11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess

The adverse metabolic effects of prescribed and endogenous glucocorticoid (GC) excess, Cushing syndrome, create a significant health burden. We found that tissue regeneration of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), rather than circulating delivery, is critical to developing the phenotype of GC excess; 11β-HSD1 KO mice with circulating GC excess are protected from the glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, and dermal atrophy of Cushing syndrome. Whereas liver-specific 11β-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11β-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess. These data challenge our current view of GC action, demonstrating 11β-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating GC excess, offering 11β-HSD1 inhibition as a previously unidentified approach to treat Cushing syndrome.Estimates suggest that 1–2% of the population of the United States and United Kingdom take prescribed glucocorticoids (GCs) for the treatment of a broad spectrum of inflammatory and autoimmune diseases (1, 2). Despite the efficacy of GCs, 70% of patients experience an adverse systemic side-effect profile. The resultant Cushingoid features include central obesity, proximal myoatrophy, hypertension, skin thinning, osteoporosis, hepatic steatosis, insulin resistance, and type 2 diabetes (3, 4). Collectively, this contributes to increased risk of cardiovascular morbidity and mortality (5, 6). These features are replicated in patients with much rarer endogenous GC excess (Cushing syndrome), as first described by Harvey Cushing in 1932 (7). Current medical therapeutic options that reverse the tissue-specific consequences of hypercortisolism are limited.GC availability and action depend not only upon circulating levels but also on tissue-specific intracellular metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). Key metabolic tissues including liver, adipose tissue, and skeletal muscle express 11β-HSD type 1 (11β-HSD1), which coverts inactive cortisone to active cortisol [11-dehydrocorticosterone (11DHC) and corticosterone (CORT) in rodents, respectively] (8). In the setting of GC excess, the relative contribution to the metabolic effects induced by GCs of simple delivery of active GCs (cortisol or CORT) to a target tissue, compared with the regeneration of active GCs by 11β-HSD1 within the tissue, has not been determined.Type 2 11β-HSD (11β-HSD2) is predominately expressed in the kidney, colon, and salivary gland and catalyzes the inactivation of cortisol to cortisone (CORT to 11DHC in rodents). This not only protects the mineralocorticoid receptor from occupancy by cortisol but also crucially provides substrate for 11β-HSD1 in peripheral tissues.Transgenic animal models have highlighted the critical role of 11β-HSD1 in the regulation of metabolic phenotype in individual tissues. Mice overexpressing 11β-HSD1, specifically in adipose tissue, develop visceral obesity, insulin resistance, dyslipidemia, and hypertension (9, 10). Similarly, liver-specific 11β-HSD1 overexpression results in insulin resistance and hypertension, but not obesity (11). Importantly, circulating CORT levels were not elevated in either model, suggesting increased intracellular GC availability underpins the observed phenotypes. Indeed, this was confirmed in the adipose-specific 11β-HSD1–overexpressing mice, where twofold higher intraadipose CORT levels were recorded in comparison with WT controls (9). Ultimately, this has led to the development of selective 11β-HSD1 inhibitors as a potential treatment for patients with diabetes, obesity, and hypertension (12, 13).Although it is clear that 11β-HSD1 has a critical role to play in governing GC availability, its potential dynamic role in the setting of GC excess has not been fully explored (14–16). We have previously reported a patient with Cushing disease who was protected from the classic Cushing phenotype, owing to a functional defect in 11β-HSD1 activity, as evidenced by serum and urinary biomarkers (17). Based on this observation, we have hypothesized that tissue intrinsic 11β-HSD1 activity is the major determinant of the manifestations of GC excess and that 11β-HSD1 deletion will ameliorate the associated metabolic abnormalities. To determine the relative tissue-specific contribution to this effect, we have generated tissue-specific 11β-HSD1 deletions in liver and adipose tissue.     

Comparing human and mouse salivary glands: A practice guide for salivary researchers

Mice are a widely utilized in vivo model for translational salivary gland research but must be used with caution. Specifically, mouse salivary glands are similar in many ways to human salivary glands (i.e., in terms of their anatomy, histology, and physiology) and are both readily available and relatively easy and affordable to maintain. However, there are some significant differences between the two organisms, and by extension, the salivary glands derived from them must be taken into account for translational studies. The current review details pertinent similarities and differences between human and mouse salivary glands and offers practical guidelines for using both for research purposes.     

Fertility of Spinal Cord Injured Males: Effect of Genitourinary Infection and Bladder Management on Results of Electroejaculation

ABSTRACT

Thirty-eight men undergoing electroejaculation (EEJ) procedures for anejaculatory infertility were examined for the presence or absence of infection in urine and semen. In 29 spinal cord injury patients, a high incidence of infected urine and infected semen (41% and 56%, respectively) was seen, in contrast to patients with normal bladder function (0% and 11 %).

