Long Term Use of HU210 Adversely Affects Spermatogenesis in Rats by modulating the Endocannabinoid System

Recent societal acceptance of cannabinoids as recreational and therapeutic drugs has posed a potential hazard to male reproductive health. Mammals have a highly sophisticated endogenous cannabinoid (ECS) system that regulates male (and female) reproduction and exo-cannabinoids may influence it adversely. Therefore it is imperative to determine their effects on male reproduction so that men can make informed choices as to their use. Here, an animal model was used to administer HU210, a synthetic analogue of ?9-tetrahydrocannabinol (THC) and potent cannabinoid receptor (CB) agonist to determine its effects on reproductive organ weights, spermatogenesis, testicular histology and sperm motility. Its effects on the physiological endocannabinoid system were also investigated. Spermatogenesis was markedly impaired with reductions in total sperm count after 2 weeks of exposure. Spermatogenic efficiency was depleted, and Sertoli cell number decreased as exposure time increased with seminiferous tubules showing germ cell depletion developing into atrophy in some cases. Sperm motility was also adversely affected with marked reductions from 2 weeks on. HU210 also acted on the sperm’s endocannabinoid system. Long term use of exo-cannabinoids has adverse effects on both spermatogenesis and sperm function. These findings highlight the urgent need for studies evaluating the fertility potential of male recreational drug users.

Differences in the Endocannabinoid System of Sperm from Fertile and Infertile Men

Male infertility is a major cause of problems for many couples in conceiving a child. Recently, lifestyle pastimes such as alcohol, tobacco and marijuana have been shown to have further negative effects on male reproduction. The endocannabinoid system (ECS), mainly through the action of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) at cannabinoid (CB(1), CB(2)) and vanilloid (TRPV1) receptors, plays a crucial role in controlling functionality of sperm, with a clear impact on male reproductive potential. Here, sperm from fertile and infertile men were used to investigate content (through LC-ESI-MS), mRNA (through quantitative RT-PCR), protein (through Western Blotting and ELISA) expression, and functionality (through activity and binding assays) of the main metabolic enzymes of AEA and 2-AG (NAPE-PLD and FAAH, for AEA; DAGL and MAGL for 2-AG), as well as of their binding receptors CB(1), CB(2) and TRPV1. Our findings show a marked reduction of AEA and 2-AG content in infertile seminal plasma, paralleled by increased degradation: biosynthesis ratios of both substances in sperm from infertile versus fertile men. In addition, TRPV1 binding was detected in fertile sperm but was undetectable in infertile sperm, whereas that of CB(1) and CB(2) receptors was not statistically different in the two groups. In conclusion, this study identified unprecedented alterations of the ECS in infertile sperm, that might impact on capacitation and acrosome reaction, and hence fertilization outcomes. These alterations might also point to new biomarkers to determine male reproductive defects, and identify distinct ECS elements as novel targets for therapeutic exploitation of ECS-oriented drugs to treat male fertility problems. 

Cannabinoid Receptor influences Chromatin Remodelling in Mouse Spermatids by affecting Content of Transition Protein 2 mRNA and Histone Replacement

Marijuana smokers and animals treated with ?9-tetrahydrocannabinol, THC, the principal component of marijuana, show alterations of sperm morphology suggesting a role for cannabinoids in sperm differentiation and/or maturation. Since the cannabinoid receptor 1 (CNR1) activation appears to play a pivotal role in spermiogenesis, the developmental stage where DNA is remodeled, we hypothesized that CNR1 receptors might also influence chromatin quality in sperm. We used Cnr1 null mutant (Cnr1-/-) mice to study the possible role of endocannabinoids on sperm chromatin during spermiogenesis. We demonstrated that CNR1 activation regulated chromatin remodeling of spermatids by either increasing Tnp2 levels or enhancing histone displacement. Comparative analysis of WT, Cnr1+/- and Cnr1-/- animals suggested the possible occurrence of haploinsufficiency for Tnp2 turnover control by CNR1, while histone displacement was disrupted to a lesser extent. Further, flow cytometry analysis demonstrated that the genetic loss of Cnr1 decreased sperm chromatin quality and was associated with sperm DNA fragmentation. This damage increased during epididymal transit, from caput to cauda. Collectively, our results show that the expression/activity of CNR1 controls the physiological alterations of DNA structure during spermiogenic maturation and epididymal transit. Given the deleterious effects of sperm DNA damage on male fertility, we suggest that the reproductive function of marijuana users may also be impaired by deregulation of the endogenous endocannabinoid system.

