A Small Molecule Activator of p300/CBP Histone Acetyltransferase Promotes Survival and Neurite Growth in a Cellular Model of Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterised by motor and non-motor symptoms, resulting from the degeneration of nigrostriatal dopaminergic neurons and peripheral autonomic neurons. Given the limited success of neurotrophic factors in clinical trials, there is a need to identify new small molecule drugs and drug targets to develop novel therapeutic strategies to protect all neurons that degenerate in PD. Epigenetic dysregulation has been implicated in neurodegenerative disorders, while targeting histone acetylation is a promising therapeutic avenue for PD. We and others have demonstrated that histone deacetylase inhibitors have neurotrophic effects in experimental models of PD. Activators of histone acetyltransferases (HAT) provide an alternative approach for the selective activation of gene expression, however little is known about the potential of HAT activators as drug therapies for PD. To explore this potential, the present study investigated the neurotrophic effects of CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide), which is a potent small molecule activator of the histone acetyltransferase p300/CBP, in the SH-SY5Y neuronal cell line. We report that CTPB promoted the survival and neurite growth of the SH-SY5Y cells, and also protected these cells from cell death induced by the neurotoxin 6-hydroxydopamine. This study is the first to investigate the phenotypic effects of the HAT activator CTPB, and to demonstrate that p300/CBP HAT activation has neurotrophic effects in a cellular model of PD.     

Perceptions of nurses working with psychiatric consumers regarding the elimination of seclusion and restraint in psychiatric inpatient settings and emergency departments: An Australian survey

Seclusion and restraint continue to be used across psychiatric inpatient and emergency settings, despite calls for elimination and demonstrated efficacy of reduction initiatives. This study investigated nurses’ perceptions regarding reducing and eliminating the use of these containment methods with psychiatric consumers. Nurses (n = 512) across Australia completed an online survey examining their views on the possibility of elimination of seclusion, physical restraint, and mechanical restraint as well as perceptions of these practices and factors influencing their use. Nurses reported working in units where physical restraint, seclusion, and, to a lesser extent, mechanical restraint were used. These were viewed as necessary last resort methods to maintain staff and consumer safety, and nurses tended to disagree that containment methods could be eliminated from practice. Seclusion was considered significantly more favourably than mechanical restraint with the elimination of mechanical restraint seen as more of a possibility than seclusion or physical restraint. Respondents accepted that use of these methods was deleterious to relationships with consumers. They also felt that containment use was a function of a lack of resources. Factors perceived to reduce the likelihood of seclusion/restraint included empathy and rapport between staff and consumers and utilizing trauma‐informed care principles. Nurses were faced with threatening situations and felt only moderately safe at work, but believed they were able to use their clinical skills to maintain safety. The study suggests that initiatives at multiple levels are needed to help nurses to maintain safety and move towards realizing directives to reduce and, where possible, eliminate restraint use.     

Recovery college as a transition space in the journey towards recovery: An Australian qualitative study

Recovery colleges are formal learning programs that aim to support people with a lived experience of mental illness. In this study, we aimed to explore the experiences of participants in a pilot recovery college that opened in Adelaide, South Australia, in 2016. A qualitative exploratory study was conducted involving interviews with learners (n = 8) and focus groups with lived experience facilitators (course facilitators with a lived experience of mental illness, n = 5), Clinician facilitators (mental health service staff facilitators, n = 4), and care coordinators (staff providing case management support, n = 5). Three main themes (hope, identity, and the recovery college as a transition space) and two subthemes (recovery college experience and outcomes) were identified. The results showed that the recovery college provided a transition space for shifting learners' identities from patient to student, facilitated by the experiences and outcomes of the recovery college, providing hope for the future. This study highlights the importance of providing mentally healthy and non‐stigmatizing learning environments to promote and cement recovery for people with a lived experience of mental illness.     

Different risk of deep vein thrombosis and pulmonary embolism in carriers with factor V Leiden compared with non-carriers, but not in other thrombophilic defects. Results from a large retrospective family cohort study

The term factor V Leiden (FVL) paradox is used to describe the different risk of deep vein thrombosis and pulmonary embolism that has been found in carriers of FVL. In a thrombophilic family-cohort, we estimated differences in absolute risks of deep vein thrombosis and pulmonary embolism for various thrombophilic defects. Of 2,054 relatives, 1,131 were female, 41 had pulmonary embolism and 126 deep vein thrombosis. Annual incidence for deep vein thrombosis in non-carriers of FVL was 0.19% (95%CI, 0.16–0.23), and 0.41% (95%CI, 0.28–0.58) in carriers; relative risk (RR) 2.1 (95%CI, 1.4–3.2). For pulmonary embolism these incidences were similar in carriers and non-carriers 0.07%, respectively; RR 1.0 (95% CI, 0.4–2.5). When co-inheritance of other thrombophilic defects was excluded the RR for deep vein thrombosis in FVL carriers was 7.0 (95%CI, 2.3–21.7) compared to non-carriers and 2.8 (95%CI, 0.5–14.4) for pulmonary embolism. For other thrombophilic defects no such effect was observed. Thus the FVL paradox was confirmed in our study. However, a similar paradox in carriers of other thrombophilic defects was not observed.     

