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Personal protective equipment (PPE) has been an invaluable yet limited resource when it comes to protecting healthcare workers against infection during the 2019 coronavirus (COVID-19) pandemic. In the US, N95 respirator supply chains are severely strained and conservation strategies are needed. A multidisciplinary team at the Washington University School of Medicine, Barnes Jewish Hospital, and BJC Healthcare was formed to implement a program to disinfect N95 respirators. The process described extends the life of N95 respirators using vaporized hydrogen peroxide (VHP) disinfection and allows healthcare workers to retain their own N95 respirator across a large metropolitan healthcare system.

Background Early exposure to alcohol in adolescence is associated with a range of long term harms. Better understanding of trajectories of alcohol use from adolescence to early adulthood would help target prevention strategies to high risk groups. Methods Christchurch (New Zealand) general population birth cohort (n = 1265). A latent trajectory model of drinking behaviour at age 14–16 was used to predict drinking outcomes at age 18–35, net of covariate factors known to be associated with substance use outcomes in this cohort. Results Three classes of adolescent alcohol use were identified. These were: occasional drinkers, emergent binge drinkers and increasing heavy drinkers. Conclusions This analysis identifies three groups of adolescent alcohol users with differing patterns of use. Emergent binge drinkers likely require public policy responses to alcohol use whereas increasing heavy drinkers are potentially able to be identified individually on the basis of patterns of alcohol use and social variables. This group may benefit from psychosocial interventions and are unlikely to respond to a broad public health approach.

Purpose Parenting is a modifiable factor affecting the development of alcohol use disorder (AUD); however, the persistence of this effect into adulthood remains poorly understood. This study aimed to explore the longitudinal relationship between positive parenting and AUD in adulthood. Methods Data were gathered from the Christchurch Health and Development Study (CHDS), a birth cohort of 1,265 children born in Christchurch (New Zealand) in mid-1977. Positive parenting was quantified to age 16, and included the extent to which cohort members self-reported: high scores on measures of maternal and paternal care; low scores on a measure of maternal and paternal overprotection; high scores on a measure of parental attachment; low scores on a measure of parental intimate partner violence; and occasional or no use of physical punishment. Outcome measures were AUD incidence and symptoms at ages 15–35, with potential confounding factors and time-dynamic covariates included. Results There was a significant association between positive parenting and AUD outcomes, with higher levels of positive parenting associated with a lower incidence of AUD and AUD symptoms. Controlling for confounding factors reduced the association between positive parenting and AUD outcomes, but they remained statistically significant. Adjustment for mental health, life stress, and employment reduced the magnitude of the association between positive parenting and alcohol outcomes to statistical nonsignificance. Conclusions Parenting factors in childhood and adolescence are linked to AUD outcomes in adulthood, as well as mental health, substance use, and life stress. Investment in positive parenting in adolescence may reduce AUD and associated harms in adulthood.

International public policy on age of first alcoholic drink (AFD) has emphasised the long-term benefits of delaying AFD. This study aimed to compare AFD to age of first intoxication (AFI) as predictors of substance use disorder and mental disorder outcomes in adulthood.Data were obtained from a longitudinal birth cohort in Christchurch, New Zealand. Participants were born in 1977. Analysis samples ranged from n = 1025 (age 18) to n = 962 (age 35). Measures of AFD and AFI were generated using parental- and self-report data collected from age 11. Outcomes at age 18-35 were alcohol quantity consumed, DSM-IV alcohol use disorder (AUD) and AUD symptoms, major depression, anxiety disorder, and nicotine, cannabis, and other illicit drug dependence. Covariate factors measured during childhood included family socioeconomic status, family functioning, parental alcohol-related attitudes/behaviours, and individual factors.There was a significant unadjusted association between AFD and symptoms of AUD (p .001) and nicotine dependence (p .05) but not other outcomes. AFI was significantly (p .05) associated with all outcomes. After adjustment for covariates, the association between AFD and outcomes was not statistically significant. Conversely, in adjusted models, statistically significant (p .05) associations remained between AFI and all AUD and substance use disorder outcomes but not alcohol consumption or mental disorder outcomes.AFI was a more robust predictor of adult substance use disorder outcomes than AFD. Public health and policy interventions aimed at prevention of long term harms from alcohol should therefore focus on AFI rather than AFD.