No clear evidence of an association between plasma concentrations of n-3 long-chain polyunsaturated fatty acids and depressed mood in a non-clinical population

Previous research suggests that low n-3 long-chain polyunsaturated fatty acid (n-3PUFA) status is associated with higher levels of depression in clinical populations. This analysis aimed to investigate the relationship between depressed mood and n-3PUFA status in a non-clinical population. The analysis was conducted on data collected as part of a large randomized controlled trial investigating the impact of n-3PUFA supplementation on depressed mood in a community-based population. On entry into the trial, data on depressed mood were collected using the Depression, Anxiety and Stress Scales (DASS) and the Beck Depression Inventory (BDI). Plasma concentrations of various n-3PUFAs and n-6 long-chain polyunsaturated fatty acids (n-6PUFAs) were obtained from fasting venous blood samples, and various demographics were also measured. Using regression, there was no evidence of an association between either measure of depressed mood and any of the measures of n-3PUFA status or of n-6PUFA: n-3PUFA ratios. Clear associations were also not found when demographic factors were included in the analyses. These findings suggest that n-3PUFAs may not have a role in the aetiology of minor depression. This is also consistent with the results of other studies that have not demonstrated an association between depressed mood and n-3PUFA status in non-clinical populations and epidemiological studies that have not demonstrated an association between depressed mood and n-3PUFA intake in these populations. (C) 2008 Elsevier Ltd. All rights reserved.

Cognitive-behavioural interventions for children who have been sexually abused

Background: Despite differences in how it is defined, there is a general consensus amongst clinicians and researchers that the sexual abuse of children and adolescents (’child sexual abuse’) is a substantial social problem worldwide. The effects of sexual abuse manifest in a wide range of symptoms, including fear, anxiety, post-traumatic stress disorder and various externalising and internalising behaviour problems, such as inappropriate sexual behaviours. Child sexual abuse is associated with increased risk of psychological problems in adulthood. Cognitive-behavioural approaches are used to help children and their non-offending or ’safe’ parent tomanage the sequelae of childhood sexual abuse. This review updates the first Cochrane review of cognitive-behavioural approaches interventions for children who have been sexually abused, which was first published in 2006.

Objectives: To assess the efficacy of cognitive-behavioural approaches (CBT) in addressing the immediate and longer-term sequelae of sexual abuse on children and young people up to 18 years of age.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2011 Issue 4); MEDLINE (1950 to November Week
3 2011); EMBASE (1980 to Week 47 2011); CINAHL (1937 to 2 December 2011); PsycINFO (1887 to November Week 5 2011); LILACS (1982 to 2 December 2011) and OpenGrey, previously OpenSIGLE (1980 to 2 December 2011). For this update we also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP).

Selection criteria: We included randomised or quasi-randomised controlled trials of CBT used with children and adolescents up to age 18 years who had experienced being sexually abused, compared with treatment as usual, with or without placebo control.

Data collection and analysis: At least two review authors independently assessed the eligibility of titles and abstracts identified in the search. Two review authors independently extracted data from included studies and entered these into Review Manager 5 software. We synthesised and presented data in both written and graphical form (forest plots).

Main results: We included 10 trials, involving 847 participants. All studies examined CBT programmes provided to children or children and a nonoffending parent. Control groups included wait list controls (n = 1) or treatment as usual (n = 9). Treatment as usual was, for the most part, supportive, unstructured psychotherapy. Generally the reporting of studies was poor. Only four studies were judged ’low risk of bias’ with regards to sequence generation and only one study was judged ’low risk of bias’ in relation to allocation concealment. All studies were judged ’high risk of bias’ in relation to the blinding of outcome assessors or personnel; most studies did not report on these, or other issues of bias. Most studies reported results for study completers rather than for those recruited.

