The effects of social exclusion on the ERN and the cognitive control of action monitoring

The current study investigated the influence of social exclusion, created through the Cyberball paradigm, on cognitive control using neural and behavioral measures of action monitoring. Healthy young adults performed a modified flanker task while their post‐error behavior (accuracy, RT) and error‐related negativity (ERN) were assessed. Results indicated that excluded participants showed decreased ERN and post‐error response accuracy compared to included participants following their social interactions. These findings suggest that a common neural framework may exist for cognitive control processes and that cognitive control allocated toward exclusion‐related processing following exclusionary social interactions may disrupt the capability to support self‐regulatory action monitoring.     

Herbal medicine for the management of polycystic ovary syndrome (PCOS) and associated oligo/amenorrhoea and hyperandrogenism; a review of the laboratory evidence for effects with corroborative clinical findings

Background

Polycystic ovary syndrome (PCOS) is a prevalent, complex endocrine disorder characterised by polycystic ovaries, chronic anovulation and hyperandrogenism leading to symptoms of irregular menstrual cycles, hirsutism, acne and infertility. Evidence based medical management emphasises a multidisciplinary approach for PCOS, as conventional pharmaceutical treatment addresses single symptoms, may be contra-indicated, is often associated with side effects and not effective in some cases. In addition women with PCOS have expressed a strong desire for alternative treatments. This review examines the reproductive endocrine effects in PCOS for an alternative treatment, herbal medicine. The aim of this review was to identify consistent evidence from both pre-clinical and clinical research, to add to the evidence base for herbal medicine in PCOS (and associated oligo/amenorrhoea and hyperandrogenism) and to inform herbal selection in the provision clinical care for these common conditions.

Methods

We undertook two searches of the scientific literature. The first search sought pre-clinical studies which explained the reproductive endocrine effects of whole herbal extracts in oligo/amenorrhoea, hyperandrogenism and PCOS. Herbal medicines from the first search informed key words for the second search. The second search sought clinical studies, which corroborated laboratory findings. Subjects included women with PCOS, menstrual irregularities and hyperandrogenism.

Results

A total of 33 studies were included in this review. Eighteen pre-clinical studies reported mechanisms of effect and fifteen clinical studies corroborated pre-clinical findings, including eight randomised controlled trials, and 762 women with menstrual irregularities, hyperandrogenism and/or PCOS. Interventions included herbal extracts of Vitex agnus-castus, Cimicifuga racemosa, Tribulus terrestris, Glycyrrhiza spp., Paeonia lactiflora and Cinnamomum cassia. Endocrine outcomes included reduced luteinising hormone (LH), prolactin, fasting insulin and testosterone. There was evidence for the regulation of ovulation, improved metabolic hormone profile and improved fertility outcomes in PCOS. There was evidence for an equivalent effect of two herbal medicines and the pharmaceutical agents bromocriptine (and Vitex agnus-castus) and clomiphene citrate (and Cimicifuga racemosa). There was less robust evidence for the complementary combination of spirinolactone and Glycyrrhiza spp. for hyperandrogenism.

Conclusions

Preclinical and clinical studies provide evidence that six herbal medicines may have beneficial effects for women with oligo/amenorrhea, hyperandrogenism and PCOS. However the quantity of pre-clinical data was limited, and the quality of clinical evidence was variable. Further pre-clinical studies are needed to explain the effects of herbal medicines not included in this review with current clinical evidence but an absence of pre-clinical data.

     

A high affinity recombinant antibody to the human EphA3 receptor with enhanced ADCC activity

Abstract

EphA3is expressed in solid tumors and leukemias and is an attractive target for the therapy. We have generated a panel of Humaneered® antibodies to the ligand-binding domain using a Fab epitope-focused library that has the same specificity as monoclonal antibody mIIIA4. A high-affinity antibody was selected that competes with the mIIIA4 antibody for binding to EphA3 and has an improved affinity of ～1?nM. In order to generate an antibody with potent cell-killing activity the variable regions were assembled with human IgG1k constant regions and expressed in a Chinese hamster ovary (CHO) cell line deficient in fucosyl transferase. Non-fucosylated antibodies have been reported to have enhanced binding affinity for the IgG receptor CD16a (FcγRIIIa). The affinity of the antibody for recombinant CD16a was enhanced approximately 10-fold. This resulted in enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity against EphA3-expressing leukemic cells, providing a potent antibody for the evaluation as a therapeutic agent.     