Here we define an important role for heat shock factor 1 (HSF1) in the cellular response to genotoxic agents. We demonstrate for the first time that HSF1 can complex with nuclear p53 and that both proteins are co-operatively recruited to p53-responsive genes such as p21. Analysis of natural and synthetic cis elements demonstrates that HSF1 can enhance p53-mediated transcription, whilst depletion of HSF1 reduces the expression of p53-responsive transcripts. We find that HSF1 is required for optimal p21 expression and p53-mediated cell-cycle arrest in response to genotoxins while loss of HSF1 attenuates apoptosis in response to these agents. To explain these novel properties of HSF1 we show that HSF1 can complex with DNA damage kinases ATR and Chk1 to effect p53 phosphorylation in response to DNA damage. Our data reveal HSF1 as a key transcriptional regulator in response to genotoxic compounds widely used in the clinical setting, and suggest that HSF1 will contribute to the efficacy of these agents.

Tat-interactive protein 60 kDa is a nuclear acetyltransferase that both coactivates and corepresses transcription factors and has a definitive function in the DNA damage response. Here, we provide evidence that Tat-interactive protein 60 kDa is phosphorylated by protein kinase C epsilon. In vitro, protein kinase C epsilon phosphorylates Tat-interactive protein 60 kDa on at least two sites within the acetyltransferase domain. In whole cells, activation of protein kinase C increases the levels of phosphorylated Tat-interactive protein 60 kDa and the interaction of Tat-interactive protein 60 kDa with protein kinase C epsilon. A phosphomimetic mutant Tat-interactive protein 60 kDa has distinct subcellular localisation compared to the wild-type protein in whole cells. Taken together, these findings suggest that the protein kinase C epsilon phosphorylation sites on Tat-interactive protein 60 kDa are important for its subcellular localisation. Regulation of the subcellular localisation of Tat-interactive protein 60 kDa via phosphorylation provides a novel means of controlling Tat-interactive protein 60 kDa function.

BACKGROUND Small molecule MDM2 antagonists including nutlin-3 have been shown to be effective against a range of cancer cell types and nutlin-3 can inhibit growth of LNCaP xenografts. We compared the efficacy of nutlin-3 in three prostate cancer cell types and provide an insight into the mechanism of nutlin-3. METHODS Nutlin-3 efficacy was measured using proliferation assays, cell cycle analysis, apoptosis assays, quantitative RT-PCR, and immunoblotting. Chromatin immunoprecipitation (ChIP) assays were also performed. RESULTS Nutlin-3 can specifically inhibit proliferation of LNCaP cells through cell cycle arrest and apoptosis. This coincides with increased levels of the p53-responsive transcripts p21, PUMA, gadd45, and Mdm2 and recruitment of p53 to chromatin. Nutlin-3 also reduces androgen receptor levels, resulting in altered receptor recruitment to chromatin. CONCLUSION Our study demonstrates that small molecule MDM2 antagonists might be useful in the treatment of human prostate cancers that retain functional p53 and androgen receptor signaling. Prostate 67: 900–906, 2007. © 2007 Wiley-Liss, Inc.

AimThe purpose of this study is to evaluate an educational programme, ‘Diabetes Connect: Connecting Professions’, which was developed to enhance communication across primary care networks, to support best practice in clinical interventions and progress multidisciplinary team work to benefit patients in diabetes care.MethodsA total of 26 workshops were successfully delivered for 309 primary care professionals across the state of Queensland in Australia from November 2011. It consists of two separate, but complementary training elements: a series of online clinical education training modules and state-wide interprofessional learning workshops developed to enhance professional competencies. The evaluation design included completion of online surveys by the participants at two time points: first upon registering for the online modules or workshops; second, one week after attending a workshop. The survey included questions to evaluate the change in role performance measures.FindingsOverall, significant increases in participants’ current knowledge, perceived ability to adopt this knowledge at work and willingness to change professional behaviour in the short term were observed.ConclusionThe study suggests that for maximum benefit both, workshop and online training, should be combined and made available widely. Future programmes should use a randomised trial design to test the delivery model.