Depression, post-traumatic stress disorder (PTSD), anxiety and child behaviour problems were the primary outcomes. Data suggest that CBT may have a positive impact on the sequelae of child sexual abuse, but most results were not statistically significant. Strongest evidence for positive effects of CBT appears to be in reducing PTSD and anxiety symptoms, but even in these areas effects tend to be 'moderate’ at best. Meta-analysis of data from five studies suggested an average decrease of 1.9 points on the Child Depression Inventory immediately after intervention (95% confidence interval (CI) decrease of 4.0 to increase of 0.4; I2 = 53%; P value for heterogeneity = 0.08), representing a small to moderate effect size. Data from six studies yielded an average decrease of 0.44 standard deviations on a variety of child post-traumatic stress disorder scales (95% CI 0.16 to 0.73; I2 = 46%; P value for heterogeneity = 0.10). Combined data from five studies yielded an average decrease of 0.23 standard deviations on various child anxiety scales (95% CI 0.3 to 0.4; I2=0%; P value for heterogeneity = 0.84). No study reported adverse effects.

Authors’ conclusions: The conclusions of this updated review remain the same as those when it was first published. The review confirms the potential of CBT to address the adverse consequences of child sexual abuse, but highlights the limitations of the evidence base and the need for more carefully conducted and better reported trials.

Establishing a population-based patient-reported outcomes study (PROMs) using national cancer registries across two jurisdictions: The Prostate Cancer Treatment, your experience (PiCTure) study

Objective: To establish an international patient-reported outcomes (PROMs) study among prostate cancer survivors, up to 18 years postdiagnosis, in two countries with different healthcare systems and ethical frameworks. Design: A cross-sectional, postal survey of prostate cancer survivors sampled and recruited via two population-based cancer registries. Healthcare professionals (HCPs) evaluated patients for eligibility to participate. Questionnaires contained validated instruments to assess health-related quality of life and psychological well-being, including QLQ-C30, QLQPR-25, EQ-5D-5L, 21-question Depression, Anxiety and Stress Scale (DASS-21) and the Decisional Regret Scale. Setting: Republic of Ireland (RoI) and Northern Ireland (NI). Primary outcome measures: Registration completeness, predictors of eligibility and response, data missingness, unweighted and weighted PROMs. Results: Prostate cancer registration was 80% (95% CI 75% to 84%) and 91% (95% CI 89% to 93%) complete 2 years postdiagnosis in NI and RoI, respectively. Of 12 322 survivors sampled from registries, 53% (n=6559) were classified as eligible following HCP screening. In the multivariate analysis, significant predictors of eligibility were: being ≤59 years of age at diagnosis (p<0.001), short-term survivor (<5 years postdiagnosis; p<0.001) and from RoI (p<0.001). 3348 completed the questionnaire, yielding a 54% adjusted response rate. 13% of men or their families called the study freephone with queries for assistance with questionnaire completion or to talk about their experience. Significant predictors of response in multivariate analysis were: being ≤59 years at diagnosis (p<0.001) and from RoI (p=0.016). Mean number of missing questions in validated instruments ranged from 0.12 (SD 0.71; EQ-5D-5L) to 3.72 (SD 6.30; QLQ-PR25). Weighted and unweighted mean EQ-5D-5L, QLQ-C30 and QLQ-PR25 scores were similar, as were the weighted and unweighted prevalences of depression, anxiety and distress. Conclusions: It was feasible to perform PROMs studies across jurisdictions, using cancer registries as sampling frames; we amassed one of the largest, international, population-based data set of prostate cancer survivors. We highlight improvements which could inform future PROMs studies, including utilising general practitioners to assess eligibility and providing a freephone service.

Earthquake aftershock anxiety: An examination of psychosocial contributing factors and symptomatic outcomes.

