Assessing the clinical significance of treatment outcomes for distressing voices in routine clinical practice

Determining reliable and clinically significant change is central to evidence‐based practice yet rarely used in routine clinical settings. This paper illustrates these methods in the context of an evaluation of cognitive behaviour therapy for distressing auditory hallucinations (“voices”). We used data from a clinical sample attending Perth Voices Clinic, a transdiagnostic outpatient service for distressing voices, and a previously published reference sample of healthy voice hearers. Our outcomes on the primary measure of voice distress, derived from a previous factor analysis of the Psychotic Symptom Rating Scale‐Auditory Hallucinations subscale, showed that 62.9% of clients were classified as Recovered/Improved, 35.5% were classified as Unchanged, and 0.02% were classified as Deteriorated. Partial support for the validity of these classifications was obtained from the scores on the Depression, Anxiety, Stress Scales (Lovibond & Lovibond, 1995) but not on the Social and Occupational Functional Assessment Scale (Goldman et al., 1992). Clients classified as Recovered showed better emotional functioning on the Depression, Anxiety, Stress Scales compared with those who did not make a clinically significant change in voice distress. A tool is provided to assist practitioners to evaluate whether individual clients have benefited from therapy for distressing voices or not, which can be used to guide future treatment decisions ( https://osf.io/gd9e5/ ).     

Regulatory T-cells in helminth infection: induction,function and therapeutic potential

Helminth parasites infect an alarmingly large proportion of the world's population, primarily within tropical regions, and their ability to down-modulate host immunity is key to their persistence. Helminths have developed multiple mechanisms that induce a state of hyporesponsiveness or immune suppression within the host; of particular interest are mechanisms that drive the induction of regulatory T-cells (Tregs). Helminths actively induce Tregs either directly by secreting factors, such as the TGF-β mimic Hp-TGM, or indirectly by interacting with bystander cell types such as dendritic cells and macrophages that then induce Tregs. Expansion of Tregs not only enhances parasite survival but, in cases such as filarial infection, Tregs also play a role in preventing parasite-associated pathologies. Furthermore, Tregs generated during helminth infection have been associated with suppression of bystander immunopathologies in a range of inflammatory conditions such as allergy and autoimmune disease. In this review, we discuss evidence from natural and experimental infections that point to the pathways and molecules involved in helminth Treg induction, and postulate how parasite-derived molecules and/or Tregs might be applied as anti-inflammatory therapies in the future.     

Error processing-associated event-related potentials in schizophrenia and unaffected siblings

A reduction in the error-related negativity (ERN), a response-locked event-related potential (ERP) observed when participants commit errors during processing of stimuli, is a well-replicated cerebral abnormality in schizophrenia. However, the extent to which this abnormality reflects susceptibility to schizophrenia rather than overt change in behavioural state is unclear. As the unaffected siblings of individuals with schizophrenia are at an increased genetic risk, this study examines whether they display abnormality of the ERN similar to that observed in individuals with schizophrenia. ERPs were recorded from 29 individuals with schizophrenia, 36 unaffected siblings and 35 healthy control participants while they performed a simple Go/No-Go task. Group differences in the ERN and also in the error positivity (Pe), a response-locked positive component that follows the ERN, were investigated. Reductions of ERN amplitudes were found in both individuals with schizophrenia and siblings. No significant abnormalities were observed in Pe. The finding of reduced ERN amplitudes in siblings without prodromal symptoms supports the hypothesis that the abnormality is not a consequence of behavioural disturbance, and that it is a trait marker for susceptibility to schizophrenia, rather than being a result of illness or medication.     

Inherited 18q23 duplication in a fetus with multiple congenital anomalies

We report on a fetus with multiple congenital anomalies including atypical lissencephaly, corpus callosum agenesis, cerebellar hypoplasia, cleft palate, ventricular septal defect, and hypoplastic aortic arch. The initial routine chromosome study failed to detect any abnormality. Subtelomeres analysis by MLPA identified an 18q23 duplication inherited from its healthy father. We describe the anomalies identified and discuss diagnosis and the causability of this telomeric duplication.     

Neuronal activity modifies the DNA methylation landscape in the adult brain

DNA methylation has been traditionally viewed as a highly stable epigenetic mark in postmitotic cells. However, postnatal brains appear to show stimulus-induced methylation changes, at least in a few identified CpG dinucleotides. How extensively the neuronal DNA methylome is regulated by neuronal activity is unknown. Using a next-generation sequencing-based method for genome-wide analysis at single-nucleotide resolution, we quantitatively compared the CpG methylation landscape of adult mouse dentate granule neurons in vivo before and after synchronous neuronal activation. About 1.4% of 219,991 CpGs measured showed rapid active demethylation or de novo methylation. Some modifications remained stable for at least 24 h. These activity-modified CpGs showed a broad genomic distribution with significant enrichment in low-CpG density regions, and were associated with brain-specific genes related to neuronal plasticity. Our study implicates modification of the neuronal DNA methylome as a previously underappreciated mechanism for activity-dependent epigenetic regulation in the adult nervous system.     

Predictors of palliative care consultation on an inpatient gynecologic oncology service: Are we following ASCO recommendations?

Objective

Determine predictors of inpatient palliative care (PC) consultation and characterize PC referral patterns with respect to recommendations from the American Society of Clinical Oncology (ASCO).

