of people diagnosed with AD dementia by a healthcare provider in Japan. Caregivers were identified via online panels and invited to participate in an online survey between 2014 and 2015. Caregivers completed survey items for themselves, in addition to providing proxy measures for patients with AD dementia for whom they were caring. Patient and caregiver HRQoL was measured using the EuroQoL 5-Dimension (EQ-5D). Additional outcomes for caregivers of AD dementia patients included the Patient Health Questionnaire (PHQ-9) of depressive symptomology, as well as comorbidities experienced since initiating caregiving for their AD dementia patients. These outcomes were examined as a function of AD dementia severity, as measured by long-term care insurance (LTCI) categories. Bivariate analyses between LTCI and outcomes were conducted using independent t-tests and chi-square tests. Multivariable analyses, controlling for potential confounders, were conducted using generalized linear models (GLMs) specifying a normal distribution. RESULTS: Across 300 caregiver respondents, multivariable results revealed that increasing AD dementia severity was significantly associated with poorer patient and caregiver EQ-5D scores and a high proportion of caregivers (30.0%) reported PHQ-9 scores indicative of major depressive disorder (MDD). The most frequent comorbidities experienced after becoming caregivers of AD dementia patients included hypertension (12.7%) and insomnia (11.0%). Depression and other comorbidities did not differ significantly by patient severity. CONCLUSIONS: The current study provides unique insight into the specific degree of incremental burden associated with increasing AD dementia severity among patients and caregivers alike. Importantly, greater disease severity was associated with poorer quality of life among both patients and caregivers. These results suggest that earlier detection and treatment of AD dementia may provide an opportunity to reduce the burden of disease for patients, caregivers, and society at large.

Phospholipase Cδ1 induces E-cadherin expression and suppresses malignancy in colorectal cancer cells.

Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in CRC predict the ineffectiveness of EGF receptor-targeted therapy. Previous transcriptional microarray analysis suggests the association between phospholipase Cδ1 (PLCδ1) expression and KRAS mutation status in CRC. However, both the roles and the regulatory mechanisms of PLCδ1 in CRC are not known. Here, we found that the expression of PLCδ1, one of the most basal PLCs, is down-regulated in CRC specimens compared with normal colon epithelium by immunohistochemistry. Furthermore, we examined the roles of PLCδ1 in CRC cell lines that harbor an activating KRAS mutation. Ectopic expression of PLCδ1 in CRC cells induced the expression of E-cadherin, whereas knockdown of PLCδ1 repressed the expression of E-cadherin. Moreover, the overexpression of PLCδ1 suppressed the expression of several mesenchymal genes and reduced cell motility, invasiveness, and in vivo tumorigenicity of SW620 CRC cells. We also showed that PLCδ1 expression is repressed by the KRAS/mitogen-activated protein kinase kinase (MEK) pathway. Furthermore, PLCδ1 suppressed the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 through E-cadherin induction in CRC cells, suggesting the presence of a negative regulatory loop between KRAS/MEK/ERK signaling and PLCδ1. These data indicate that PLCδ1 has tumor-suppressive functions in CRC through E-cadherin induction and KRAS/MEK/ERK signal attenuation.

Generalized second law for a simple chaotic system.

The generalized second law (nonequilibrium maximum work formulation) is derived for a simple chaotic system. We consider a probability density, prepared in the far past, which weakly converges to an invariant density due to the mixing property. The generalized second law is then rewritten for an initial invariant density. Gibbs-Shannon entropy is constant in time, but the invariant density has a greater entropy than the prepared density. The maximum work is reduced due to the greater entropy of the invariant density. If and only if the invariant density is a canonical distribution, work is not extractable by any cyclic operation. This gives us the unique equilibrium state. Our argument is extended for a power invariant density such as the Tsallis distribution. On the basis of the Tsallis entropy, the maximum q-work formulation is derived. If and only if the invariant density is a Tsallis distribution, the q-work is no longer extractable by any cyclic operation.

Current approach to the diagnosis of IgG4-related disease - Combination of comprehensive diagnostic and organ-specific criteria.

IgG4-related disease (IgG4-RD) is a fascinating clinical entity proposed by Japanese investigators, and includes a wide variety of diseases, formerly diagnosed as Mikulicz's disease (MD), autoimmune pancreatitis (AIP), interstitial nephritis, prostatitis, retroperitoneal fibrosis, etc. Although all clinicians in every field of medicine may encounter this new disease, a unifying diagnostic criterion has not been established. In 2011, the Japanese IgG4 team, organized by the Ministry of Health, Labor and Welfare (MHLW) of Japan, published comprehensive diagnostic criteria for IgG4-RD. Several problems with these criteria have arisen in clinical practice, however, including the difficulty obtaining biopsy samples from some patients, and the sensitivity and the specificity of techniques used to measure serum IgG4 concentrations. Although serum IgG4 concentration is an important clinical marker for IgG4-RD, its diagnostic utility in differentiating IgG4-RD from other diseases, called IgG4-RD mimickers, remains unclear. This review describes the current optimal approach for the diagnosis of IgG4-RD, based on both comprehensive and organ-specific diagnostic criteria, in patients with diseases such as IgG4-related pancreatitis (AIP), sclerosing cholangitis, and renal, lung and orbital diseases.