This study examined the direct and indirect effects of cognitions and anxiety associated with aftershocks on psychological symptoms (anxiety, depression, acute stress) and daily functioning (general and relationship). Participants were 600 adults from Christchurch. Data collection was approximately four months after the fatal 2011 earthquake. Path analysis was used. Socioeconomic status was directly associated with appraisals of uncontrollability of response to aftershocks. These cognitions were directly related to aftershock anxiety, which heightened general anxiety, depression and acute stress symptoms. These symptoms were directly associated with relationship and general life dysfunction. Aftershock anxiety plays a significant role in ongoing psychological distress associated with earthquakes.

Mode of prostate cancer detection is associated with the psychological wellbeing of survivors: results from the PiCTure study

Purpose: Many men with prostate cancer are asymptomatic, diagnosed following prostate specific antigen (PSA) testing. We investigate whether mode of detection, i.e. ‘PSA detected’ or ‘clinically detected’, was associated with psychological wellbeing among prostate cancer survivors. Methods: A cross-sectional postal questionnaire was administered in 2012 to 6559 prostate cancer (ICD10 C61) survivors up to 18 years post-diagnosis, identified through population-based cancer registries in Ireland. Psychological wellbeing was assessed using the Depression Anxiety Stress Scale-21. Logistic regression was used to investigate associations between mode of detection and depression, anxiety and stress, adjusting for socio-demographic and clinical confounders. Results: The response rate was 54 % (3348/6262). Fifty-nine percent of survivors were diagnosed with asymptomatic PSA-tested disease. Prevalence of depression (13.8 vs 20.7 %; p < 0.001), anxiety (13.6 vs 20.9 %; p < 0.001) and stress (8.7 vs 13.8 %; p < 0.001) were significantly lower among survivors diagnosed with PSA-detected, than clinically detected disease. After adjusting for clinical and socio-demographic factors, survivors with clinically detected disease had significantly higher risk of depression (odds ratio (OR) = 1.46 95 % CI 1.18, 1.80; p = 0.001), anxiety (OR = 1.36 95 % CI 1.09, 1.68; p = 0.006) and stress (OR = 1.43 95 % CI 1.11, 1.85; p = 0.006) than survivors with PSA-detected disease. Conclusions: These findings contribute to the ongoing debate on benefits and risks of PSA testing and may be considered by policy makers formulating population-based prostate cancer screening policies. The relatively high prevalence of negative psychological states among survivors means that a ‘risk-adapted approach’ should be implemented to screen survivors most at risk of psychological morbidity for psychological health, and mode of detection could be considered as a risk stratum.

Clinical evaluation of three incision size-dependent phacoemulsification systems.

PURPOSE:

To compare the outcomes of cataract surgery performed with 3 incision size-dependent phacoemulsification groups (1.8, 2.2, and 3.0 mm).

DESIGN:

Prospective randomized comparative study.

METHODS:

One hundred twenty eyes of 120 patients with age-related cataract (grades 2 to 4) were categorized according to the Lens Opacities Classification System III. Eligible subjects were randomly assigned to 3 surgical groups using coaxial phacoemulsification through 3 clear corneal incision sizes (1.8, 2.2, and 3.0 mm). Different intraoperative and postoperative outcome measures were obtained, with corneal incision size and surgically induced astigmatism as the main clinical outcomes.

RESULTS:

There were no statistically significant differences in most of the intraoperative and postoperative outcome measures among the 3 groups. However, the mean cord length of the clear corneal incision was increased in each group after surgery. The mean maximal clear corneal incision thickness in the 1.8-mm group was significantly greater than for the other groups at 1 month. The mean surgically induced astigmatism in the 1.8- and 2.2-mm groups was significantly less than that in the 3.0-mm group after 1 month, without significant difference between the 1.8- and 2.2-mm groups.

CONCLUSIONS:

With appropriate equipment, smaller incisions may result in less astigmatism, but the particular system used will influence incision stress and wound integrity, and may thus limit the reduction in incision size and astigmatism that is achievable.