Tip60 is a histone acetyltransferase (HAT) implicated in a wide range of cellular functions, including mRNA synthesis and DNA repair. In the present report we propose a model based on which Tip60 is actively involved in ribosomal gene transcription through acetylation of UBF, a ribosomal specific transcription factor, as well as through its direct recruitment to the human ribosomal gene promoter, as shown by chromatin immunoprecipitation experiments. Electron microscopy studies revealed that Tip60 resides in sites of active rDNA transcription within the nucleolus, while it co-localizes with UBF as shown by confocal microscopy. In addition, in vivo transcription assays demonstrated that the nucleolar fraction of Tip60 localizes to sites of newly synthesized rRNA. Finally, functional assays established that Tip60 complexes with, and targets UBF for acetylation. The present study underlines the importance of acetylation in rDNA transcription and directly implicates Tip60 in the process of ribosomal gene transcription.

Objectives: To examine the effect of androgen treatment upon histone deacetylase 4 (HDAC4) localisation and, thus, enzymatic function in androgen sensitive prostate cancer (CaP) models. To study HDAC4 expression in benign prostatic hyperplasia, primary and hormone refractory (HR) CaP and to investigate the involvement of histone deacetylase activity in the development of the androgen insensitive phenotype. Methods: Immunohistochemical staining of prostate sections of both benign tissue and primary and hormone relapsed prostate cancer, as well as of the CWR22 mouse xenograft model, and indirect quantitative immunofluorescence staining of endogenous HDAC4 in LNCaP cells. Results: HDAC4 is recruited to the nuclei of HR cancer cells, where it may exert an inhibitory effect on differentiation and contribute to the development of the aggressive phenotype of late stage CaP. The above may result from the loss of androgen responsiveness characterising HR CaP, since HDAC4 nuclear localisation is regulated by androgens in androgen responsive systems (i.e. LNCaP, CWR22) reflecting earlier phase disease. Conclusions: HDAC4 may contribute to the development of HR CaP and, therefore, constitute a potential therapeutic target, particularly in the most lethal phase of androgen independence.

Two experiments tested memory for a once-heard voice. Experiment 1 showed that hearing an unknown voice utter the same sentence three times improved recognition of the voice a week later compared with hearing only a single utterance of the sentence, but instructions to attend to the voice did not. The impairment caused by seeing the speaker's face during the original utterance (the Face Overshadowing Effect--FOE) occurred only with the single utterance and was unaffected by instructions. It was concluded that length of utterance without increase in speech variety aids voice recognition, and that the FOE is not due to voluntary attention to face rather than voice, but may be due to involuntary attention to the initial exposure of the face. Experiment 2 investigated whether exposure to the face before the onset of speech reduced the FOE. Such an effect was observed and it was concluded that the FOE is due to involuntary preference for processing face information in order to aid later recognition of the individual, while speech is processed primarily for meaning. Absence of an FOE on memory for the words uttered was consistent with this interpretation.

Results were combined from 5 experiments by Cook in 1998 with 728 participants who listened to one male voice and one female voice each saying a sentence, then attempted to recognise the voices from line-ups of six voices presented a week later. While 352 male listeners did not differ significantly in recognising female and male voices (38% correct vs 41%), 376 female listeners were significantly more likely to recognise female than male voices (51% vs 43% correct). There was no evidence for individual differences in voice recognition in that listeners who recognised the male voice were no more likely to recognise the female voice than those who failed to recognise the male voice.