Every urologist and oncologist should know about treating sexual and gender minority prostate cancer patients: translating research findings into clinical practice

In 2016, the NIH designated sexual and gender minorities (SGM) a health disparity population. The next year, the American Society of Clinical Oncology highlighted the need to improve the suboptimal cancer and survivorship care received by SGM populations. There are currently no evidence-based training programs in culturally competent care of prostate cancer patients who are gay, bisexual and/or transgender. In this selective review, we summarize findings from the largest quantitative studies focused on sexual minority prostate cancer survivors and from 65 interviews with NIH staff, clinicians, and cancer clinics in 11 US cities. The report is divided into three parts and uses a question and answer format to address 21 questions relevant to clinicians providing care to SGM prostate cancer patients. First, we identify population-specific issues that are culturally relevant in the care of SGM patients with prostate cancer. While a body of research has emerged on sexual minority prostate cancer patients, the literature on gender minorities is limited to single case reports and inadequate to inform practice. This review covers definitions, population size, cultural and historical context, sexual behavior, population invisibility, sexual orientation and gender identity (SOGI) in the electronic medical record, disparities and evidence of discrimination in treatment provision. The second part focuses on promoting evidence-informed, patient-centered care. This includes current practices in assessing sexual orientation, management of disclosure of sexual orientation, how to address common problems sexual minority men experience post-treatment, common questions sexual minority patients have, management of urinary incontinence, HIV and STI risk during and post-treatment, and sub-groups of sexual minority patients with worse outcomes. It then identifies how male partners differ in prostate cancer support, current research on rehabilitation for sexual minority men, issues in advanced prostate cancer, and things to avoid with minority patients. Finally, we examine the cultural divide between provider and patient, advocating for cultural humility when working with minority patients. Training programs and continuing education can help providers both to become more aware of their own cultural assumptions, informed about health disparities, and able to provide quality care, and to make clinics more welcoming to SGM patients.     

El cáncer colorrectal en la poliposis adenomatosa familiar: ¿existen factores clínicos de predicción?

BackgroundFamilial Adenomatous Polyposis (FAP) is a hereditary disorder with multiple colorectal polyps that exhibit an almost inevitable risk of colorectal cancer (CRC) in untreated patients.GoalsTo evaluate clinical features related to CRC risk at diagnosis.Material and methodsCharts from 88 patients were reviewed to collect information regarding age, family history, symptoms, polyposis severity and association with CRC.Results41 men (46.6%) and 47 women (53.4%) were assisted. CRC was detected in 53 patients (60.2%), with a frequency of 9.1% under 20 years, 58% between 21–40 and 85% over 41 years of age. Average age of patients without CRC was lower at treatment (29.5 vs. 40.0 years; p=0.001). Family history was reported by 58 patients (65.9%), whose average age did not differ from those who didn’t report it (33.4 vs. 34.4; p=0.17). Asymptomatic patients comprised 10.2% of the total; in this group, CRC incidence was much lower when compared to those presenting symptoms (1.1% vs. 65.8%; p=0.001). Patients without CRC presented a shorter length of symptoms (15.2 vs. 26.4 months; p=0.03) and less frequent weight loss (11.4% vs. 33.9%; p=0.01). At colonoscopy, polyposis was classified as attenuated in 12 patients (14.3%), who presented greater average age (48.2 vs. 33.3 years; p=0.02) and equal CRC incidence (58.3% vs. 58.3%; p=0.6) when compared to those with classic polyposis.ConclusionsThe risk of CRC in FAP patients 1) increases significantly after the second decade; 2) is associated with higher age, weight loss, presence and duration of simptomatology; 3) is similar in patients with attenuated or classic phenotype.     

Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women

Hereditary thrombophilia is associated with an increased risk of fetal loss. Assuming that fetal loss is due to placental thrombosis, anticoagulant treatment might improve pregnancy outcome. In an observational family cohort study, we prospectively assessed the effects of anticoagulant drugs on fetal loss rates in women with hereditary deficiencies of antithrombin, protein C or protein S. The cohort contained 376 women (50 probands and 326 deficient or non-deficient relatives). Probands were consecutive deficient patients with venous tromboembolism. Thromboprophylaxis during pregnancy was recommended in deficient women, irrespective of prior venous thromboembolism, and in non-deficient women with prior venous thromboembolism. Outcome of first pregnancy was analysed in 55 eligible women. Of 37 deficient women, 26 (70%) received thromboprophylaxis during pregnancy, compared with three of 18 (17%) non-deficient women. Fetal loss rates were 0% in deficient women with thromboprophylaxis versus 45% in deficient women without (P = 0.001) and 7% in non-deficient women without thromboprophylaxis (P = 0.37). The adjusted relative risk of fetal loss in women who received thromboprophylaxis versus women who did not was 0.07 (95% confidence interval 0.001-0.7; P = 0.02). Our data suggest that anticoagulant treatment during pregnancy reduces the high fetal loss rate in women with hereditary deficiencies of antithrombin, protein C or protein S.     

Epstein-Barr virus-DNA load monitoring late after lung transplantation: a surrogate marker of the degree of immunosuppression and a safe guide to reduce immunosuppression

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is a serious complication after lung transplantation and its relation with Epstein-Barr virus (EBV) is well recognized. It has been postulated that preemptive reduction of immunosuppression guided by EBV-DNA load may lead to a significantly lower incidence of PTLD, because of the reconstitution of T-cell control. In this report, we describe the feasibility of this approach in terms of safety with regard to the risk of acute as well as chronic allograft rejection in 75 lung transplant recipients transplanted between 1990 and 2001 and followed for this study from June 1, 2001 until January 1, 2006. METHODS: From all patients visiting our outpatient clinic, EBV-DNA load was measured at least twice a year during the study period. In patients with positive results, measurements were repeated every two to four weeks. EBV reactivation was defined as two consecutive EBV-DNA load measurements with a rising trend; with the last measurement exceeding 10.000 copies/mL under stable immunosuppression. In such case, immunosuppression was reduced. RESULTS: EBV reactivation was observed in 26/75 patients (35%). One (1.5%) of these patients developed PTLD during the study period. Acute rejection, acceleration of chronic allograft rejection, or worse survival were not observed after reduction of immunosuppression. CONCLUSIONS: Preemptive reduction of immunosuppression after lung transplantation guided by EBV-DNA load appears to be a safe approach for the prevention of PTLD in lung transplant recipients late after transplantation.     

The use of metformin for women with PCOS undergoing IVF treatment

BACKGROUND: Metformin appears to improve reproductive function in some women with polycystic ovary syndrome (PCOS). We wished to explore the effect of metformin in women with PCOS undergoing IVF. METHODS: A randomized, placebo-controlled, double-blind study was carried out between 2001 and 2004. Patients with PCOS undergoing IVF/ICSI treatment using a long GnRH agonist protocol were randomized to receive metformin (MET), 850 mg, or placebo (PLA) tablets twice daily from the start of the down-regulation process until the day of oocyte collection. The primary outcome was to be an improvement in the overall fertilization rate. RESULTS: One-hundred and one IVF/ICSI cycles were randomized to receive metformin (52) or to receive placebo (49). There was no difference in the total dose of rFSH required per cycle (median dose: MET = 1200 U, PLA = 1300 U; P = 0.937). The median number of oocytes retrieved per cycle (MET = 17.2, PLA = 16.2; P = 0.459) and the overall fertilization rates (MET = 52.9%, PLA = 54.9%; P = 0.641) did not differ. However, both the clinical pregnancy rates beyond 12 weeks gestation per cycle (MET = 38.5%, PLA = 16.3%; P = 0.023) and per embryo transfer (MET = 44.4%, PLA = 19.1%; P = 0.022) were significantly higher in those treated with metformin. Furthermore, a significant decrease in the incidence of severe ovarian hyperstimulation syndrome (OHSS) was observed (MET = 3.8%, PLA = 20.4%; P = 0.023), and this was still significant after adjustment for BMI, total rFSH dose and age (OR = 0.15; 95% CI: 0.03, 0.76; P = 0.022). CONCLUSION: Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of OHSS.     

Inhaler devices: what remains to be done?

The 1000 Years of Pharmaceutical Aerosols Conference convened posing the question; "what remains to be done?" When applying this question to the topic of inhaler devices, two hugely different perspectives could be taken. On the one hand, it could be argued that because there is an array of delivery systems available and the industry, prescribing physicians and patients alike have considerable choice, why would we believe it necessary to do anything further? On the other hand, as an industry, we are constantly reminded by our "customers" that the inhaler devices available are less than adequate, and in some cases woefully inadequate, that they are not "patient" friendly, not intuitive to use and importantly do nothing to encourage the patient to take the medication as intended and as prescribed. So, taking the second point of view as more reflective of reality--the Voice of the Customer--our starting point must be that there is still much to do in the field of inhaler devices. The purpose of this article is to outline some key basic requirements for inhaler design and perhaps to question some of the entrenched thinking that has pervaded inhaler product design for too many years.