Urinary infection was associated with slightly lower sperm quality and lower pregnancy rates (10% vs 30% in the presence of sterile urine). Semen infection had no effect on sperm counts or pregnancy rates. If intermittent self-catheterization (ISC) was used to empty the neurogenic bladder, slightly better sperm quality was seen, the total failure rate was less, and much better pregnancy rates (44%) resulted than for patients using an alternative bladder management (7%).

Antibiotics did not reduce the incidence of urine or semen infection, but did improve sperm counts slightly. Continuous prophylaxis was associated with bacterial resistance to many oral antibiotics and had no advantage over a short course of antibiotics prior to the procedure.

Despite the above associations, the sperm quality in our patient population was never normal compared with that of men who ejaculate normally. We conclude that the low sperm quality seen in electroejaculation specimens from spinal cord injured males is not due entirely to infection or to the type of bladder management. Short courses of antibiotics, instead of continuous antibiotic prophylaxis, may be beneficial. Intermittent catheterization is superior to other methods of neurogenic bladder management in maintaining the fertility of spinal cord injured men.     

The validity of patient- and clinician-rated measures of needs and the therapeutic relationship in psychosis: A pooled analysis

Measuring outcomes of treatments for psychosis such as needs and the quality of the therapeutic relationship is important in research and routine care. However, evidence on the validity of existing outcome measures is limited. We aimed to test the convergent, discriminant, and predictive validity of two widely used patient- and clinician-rated measures of needs and the therapeutic relationship. Multitrait-multimethod (MTMM) analysis was conducted on the Camberwell Assessment of Need Short Appraisal Schedule (CANSAS) and the Helping Alliance Scale (HAS), both the clinician (CANSAS-C, HAS-C) and patient (CANSAS-P, HAS-P) versions, in a pooled sample of 605 psychotic patients and their clinicians. CANSAS-C and CANSAS-P items loaded substantially into one common unmet needs factor. By comparison, substantial factor loadings were found for HAS-C and HAS-P items on two separate clinician- and patient-rated therapeutic relationship factors. Common unmet needs and clinician-rated therapeutic relationship factors significantly predicted reduced psychiatric in-patient days. Our findings support the convergent validity of the CANSAS, discriminant validity of the HAS, and predictive validity of CANSAS and HAS-C. The findings may inform the use of CANSAS and HAS as psychosis outcome measures in research and routine care.     

Divergent Patterns of Social Cognition Performance in Autism and 22q11.2 Deletion Syndrome (22q11DS)

Individuals with developmental disorders frequently report a range of social cognition deficits including difficulties identifying facial displays of emotion. This study examined the specificity of face emotion processing deficits in adolescents with either autism or 22q11DS compared to typically developing (TD) controls. Two tasks (face emotion recognition and weather scene recognition) were used to explore group differences in visual scanpath strategy and concurrent recognition accuracy. For faces, the autism and 22q11DS groups demonstrated lower emotion recognition accuracy and fewer fixations compared to the TD group. Individuals with autism demonstrated fewer fixations to some weather scene stimuli compared to 22q11DS and TD groups, yet achieved a level of recognition accuracy comparable to the TD group. These findings provide evidence for a divergent pattern of social cognition dysfunction in autism and 22q11DS.     

Using a hybrid model to investigate the comorbidity and symptom overlap between social phobia and the other anxiety disorders and unipolar mood disorders

New hybrid models of psychopathology have been proposed that combine the current categorical approach with symptom dimensions that are common across various disorders. The present study investigated the new hybrid model of social anxiety in a large sample of participants with anxiety disorders and unipolar mood disorders to improve understanding of the comorbidity and symptom overlap between social phobia (SOC) and the other anxiety disorders and unipolar mood disorders. Six hundred and eighty two participants from a specialized outpatient clinic for anxiety treatment completed a semi-structured diagnostic interview and the Multidimensional Assessment of Social Anxiety (MASA). A hybrid model symptom profile was identified for SOC and compared with each of the other principal diagnoses. Significant group differences were identified on each of the MASA scales. Differences also were identified when common sets of comorbidities were compared within participants diagnosed with SOC. The findings demonstrated the influence of both the principal diagnosis of SOC and other anxiety disorders and unipolar mood disorders as well as the influence of comorbid diagnoses with SOC on the six symptom dimensions. These findings highlight the need to shift to transdiagnostic assessment and treatment practices that go beyond the disorder-specific focus of the current categorical diagnostic systems.     

Are attitudes towards medication adherence associated with medication adherence behaviours among patients with psychosis? A systematic review and meta analysis

Background

Studies have shown patient attitudes to be an important predictor for health related behaviours including medication adherence. It is less clear whether patient attitudes are also associated with medication adherence among patients with psychoses.

Method

We conducted a systematic review and meta analysis of the data of studies that tested the association of attitude measures with medication adherence among patients with psychoses. 14 studies conducted between 1980 and 2010 were included.

Results

Results show a small to moderate mean weighted effect size (r ⁺ = 0.25 and 0.26 for Pearson and Spearman correlations, respectively).

Conclusions

Theory based interventions that target potentially modifiable attitude components are needed to assess the relationship between positive patient attitudes and adherence behaviours among patients with psychoses.