We have examined levels of epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) in neoplastic and non-neoplastic bladder tissue using a standard radioimmunoassay technique. Tumour samples had much higher TGF-alpha levels compared with EGF and TGF-alpha levels in malignant tissue were significantly higher than in benign bladder samples. There was, in addition, a difference in mean EGF levels from 'normal' bladder samples from non-tumour bearing areas of bladder in patients with bladder cancer compared with 'normal' bladder tissue obtained at the time of organ retrieval surgery. Levels of EGF and TGF-alpha did not correlate with levels of EGF receptor (EGFR) as determined by a radioligand binding method but levels of TGF-alpha > 10 ng gm-1 of tumour tissue did correlate with EGFR positivity defined using immunohistochemistry. These data suggest that TGF-alpha is the likely ligand for EGFR in bladder tumours.

Tip60 (KAT5) is a histone acetyltransferase (HAT enzyme) involved in multiple cellular processes including transcriptional regulation, DNA damage repair and cell signalling. In prostate cancer, aggressive cases over-express Tip60 which functions as an androgen receptor co-activator via direct acetylation of lysine residues within the KLKK motif of the receptor hinge region. The purpose of this study was to identify and characterise a Tip60 acetylase inhibitor. High-throughput screening revealed an isothiazole that inhibited both Tip60 and p300 HAT activity. This substance (initially identified as 4-methyl-5-bromoisothiazole) and other isothiazoles were synthesised and assayed against Tip60. Although an authentic sample of 4-methyl-5-bromoisothiazole was inactive against Tip60, in an in vitro HAT assay, 1,2-bis(isothiazol-5-yl)disulfane (NU9056) was identified as a relatively potent inhibitor (IC(50) 2 µM). Cellular activity was confirmed by analysis of acetylation of histone and non-histone proteins in a prostate cancer cell line model. NU9056 treatment inhibited cellular proliferation in a panel of prostate cancer cell lines (50% growth inhibition, 8-27 µM) and induced apoptosis via activation of caspase 3 and caspase 9 in a concentration- and time-dependent manner. Also, decreased androgen receptor, prostate specific antigen, p53 and p21 protein levels were demonstrated in response to treatment with NU9056. Furthermore, pre-treatment with NU9056 inhibited both ATM phosphorylation and Tip60 stabilization in response to ionising radiation. Based on the activity of NU9056 and the specificity of the compound towards Tip60 relative to other HAT enzymes, these chemical biology studies have identified Tip60 as a potential therapeutic target for the treatment of prostate cancer.

BACKGROUND Histone deacetylase 1 (HDAC1) is a co-repressor involved in differentiation and proliferation control. It is upregulated in malignant compared to benign tissue, and targets a number of transcription factors including p53. METHODS By immunohistochemistry, HDAC1 protein expression was investigated in human prostate specimens and the CWR22 mouse xenograft model. Flow cytometry and deconvolution immunofluorescence were also performed. RESULTS HDAC1 was upregulated in pre-malignant and malignant lesions, with the highest increase in expression in hormone refractory (HR) cancer. Using the CWR22 xenograft model we showed androgen dependent regulation of HDAC1. HDAC1 overexpression led to a significant increase in proliferation and a shift towards the undifferentiated cytokeratin (CK) profile in a PC3M derivative clone constitutively expressing HDAC1. CONCLUSION This study underlines the importance of HDAC1 in cell proliferation and the development of prostate cancer (CaP) and proposes a mechanism for HDAC1 nuclear recruitment. HDAC1 may constitute a crucial therapeutic target particularly in the most lethal phase of androgen independence. © 2004 Wiley-Liss, Inc.

