Syntheses and biological activities of deoxy-d-allose fatty acid ester analogs

We describe the syntheses of three different deoxy-D-allose analogs [2-deoxy-D-allose (2-DOAll), 1,2-dideoxy-D-allose (1,2-DOAll), and 1,2-didehydro-1,2-dideoxy-D-allose (1,2-DHAll)] and their fatty acid esters via regioselective lipase-catalyzed transesterification. Among them, 2-DOAll and its decanoate (2-DOAll-C10) showed higher inhibitory activity on plant growth, which is similar to D-allose (All) and its decanoate (All-C10). Bioassay results of deoxy-All-C10 on four plant species suggest that the hydroxy group at the C-1 position might be important showing growth inhibitory activity. In addition, co-addition of gibberellin (GA₃) with 1,2-DHAll-C10 and 2-DOAll-C10 recovered plant growth, suggesting that they might mainly inhibit biosynthesis of gibberellin.     

Factors associated with caregiving burden and mental health conditions in caregivers of patients with anorexia nervosa in Japan

Background

There are no studies about the caregiving burdens in families of patients with eating disorders in Japan, and only limited studies on the role of caregivers’ stress coping, social support, and mental health. This study examines caregiving burdens, mental health conditions, and associated factors in caregivers of anorexia nervosa (AN) patients in Japan.

Methods

Seventy-nine principal caregivers (70 mothers, 5 fathers, 3 spouses and 1 grandmother; mean age 56.0?±?8.0 years) for outpatients with AN (all female; mean age 26.6?±?7.9 years; BMI 14.6?±?3.2 kg/m²) were evaluated using self-report questionnaires in a cross-sectional study. The questionnaires included caregiving burden (J-ZBI_8), mental health conditions (GHQ28), stress coping styles (CISS), social support (SNQ), severity of the patient’s symptoms from the family’s perspective (ABOS), and family functioning (GF-FAD). Clinical information about the patients was also obtained.

Results

Mean caregiving burden assessed by J-ZBI_8 score was 12.4?±?7.0 (SD). The total GHQ score was 31.6?±?13.7 (Likert scoring) and 9.2?±?7.0 (GHQ scoring). Of the respondents, 48 (60.7 %) indicated a high risk for mental health problems that exceeded the cutoff point of the GHQ. Significantly higher caregiving burden and poor mental health conditions were shown in the group who had contact with patients?>?6 h a day compared to the group with daily patient contact?<?3 h (F (2, 76)?=?3.19, p?=?0.047 and F (2, 76)?=?9.39, p?<?0.001, respectively). Stepwise multiple regression analysis indicated that the factors that significantly predicted the caregiving burden were severity of the patient’s symptoms from the family’s perspective (β?=?0.47, p?<?0.001) and Emotion-Oriented Coping (β?=?0.38, p?=?0.002) (R²?=?0.401), while predictors of mental health conditions were Emotion-Oriented Coping (β?=?0.522, p?<?0.001), Affective Support (β?=??0.419, p?<?0.001), and contact time with patient (β?=?0.201, p?=?0.042) (R²?=?0.602).

Conclusion

Caregivers of AN patients experienced heavy burdens and manifested poor mental health conditions. The severity of the patient’s symptoms from the family’s perspective and the greater use of emotion-oriented coping were associated with higher burdens. Greater use of emotion-oriented coping, less affective support and longer contact with patients were related to worse mental health conditions. Interventions to promote caregivers’ adaptive coping styles may help reduce their caregiving burden and improve their mental health.

     

Squalene Inhibits ATM-Dependent Signaling in γIR-Induced DNA Damage Response through Induction of Wip1 Phosphatase

Ataxia telangiectasia mutated (ATM) kinase plays a crucial role as a master controller in the cellular DNA damage response. Inhibition of ATM leads to inhibition of the checkpoint signaling pathway. Hence, addition of checkpoint inhibitors to anticancer therapies may be an effective targeting strategy. A recent study reported that Wip1, a protein phosphatase, de-phosphorylates serine 1981 of ATM during the DNA damage response. Squalene has been proposed to complement anticancer therapies such as chemotherapy and radiotherapy; however, there is little mechanistic information supporting this idea. Here, we report the inhibitory effect of squalene on ATM-dependent DNA damage signals. Squalene itself did not affect cell viability and the cell cycle of A549 cells, but it enhanced the cytotoxicity of gamma-irradiation (γIR). The in vitro kinase activity of ATM was not altered by squalene. However, squalene increased Wip1 expression in cells and suppressed ATM activation in γIR-treated cells. Consistent with the potential inhibition of ATM by squalene, IR-induced phosphorylation of ATM effectors such as p53 (Ser15) and Chk1 (Ser317) was inhibited by cell treatment with squalene. Thus, squalene inhibits the ATM-dependent signaling pathway following DNA damage through intracellular induction of Wip1 expression.     