Self-injurious behaviours are associated with alterations in the somatosensory system in children with autism spectrum disorder

Children with autism spectrum disorder (ASD) frequently engage in self-injurious behaviours, often in the absence of reporting pain. Previous research suggests that altered pain sensitivity and repeated exposure to noxious stimuli are associated with morphological changes in somatosensory and limbic cortices. Further evidence from postmortem studies with self-injurious adults has indicated alterations in the structure and organization of the temporal lobes; however, the effect of self-injurious behaviour on cortical development in children with ASD has not yet been determined. Thirty children and adolescents (mean age = 10.6 ± 2.5 years; range 7–15 years; 29 males) with a clinical diagnosis of ASD and 30 typically developing children (N = 30, mean age = 10.7 ± 2.5 years; range 7–15 years, 26 males) underwent T1-weighted magnetic resonance and diffusion tensor imaging. No between-group differences were seen in cerebral volume, surface area or cortical thickness. Within the ASD group, self-injury scores negatively correlated with thickness in the right superior parietal lobule t = 6.3, p < 0.0001, bilateral primary somatosensory cortices (SI) (right: t = 4.4, p = 0.02; left: t = 4.48, p = 0.004) and the volume of the left ventroposterior (VP) nucleus of the thalamus (r = ?0.52, p = 0.008). Based on these findings, we performed an atlas-based region-of-interest diffusion tensor imaging analysis between SI and the VP nucleus and found that children who engaged in self-injury had significantly lower fractional anisotropy (r = ?0.4, p = 0.04) and higher mean diffusivity (r = 0.5, p = 0.03) values in the territory of the left posterior limb of the internal capsule. Additionally, greater incidence of self-injury was associated with increased radial diffusivity values in bilateral posterior limbs of the internal capsule (left: r = 0.5, p = 0.02; right: r = 0.5, p = 0.009) and corona radiata (left: r = 0.6, p = 0.005; right: r = 0.5, p = 0.009). Results indicate that self-injury is related to alterations in somatosensory cortical and subcortical regions and their supporting white-matter pathways. Findings could reflect use-dependent plasticity in the somatosensory system or disrupted brain development that could serve as a risk marker for self-injury.     

Autopage and the Use of Computer Scripts to Automate Microtasks

Paging referring clinicians with imaging results is a frequently repeated “microtask” performed by practicing radiologists. Many institutions use online alpha-paging systems to provide this integral part of safe and efficient patient care. Although sending an alpha-page can often be accomplished within one minute, current tools may disrupt workflow by distracting users with a series of tedious mouse clicks. We describe the development, evaluation, and updates of a portable tool that sends alpha-pages to referring clinicians using two keystrokes. This software integrates study information obtained from the Picture Archiving and Communication System (PACS) with an existing hospital paging system.     

Surface antigen profiles of leukocytes and melanoma cells in lymph node metastases are associated with survival in AJCC stage III melanoma patients