Background: Jewish culturally supported beliefs may discourage drinking and drunkenness as ways of socialising and coping with stress. Thus Jewish men under stress may be relatively more likely to become depressed, and less likely to use and abuse alcohol. This study is the first qualitative comparison of Jews and Protestants, men and women. It examines whether alcohol-related beliefs are consistent with the alcohol-depression hypothesis, i.e. that positive beliefs about alcohol use and effects are associated with high alcohol use and low depression.Material and discussion: A thematic (interpretive phenomenological) analysis on open-ended question responses, from 70 Jews and 91 Protestants, and on semi-structured interviews with five Jews and four Protestants, identified three salient themes: the importance of retaining self-control; the pleasures of losing inhibitions; and the relations of alcohol-related behaviour to identity. Compared to Protestants, Jews described alcohol-related behaviour as threatening to self-control, loss of inhibition as unenjoyable and dangerous and distinguished between the kinds of drinking behaviours appropriate for Jews and others. Sub-themes for Protestant men were denial that drinking threatens self-control, and appropriateness of going to the pub.Conclusions: The themes identified are not measurable using published research instruments. Alcohol-related behaviour may be a feature of Jewish identity. The beliefs identified are consistent with the alcohol-depression hypothesis.

It has been suggested that Protestant culture has become more tolerant towards suicide in the previous century, while Jewish culture has traditionally not condoned suicide. There have been reports that suicide rates are somewhat lower among Jews than among people of Protestant background. We asked whether there were differences between Jews' and Protestants' beliefs about suicide that might relate to these suggestions and reports. Beliefs about suicide were assessed from the Reasons For Living Inventory (RFL), and with questions about the acceptability of suicide in some circumstances. Self-reported suicide ideation and attempts were also assessed. Some religious-cultural differences were found in beliefs about suicide, but not with regard to ideation and behavior. We discussed the relations between differences in belief, and reported differences in suicide prevalence, and suggested that most of the belief differences were consistent with reported patterns of prevalence. Notably, Jews believed more strongly than Protestants that moral-religious objections to suicide were reasons for living, and that suicide was less acceptable in certain circumstances.

Prostate cancer (CaP) is initially androgen sensitive and responsive to hormone ablation therapy. However, cancer growth recurs despite androgen deprivation in the majority of cases of advanced disease. The molecular basis of this progression still remains unknown. The significance of androgen receptor (AR) coactivator proteins in this androgen-dependent malignancy is only beginning to emerge. In the present study, we examined the role of Tat interactive protein, 60 kDa (Tip60), an AR coactivator, in CaP progression. In hormone refractory CaP biopsies, we observed a nuclear accumulation of Tip60 expression in contrast to a more diffuse distribution pattern observed in benign prostate hyperplasia and primary CaP. Furthermore, in both the prostate xenograft model CWR22 and the LNCaP CaP cell line, we observed that androgen withdrawal promoted upregulation of Tip60 as well as nuclear accumulation. In contrast, androgen exposure resulted in decreased Tip60 expression that was more closely linked to a cytoplasmic presence. Chromatin immunoprecipitation analysis revealed Tip60's recruitment to the PSA gene promoter in both androgen-dependent and -independent cell lines. Thus, in vitro and in vivo data support a possible role for Tip60 in the molecular pathway leading to the development of androgen-independent CaP following long-term androgen deprivation therapy.

Background: Some research has suggested that Jews drink less alcohol than other cultural groups, and may have different beliefs about its use. Differences in beliefs about alcohol, and different patterns of use, may play a role in accounting for cultural and gender variations in depression prevalence. Alcohol may act as an escape route from depression, thus deflating depression rates in certain groups of people, in particular, men from Protestant backgrounds. Methods: Self-reported use and beliefs about alcohol were assessed in a sample of UK 70 Jews and 91 Protestants, including non-practising people of Jewish and Protestant background. The effects of religious group and of gender on measures of alcohol behaviour and beliefs were examined. Results: Some differences were found between Jews and Protestants. Jews had less favourable beliefs about alcohol and drank less than Protestants. More importantly, and in line with our hypotheses, there were gender differences in Protestants but not Jews with respect to some beliefs about alcohol and actual use of alcohol. Conclusions: The study goes some way in supporting the notion that religious-cultural and gender differences in beliefs and behaviour towards alcohol may contribute to religious-cultural and gender differences in rates of depression.