Disparity and Trends in Secondhand Smoke Exposure among Japanese Employees,Particularly Smokers vs. Non-Smokers

BackgroundMonitoring disparities in secondhand smoke (SHS) exposure is important for tailoring smoke-free policies to the needs of different groups. We examined disparity and trends in SHS exposure among both nonsmokers and smokers at Japanese workplaces between 2002 and 2012.MethodsA total of 32,940 employees in nationally representative, population-based, repeated cross-sectional surveys in 2002, 2007 and 2012 in Japan was analyzed. Adjusted rate ratios for workplace SHS exposure from other people (“everyday” and “everyday or sometimes”) were calculated according to covariates, using log-binomial regression models with survey weights. In this survey, employees who do not smoke at workplace are defined as workplace-nonsmokers; and those smoke at workplace are used as workplace-smokers. SHS exposure for smokers does not involve their own SHS.ResultsWhile everyday SHS exposure prevalence in workplace-nonsmokers decreased markedly (33.2% to 11.4%), that in workplace-smokers decreased only slightly (63.3% to 55.6%). Workplace-smokers were significantly more likely to report everyday SHS exposure than workplace-nonsmokers, and the degree of association increased over time: compared with the nonsmokers (reference), covariates-adjusted rate ratio (95% confidence interval) for the smokers increased from 1.70 (1.62–1.77) in 2002 to 4.16 (3.79–4.56) in 2012. Similar results were observed for everyday or sometimes SHS exposure. Compared with complete workplace smoking bans, partial and no bans were consistently and significantly associated with high SHS exposure among both nonsmokers and smokers. We also observed disparities in SHS exposure by employee characteristics, such as age group and worksite scale.ConclusionsAlthough overall SHS exposure decreased among Japanese employees between 2002 and 2012, the SHS exposure disparity between nonsmokers and smokers widened. Because smokers reported more frequent SHS exposure than nonsmokers, subsequent mortality due to SHS exposure may be higher in smokers than in nonsmokers. This information may be useful for advocating workplace smoke-free policies.     

Lung Transplantation for Lymphangioleiomyomatosis in Japan

Background

Lung transplantation has been established as the definitive treatment option for patients with advanced lymphangioleiomyomatosis (LAM). However, the prognosis after registration and the circumstances of lung transplantation with sirolimus therapy have never been reported.

Methods

In this national survey, we analyzed data from 98 LAM patients registered for lung transplantation in the Japan Organ Transplantation Network.

Results

Transplantation was performed in 57 patients as of March 2014. Survival rate was 86.7% at 1 year, 82.5% at 3 years, 73.7% at 5 years, and 73.7% at 10 years. Of the 98 patients, 21 had an inactive status and received sirolimus more frequently than those with an active history (67% vs. 5%, p<0.001). Nine of twelve patients who remained inactive as of March 2014 initiated sirolimus before or while on a waiting list, and remained on sirolimus thereafter. Although the statistical analysis showed no statistically significant difference, the survival rate after registration tended to be better for lung transplant recipients than for those who awaited transplantation (p = 0.053).

Conclusions

Lung transplantation is a satisfactory therapeutic option for advanced LAM, but the circumstances for pre-transplantation LAM patients are likely to alter with the use of sirolimus.     

High Mortality of Disseminated Non-Tuberculous Mycobacterial Infection in HIV-Infected Patients in the Antiretroviral Therapy Era

Background

Little information is available on the mortality and risk factors associated with death in disseminated non-tuberculous mycobacterial infection (dNTM) in HIV-infected patients in the ART-era.

Methods

In a single-center study, HIV-infected dNTM with positive NTM culture from sterile sites between 2000 and 2013 were analysed. The clinical characteristics at commencement of anti-mycobacterial treatment (baseline) were compared between those who survived and died.

Results

Twenty-four patients were analyzed. [The median CD4 27/μL (range 2–185)]. Mycobacterium avium and M. intracellulare accounted for 20 (83%) and 3 (13%) of isolated NTM. NTM bacteremia was diagnosed in 15 (63%) patients. Seven (29%) patients died, and NTM bacteremia was significantly associated with mortality (p = 0.022). The baseline CD4 count was significantly lower in the non-survivors than the survivors (median 7/μL versus 49, p = 0.034). Concomitant AIDS-defining diseases or malignancies were not associated with mortality. Immune-reconstitution syndrome (IRS) occurred to 19 (79%) patients (8 paradoxical and 11 unmasking), and prognosis tended to be better in unmasking-IRS than the other patients (n = 13) (p = 0.078). Patients with paradoxical-IRS had marginally lower CD4 count and higher frequency of bacteremia than those with unmasking-IRS (p = 0.051, and 0.059). Treatment with systemic corticosteroids was applied in 63% and 55% of patients with paradoxical and unmasking-IRS, respectively.

Conclusion

dNTM in HIV-infected patients resulted in high mortality even in the ART-era. NTM bacteremia and low CD4 count were risk factors for death, whereas patients presented with unmasking-IRS had marginally better prognosis. IRS occurred in 79% of the patients, suggesting difficulty in the management of dNTM.     

Cloning of a full-length cDNA encoding bovine thymus poly(ADP-ribose) synthetase: evolutionarily conserved segments and their potential functions

The primary structure of bovine thymus poly(ADP-ribose) synthetase, as deduced from the nucleotide sequence of a cloned cDNA, indicated that this enzyme is composed of 1016 amino acids (aa) with an M_r of 113481. An abundance of Lys and Arg residues was in accord with the known basic nature of this protein. A comparison with reported sequences of human counterparts revealed: (1) three functional domains separated by partial proteolysis, i.e., DNA-binding (N-terminal), auto-modification (central), and NAD-binding (C-terminal) domains, have, in this order, increasing degrees of homology; (2) the DNA-binding domain is composed of two distinct regions: one, less conserved, containing zinc-binding fingers and the other, more conserved, containing helix-turn-helix motifs; (3) all Glu and Asp residues in the automodification domain are conserved; and (4) a 78-aa stretch encompassing the nucleotide-binding fold in the NAD-binding domain is completely conserved. These results are compatible with specific features of each domain, i.e., complex DNA-enzyme interactions, multiple automodification at acidic aa residues, and a stringent specificity for the substrate, NAD.