Methods

Women with a gynecologic malignancy admitted to the gynecologic oncology service 3/2012–8/2012 were identified. Demographic information, disease and treatment details and date of death were abstracted from medical records. Student's t-test, Fischer's exact test or χ²-test was used for univariate analysis. Binomial logistic regression was used for multivariate analysis.

Results

Of 340 patients analyzed, 82 (24%) had PC consultation. Univariate predictors of PC consultation included race, cancer type and stage, recurrent disease, admission frequency, admission for symptom management or malignant bowel obstruction (MBO), discharge to skilled nursing facility (SNF) and number of lines of chemotherapy. On multivariate analysis, significant predictors of PC consultation were recurrent disease (OR 2.4, 95% CI 1.1–5.3), number of admissions (≥ 3, OR 10.9, 95% CI 3.4–34.9), admission for symptom management (OR 19.4, 95% CI 7.5–50.1), discharge to SNF (OR 5, 95% CI 1.9–13.5) and death within 6 months (OR 16.5, 95% CI 6.9–39.5). Of patients considered to meet ASCO guidelines, 53% (63/118) had PC referral. Of patients referred to PC, 51.2% (42/82) died within 6 months of last admission.

Conclusions

Patients referred to inpatient PC have high disease and symptom burden and poor prognosis. High-risk patients, including those meeting ASCO recommendations, are not captured comprehensively. We continue to use PC referrals primarily for patients near the end of life, rather than utilizing early integration as recommended by ASCO.     

Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease

Molecular mimicry is a hallmark of the pathogenesis of rheumatic fever where the streptococcal group A carbohydrate epitope, N-acetyl glucosamine, and the α-helical coiled-coil streptococcal M protein structurally mimic cardiac myosin in the human disease, rheumatic carditis, and in animal models immunized with streptococcal M protein and cardiac myosin. Recent studies have unraveled the potential pathogenic mechanisms by which the immune response against the group A streptococcus attacks the rheumatic valve leading to chronic rheumatic heart disease. Both B- and T-cell responses are involved in the process, and evidence for the hypotheses of molecular mimicry and epitope spreading are reviewed.     

Manganese superoxide dismutase is reduced in the liver of male but not female humans and rodents with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is among the most common liver diseases. Oxidative stress is one of the pathogenic mechanisms contributing to the progression of simple fatty liver to non-alcoholic steatohepatitis (NASH). Manganese superoxide dismutase (MnSOD) is a mitochondrial antioxidative enzyme and here its expression in rodent and human NAFLD has been analyzed. MnSOD is found reduced in the liver of male mice fed a high fat diet and male ob/ob mice. Female mice fed an atherogenic diet to induce NASH have MnSOD protein levels comparable to controls. In a cohort of 30 controls, 41 patients with fatty liver and 39 NASH patients, MnSOD mRNA is significantly lower in the steatotic and NASH liver. When analyzed in both genders separately reduction of MnSOD expression is only found in males. Here, MnSOD mRNA negatively correlates with steatosis grade but not with extent of fibrosis or inflammation. MnSOD is, however, not reduced in primary human hepatocytes (PHH) treated with palmitate or oleate to increase cellular triglycerides. Lipopolysaccharide, TNF, IL-6, TGFβ and leptin which are all raised in NAFLD do not affect MnSOD in PHH. Adiponectin which attenuates oxidative stress partly by increasing MnSOD in macrophages does not induce MnSOD in PHH. In summary, current data show that hepatic MnSOD is reduced in male but not female humans and rodents with NAFLD.     

Menarche,pregnancy, birth spacing and menopause among the Agta women foragers of Cagayan Province,Luzon, the Philippines

The reproductive histories of 74 post-menarcheal Agta Negrito women, tropical foragers of Cagayan province, north-eastern Luzon, the Philippines are described and analysed in comparison with data collected by Howell on Dobe! Kung hunter-gatherers. Among the Agta, mean age at menarche is 17, mean age at first live birth is 20·14 years, mean completed parity is 6·53 and mean age at menopause is 44. Average height is 141·24cm and average weight 36·72 kg. No time trends were detected in age at menarche and age at first live birth among the Agta. Average spacing between live births where an infant survives until the birth of the next sibling was 2·85 years. Compared to the Dobe !Kung, Agta women have later menarche, but shorter birth spacing and a longer active childbearing span.     

Simulation of the Interaction Between Muscle Fiber Conduction Velocity and Instantaneous Firing Rate

In this study, the relationships between the early and late afterpotentials and velocity and amplitude recovery functions (VRF and ARF) in skeletal muscle were examined using model simulation. A mathematical model of the muscle fiber action potential, that incorporated a tubular slow potassium conductance, was developed and used to simulate muscle fiber action potentials at a range of interpulse intervals. The slow potassium conductance produced an afterhyperpolarization which resulted in supernormal action potential conduction velocity and amplitude for interpulse intervals >7 ms. Increasing the number of conditioning stimuli caused a further increase in conduction velocity and amplitude, and an additional phase of supernormality, with a peak at approximately 100 ms. Positive correlations between instantaneous firing rate and both conduction velocity and amplitude were also observed during simulation of repetitive stimulation of the muscle fiber. The relationships were eliminated when the slow potassium conductance channel was removed from the model. The results suggest that an afterhyperpolarization, possibly due to a slow tubular potassium conductance, could cause the VRF and ARF observed in muscle. They additionally suggest that the positive correlations between instantaneous firing rate, conduction velocity, and amplitude are directly related to the VRF and ARF.