This study examined tolerance for depression among Jewish and Protestant men and women in the United Kingdom. A measure of tolerance for depression was developed, which examined willingness to admit to and seek help for depression. More specifically, the items in the measure (developed from extended interviews) covered empathy towards sufferers, potential virtues of the illness, hopes for treatment, seeing the illness as 'normal', and telling other people about it. Existing evidence suggested that tolerance for depression might be greater amongst Jews compared with Protestants, and women compared with men. Also, Jewish men were expected to be more tolerant than Protestant men, whereas Protestant and Jewish women were not expected to differ from each other. It was found that tolerance for depression was greater amongst Jews than Protestants, and this is consistent with the elevated levels of depression amongst Jewish men as compared with Protestant men. However, findings relating to gender were mixed and were not always consistent with our expectations. The findings suggest that there may be some cultural variations in willingness to admit to and seek help for depression, and this may be worth examining in other cultural-religious groups. Individual variations in tolerance for depression may be clinically significant.

The androgen receptor (AR), a member of the nuclear hormone receptor superfamily, is thought to play an important role in the development of prostate cancer. The AR is a hormone-dependent transcription factor that activates expression of numerous androgen-responsive genes. Histone acetyltransferase-containing proteins have been shown to increase activity of several transcription factors, including nuclear hormone receptors, by eliciting histone acetylation, which facilitates promoter access to the transcriptional machinery. Conversely, histone deacetylases (HDACs) have been identified which reduce levels of histone acetylation and are associated with transcriptional repression by various transcription factors. We have previously shown that Tip60 (Tat-interactive protein, 60 kDa) is a bona fide co-activator protein for the AR. Here we show that Tip60 directly acetylates the AR, which we demonstrate is a requisite for Tip60-mediated transcription. To define a mechanism for repression of AR function, we demonstrate that AR activity is specifically down-regulated by the histone deacetylase activity of HDAC1. Furthermore, using both mammalian two-hybrid and immunoprecipitation experiments, we show that AR and HDAC1 interact, suggestive of a direct role for down-regulation of AR activity by HDAC1. In chromatin immunoprecipitation assays, we provide evidence that AR, Tip60, and HDAC1 form a trimeric complex upon the endogenous AR-responsive PSA promoter, suggesting that acetylation and deacetylation of the AR is an important mechanism for regulating transcriptional activity.

The androgen receptor (AR) is a member of the nuclear hormone receptor superfamily. Recent work in this field has been focused upon defining the mechanisms of transcriptional control exacted by members of this superfamily. Using a COOH-terminal region of the human AR in a yeast two-hybrid screen, we have identified Tip60 as an AR-interacting protein. In this report, we show that Tip60, which was originally identified as a coactivator for the human immunodeficiency virus TAT protein, can enhance AR-mediated transactivation in a ligand-dependent manner in LNCaP and COS-1 cell lines. In addition, our experiments show that Tip60 can also enhance transactivation through the estrogen receptor and progesterone receptor in a ligand-dependent manner; thus identifying Tip60 as a nuclear hormone receptor coactivator. Our studies also demonstrate that Tip60 co-immunoprecipitates with the full-length AR in vitro and that, in our system, Tip60 enhances transactivation to levels observed with the coactivators steroid receptor coactivator 1, p300, and CREB-binding protein. The importance of such proteins in enhancing nuclear hormone receptor-mediated transcriptional activation is widely accepted, and this work suggests that Tip60 may have an equally important role to play.

Observations of the coping behaviors of three-year-old children during a one hour, home-based play session were examined and compared to parental reports of behavior problems and temperament characteristics. Poor coping responses in the play situation were positively associated with behavior difficulties, but not with temperament characteristics. It is concluded that brief play sessions are useful for diagnostic purposes, but it is more important to focus observations on the child's ability to adapt and cope with the interpersonal and structural demands of the play situation rather than on the types of constructions produced or interpretations on the symbolic manipulations of toys.