Peroxisome deficiency underlies failures in hepatic immune cell development and antigen presentation in a severe Zellweger disease model.

Peroxisome biogenesis disorders (PBDs) represent a group of metabolic conditions that cause severe developmental defects. Peroxisomes are essential metabolic organelles, present in virtually every eukaryotic cell and mediating key processes in immunometabolism. To date, the full spectrum of PBDs remains to be identified, and the impact PBDs have on immune function is unexplored. This study presents a characterization of the hepatic immune compartment of a neonatal PBD mouse model at single-cell resolution to establish the importance and function of peroxisomes in developmental hematopoiesis. We report that hematopoietic defects are a feature in a severe PBD murine model. Finally, we identify a role for peroxisomes in the regulation of the major histocompatibility class II expression and antigen presentation to CD4+ T cells in dendritic cells. This study adds to our understanding of the mechanisms of PBDs and expands our knowledge of the role of peroxisomes in immunometabolism.

Modulation of the cell membrane lipid milieu by peroxisomal ß-oxidation induces Rho1 signaling to trigger inflammatory responses.

Phagocytosis, signal transduction, and inflammatory responses require changes in lipid metabolism. Peroxisomes have key roles in fatty acid homeostasis and in regulating immune function. We find that Drosophila macrophages lacking peroxisomes have perturbed lipid profiles, which reduce host survival after infection. Using lipidomic, transcriptomic, and genetic screens, we determine that peroxisomes contribute to the cell membrane glycerophospholipid composition necessary to induce Rho1-dependent signals, which drive cytoskeletal remodeling during macrophage activation. Loss of peroxisome function increases membrane phosphatidic acid (PA) and recruits RhoGAPp190 during infection, inhibiting Rho1-mediated responses. Peroxisome-glycerophospholipid-Rho1 signaling also controls cytoskeleton remodeling in mouse immune cells. While high levels of PA in cells without peroxisomes inhibit inflammatory phenotypes, large numbers of peroxisomes and low amounts of cell membrane PA are features of immune cells from patients with inflammatory Kawasaki disease and juvenile idiopathic arthritis. Our findings reveal potential metabolic markers and therapeutic targets for immune diseases and metabolic disorders.

An unusual example of hereditary multiple exostoses: a case report and review of the literature.

BACKGROUND: Hereditary multiple exostoses (HME) is a rare skeletal disorder characterised by a widespread. distribution of osteochondromas originating from the metaphyses of long bones. CASE PRESENTATION: This case study examines a 55-year-old male cadaver bequeathed to the University of Liverpool who suffered from HME, thus providing an exceptionally rare opportunity to examine the anatomical changes associated with this condition. CONCLUSIONS: Findings from imaging and dissection indicated that this was a severe case of HME in terms of the quantity and distribution of the osteochondromas and the number of synostoses present. In addition, the existence of enchondromas and the appearance of gaps within the trabeculae of affected bones make this a remarkable case. This study provides a comprehensive overview of the morbidity of the disease as well as adding to the growing evidence that diseases concerning benign cartilaginous tumours may be part of a spectrum rather than distinct entities.

A specific cognitive deficit within semantic cognition across a multi-generational family.

We report a study of eight members of a single family (aged 8-72 years), who all show a specific deficit in linking semantic knowledge to language. All affected members of the family had high levels of overall intelligence; however, they had profound difficulties in prose and sentence recall, listening comprehension and naming. The behavioural deficit was remarkably consistent across affected family members. Structural neuroimaging data revealed grey matter abnormalities in the left infero-temporal cortex and fusiform gyri: brain areas that have been associated with integrative semantics. This family demonstrates, to our knowledge, the first example of a heritable, highly specific abnormality affecting the interface between language and cognition in humans and has important implications for our understanding of the genetic basis of cognition.

Sex differences in autism spectrum disorder: evidence from a large sample of children and adolescents.

Sex differences have been found amongst toddlers and young children with autism spectrum disorder (ASD). We investigated the presence and stability of these ASD sex differences throughout childhood and adolescence. Participants (N = 325, 52 females; aged 3-18 years) consecutively received an ASD diagnosis at a clinic for assessing high-functioning ASD (mean verbal IQ = 92.6). There were no IQ sex differences. By parent report and direct observation, females had less repetitive stereotyped behaviour (RSB), with male-equivalent levels of social and communication impairment. Teachers reported males with ASD as having greater externalising and social problems than females. The female phenotype we describe was stable across our sample's age range. Their milder RSBs and less severe difficulties at school may lead to under-recognition of ASD in females.

Avoiding legal pitfalls in surrogacy arrangements.