There is an urgent need to identify more accurate prognostic biomarkers in melanoma patients, particularly in those with metastatic disease. This study aimed to identify melanoma and leukocyte surface antigens predictive of survival in a prospective series of AJCC stage IIIb/c melanoma patients (n = 29). Live cell suspensions were prepared from melanoma metastases within lymph nodes (LN). The suspensions were immuno-magnetically separated into CD45⁺ (leukocyte) and CD45^? (non-hematopoietic, enriched melanoma cell) fractions. Surface antigens on CD45^? and CD45⁺ cell populations were profiled using DotScan? microarrays (Medsaic Pty. Ltd.) and showed differential abundance levels for 52 and 78 antigens respectively. Associations of the surface profiles with clinicopathologic and outcome data (median follow-up 35.4 months post LN resection) were sought using univariate (log-rank test) and multivariate (Wald’s test; modelled with patient’s age, gender and AJCC staging at LN recurrence) survival models. CD9 (p = 0.036), CD39 (p = 0.004) and CD55 (p = 0.005) on CD45⁺ leukocytes were independently associated with distant metastasis-free survival using multivariate analysis. Leukocytes with high CD39 levels were also significantly associated with increased overall survival (OS) in multivariate analysis (p = 0.016). LNs containing leukocytes expressing CD11b (p = 0.025), CD49d (p = 0.043) and CD79b (p = 0.044) were associated with reduced OS on univariate analysis. For enriched melanoma cells (CD45^? cell populations), 11 surface antigens were significantly correlated with the disease-free interval (DFI) between diagnosis of culprit primary melanoma and LN metastasis resection. Nine antigens on CD45⁺ leukocytes also correlated with DFI. Following validation in independent datasets, surface markers identified here should enable more accurate determination of prognosis in stage III melanoma patients and provide better risk stratification of patients entering clinical trials.     

Wavelet-based intensity analysis of the mechanomyograph and electromyograph during the H-reflex

Purpose

The relationship between mechanomyography (MMG) and electromyography (sEMG) during electrically evoked muscle contraction was examined using the von Tscharner “intensity analysis,” which describes the power of a non-stationary signal as a function of both frequency and time.

Method

Data for 8 college-aged participants (3 males; 5 females) with measurable H-reflexes were analyzed. Recruitment curves for H-reflex (H), M-wave (M) using sEMG, and peak-to-peak MMG (MMG_p–p) were elicited through incremental tibial nerve stimulation. The maximum peak-to-peak values for H and M for each sample were summed (HM); and maximum intensity values were measured for MMG, H, and M following the intensity analysis and computation of total intensity (MMG_CvT, H_CvT, M_CvT). H_CvT and M_CvT were subsequently added together (HM_CvT) for comparisons.

Results

Correlations of HM:MMG_p–p, HM:MMG_CvT, HM_CvT:MMG_CvT, HM_CvT:MMG_p–p, were low (r = 0.34, 0.33, 0.09, and 0.12, respectively, p < 0.001); and correlations of HM:HM_CvT, MMG_CvT:MMG_p–p, were moderate-to-high (r = 0.69 and 0.97, respectively, p < 0.001). Correlations for individuals ranged from 0.61 to 0.99 across comparisons. The time at which maximal intensities occurred reflected the transition from a predominant H-reflex to the onset of the M-wave and declining lag times were noted with increasing intensity.

Conclusions

The intensity analysis provides insight into the frequency characteristics of the H-reflex and M-wave not seen in traditional analysis of the H-reflex. The intensity analysis may be a useful tool in studying individual variations and changes in the contraction velocities of skeletal muscle.     

Replication of the effect of SLC2A9 genetic variation on serum uric acid levels in American Indians

Increased serum uric acid (SUA) or hyperuricemia, a risk factor for gout, renal and cardiovascular diseases, is caused by either increased production or decreased excretion of uric acid or a mix of both. The solute carrier protein 2 family, member 9 (SLC2A9) gene encodes a transporter that mediates urate flux across the renal proximal tubule. Genome-wide association studies have consistently shown the association of single-nucleotide polymorphisms in this gene with SUA in majority populations. American Indian participants of the Strong Heart Family Study, belonging to multigenerational families, have high prevalence of hyperuricemia. We conducted measured genotype analyses, based on variance components decomposition method and accounting for family relationships, to assess whether the association between SUA and SLC2A9 gene polymorphisms generalized to American Indians (n=3604) of this study. Seven polymorphisms were selected for genotyping based on their association with SUA levels in other populations. A strong association was found between SLC2A9 gene polymorphisms and SUA in all centers combined (P-values: 1.3 × 10⁻³¹–5.1 × 10⁻²³) and also when stratified by recruitment center; P-values: 1.2 × 10⁻¹⁴–1.0 × 10⁻⁵. These polymorphisms were also associated with the estimated glomerular filtration rate and serum creatinine but not albumin–creatinine ratio. In summary, the association of polymorphisms in the uric acid transporter gene with SUA levels extends to a new population of American Indians.