Responding to mental health statutory drivers: experience of a low intensity cognitive behavioural therapy programme

Objectives Stress control (SC), a brief psycho-education course, was implemented to increase access to psychological therapies in line with Northern Irish mental health service statutory drivers. The first aim of this study was to gauge the efficacy of SC in a robust manner with clinical significance testing. The second aim was to assess whether demographics traditionally ‘hard-to-reach’ – males, younger adults and those from deprived areas – accessed SC. The third aim was to elucidate what prompted their access and the experiences of attendees at SC. Methods Attendees at SC were 170 adults over six iterations of the course. Pre- and post-questionnaires included the Depression Anxiety Stress Scales – 21, captured demographic details and qualitative feedback, which was subject to a mixed-methods analysis. Results SC attendees reported significant decreases on depression, anxiety and stress sub-scales post-intervention. Moreover, 38.71% ( n =36) of attendees who completed SC exhibited clinically significant improvement afterwards on one or more sub-scale. Attendance figures for males, younger adults and those classified as socioeconomically deprived were modest. Patterns within the data suggested prospective success for targeting these cohorts. Conclusions SC attracted people in need of mental healthcare input and affected quantifiable change within those people’s lives, while satisfying statutory demands for service delivery in an accessible community context. Recommendations to increase engagement with those traditionally ‘hard-to-reach’ for psychological services are provided, which, if implemented, have the potential to achieve further compliance with Northern Irish mental health statutory drivers.

An Evaluation of the Impact of the Prospective Payment System on Antidepressant Use in Nursing Home Residents

Objectives: To determine the impact of the prospective payment system (PPS) for skilled nursing facilities on the pharmacologic treatment of depression.

Methods: We used a quasi-experimental study comparing the pharmacological treatment rates for depression in the pre-PPS period (1997) to the post-PPS period (2000) in 8149 residents with documented depression living in over 500 nursing facilities in Ohio. Logistic regression models adjusting for clustering effects of residents residing in homes using generalized estimating equations provided estimates of the PPS effect on use of any antidepressant and the use of selective serotonin reuptake inhibitors (SSRIs). We evaluated the extent to which the PPS effect was modified by organizational characteristics, including structural characteristics, resource characteristics, and staff resources available in the homes.

Results: Overall, there was no difference in the likelihood of any antidepressant [odds ratio (OR), 1.05; 95% confidence interval (CI), 0.93 to 1.18, resident-adjusted model] or an SSRI being used (OR, 0.98; 95% CI, 0.86 to 1.12, resident-adjusted model) after the introduction of PPS compared with 1997 when this reimbursement system was not in place (referent group). These trends did not appear to be modified substantially by organizational characteristics.

Conclusion: Although PPS did not appear to have influenced the treatment of depression in nursing homes, systems that provide checks and balances in relation to PPS are warranted.

A PEPTIDE FROM THE CAUDAL NEUROSECRETORY-SYSTEM OF THE DOGFISH SCYLIORHINUS-CANICULA THAT IS STRUCTURALLY RELATED TO UROTENSIN-I

Using reversed-phase HPLC in combination with a radioimmunoassay for ovine corticotropin-releasing hormone (CRH), a peptide with CRH-like immunoreactivity was isolated in pure form from an extract of the caudal spinal cord region of the spotted dogfish, Scyliorhinus canicula. The primary structure of the peptide was established as Pro-Ala-Glu-Thr-Pro-Asn-Ser-Leu-Asp-Leu(10)-Thr-Phe-His-Leu-Leu-Arg-Glu-Met-Ile-Glu(20)-Ile-Ala-Lys-His-Glu-Asn-Gln-Gln-Met-Gln(30)-Ala-Asp-Ser-Asn-Arg-Arg-Ile-Met-Asp-Thr(40)-Ile . NH2. This amino acid sequence shows moderate structural similarity to Catostomus urotensin I (51%) and to human CRH (56%). The data provide, therefore, chemical evidence to support the conclusions of earlier immunohistochemical studies that the diffuse caudal neurosecretory system of elasmobranchs produces a peptide that is immunochemically related to teleost urotensin I peptides. However, the primary structure of urotensin I has been poorly conserved during evolution. (C) 1995 Academic Press, Inc.