The goal of this article is to discuss the legal pitfalls that reproductive endocrinologists face when participating in gestational surrogacy contracts. This paper was composed using Westlaw and LexisNexis commercial legal search engines to perform a review of statutes and cases pertaining to gestational surrogacy. The search results demonstrated that in the absence of suitable preparation, there is significant potential for litigation while participating in gestational agreements. Providers caring for gestational carriers have been named as parties in lawsuits for failure to provide psychological screening, failure to screen for infectious disease and participation in gestational contracts that are not compliant with state law. There is great disparity in state laws and court rulings pertaining to gestational agreements. When legal disputes arise, individual state laws and court rulings are controlling over the Uniform Parentage Act. Likewise, recommendations by the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine do not supersede state laws. The failure to abide by individual state laws unnecessarily exposes reproductive endocrinologists and their IVF facilities to potential litigation. In order to lessen exposure to litigation, an understanding of individual state legislation or historical court rulings is advised.

The ethical challenges of providing fertility care to patients with chronic illness or terminal disease.

The field of fertility is rapidly evolving, bringing opportunities for improvement in our patients' quality of life as well as bringing new ethical dilemmas. As medical science continues to advance, significant numbers of the reproductive-aged population are living with chronic and/or terminal conditions but have reasonable odds of lengthy survival and wish to have children. Likewise, there are adolescents diagnosed with cancer who are increasingly expected to achieve an improved, if not normal, life expectancy after treatment. Oftentimes these children are told they must sacrifice their ability to later have genetically related offspring; however, technologies to preserve fertility are changing this prognosis. Patients with chronic infection are living longer, more normal lives and are increasingly seeking reproductive assistance. Moreover, there is an increasing number of patients' families desiring posthumous use of gametes, which also raises ethical and legal issues. This article discusses ethical principles of bioethics and then highlights specific ethical issues through four plausible cases that may be seen in a fertility practice providing medical care to patients with chronic illness or terminal disease. It concludes that prompt referral of patients to the reproductive endocrinologist, along with a multidisciplinary approach to care, provides increased chances of successful treatment of this group of patients.

Avoidance of emotionally arousing stimuli predicts social-perceptual impairment in Asperger's syndrome.

We combined eye-tracking technology with a test of facial affect recognition and a measure of self-reported social anxiety in order to explore the aetiology of social-perceptual deficits in Asperger's syndrome (AS). Compared to controls matched for age, IQ and visual-perceptual ability, we found a group of AS adults was impaired in their recognition of fearful and sad expressions and spent significantly less time fixating the eye region of all faces. For AS subjects, but not controls, the extent of the failure to fixate the eyes predicted the degree of impairment at recognising fearful expressions. In addition, poor fear recognition and reduced fixation of the eyes were independently associated with greater levels of social anxiety in AS individuals. These findings support the hypothesis that avoidance of emotionally arousing stimuli, such as eyes, contributes to social-perceptual impairment in AS. Furthermore, our findings are consistent with theories implicating amygdala-mediated over-arousal and anxiety in the development of these social-perceptual deficits.

Emotional modulation of perception in Asperger's syndrome.

Using an attentional blink paradigm, we show that the typical enhancement of perception for emotionally arousing events is significantly reduced in Asperger's syndrome (AS) at short inter-target intervals. Control experiments demonstrate that this finding cannot be attributed to differences in the perceived arousal of the stimuli, or to a global impairment affecting any type of modulation of perceptual encoding. Because a functioning amygdala is critical for emotional modulation of the attentional blink, the findings support a role for the amygdala in the pathophysiology of AS. More specifically, they suggest there is a fundamental failure of the amygdala to modulate processing in cortex, a concept at the heart of some recent theories of amygdala involvement in the aetiology of autistic-spectrum disorders.

Impaired sadness recognition is linked to social interaction deficit in autism.

Can autistic individuals use motion cues to identify simple emotions from 2D abstract animations? We compared emotion recognition ability using a novel test involving computerised animations, and a more conventional emotion recognition test using facial expressions. Adults with autism and normal controls, matched for age and verbal IQ, participated in two experiments. First, participants viewed a series of short (5s) animations. These featured an 'emotional' triangle, interacting with a circle. They were designed to evoke an attribution of emotion to the triangle, which was rated both in terms of anger, happiness, sadness or fear from its pattern of movement, and how animate ("living") it appeared to be. Second, emotion recognition was tested from standardised photographs of facial expressions. In both experiments, adults with autism were significantly impaired relative to comparisons in their perception of sadness. This is the first demonstration that, in autism, individuals can have difficulties both in the interpretation of facial expressions and in the recognition of equivalent emotions based on the movement of abstract stimuli. Poor performance in the animations task was significantly correlated with the degree of impairment in reciprocal social interaction, assessed by the Autism Diagnostic Observation Schedule. Our findings point to a deficit in emotion recognition in autism, extending beyond the recognition of facial expressions, which is associated with a functional impairment in social interaction skills. Our results are discussed in the context of the results of neuroimaging studies that have used animated stimuli and images of faces.