The Emerging Role of the Gut-Brain-Microbiota Axis in Neurodevelopmental Disorders.

Autism spectrum disorder (ASD; autism) is a prevalent neurodevelopmental disorder associated with changes in gut-brain axis communication. Gastrointestinal (GI) symptoms are experienced by a large proportion of individuals diagnosed with autism. Several mutations associated with autism modify cellular communication via neuronal synapses. It has been suggested that modifications to the enteric nervous system, an intrinsic nervous system of the GI tract, could contribute to GI dysfunction. Changes in gut motility, permeability, and the mucosal barrier as well as shifts in the large population of microbes inhabiting the GI tract could contribute to GI symptoms. Preclinical research has demonstrated that mice expressing the well-studied R451C missense mutation in Nlgn3 gene, which encodes cell adhesion protein neuroligin-3 at neuronal synapses, exhibit GI dysfunction. Specifically, NL3R451C mice show altered colonic motility and faster small intestinal transit. As well as dysmotility, macrophages located within the gut-associated lymphoid tissue of the NL3R451C mouse caecum show altered morphology, suggesting that neuro-inflammation pathways are modified in this model. Interestingly, NL3R451C mice maintained in a shared environment demonstrate fecal microbial dysbiosis indicating a role for the nervous system in regulating gut microbial populations. To better understand host-microbe interactions, further clarification and comparison of clinical and animal model profiles of dysbiosis should be obtained, which in turn will provide better insights into the efforts taken to design personalized microbial therapies. In addition to changes in neurophysiological measures, the mucosal component of the GI barrier may contribute to GI dysfunction more broadly in individuals diagnosed with a wide range of neurological disorders. As the study of GI dysfunction advances to encompass multiple components of the gut-brain-microbiota axis, findings will help understand future directions such as microbiome engineering and optimisation of the mucosal barrier for health.

UAV Path Planning for Reconnaissance and Look-Ahead Coverage Support for Mobile Ground Vehicles.

Path planning of unmanned aerial vehicles (UAVs) for reconnaissance and look-ahead coverage support for mobile ground vehicles (MGVs) is a challenging task due to many unknowns being imposed by the MGVs' variable velocity profiles, change in heading, and structural differences between the ground and air environments. Few path planning techniques have been reported in the literature for multirotor UAVs that autonomously follow and support MGVs in reconnaissance missions. These techniques formulate the path planning problem as a tracking problem utilizing gimbal sensors to overcome the coverage and reconnaissance complexities. Despite their lack of considering additional objectives such as reconnaissance coverage and dynamic environments, they retain several drawbacks, including high computational requirements, hardware dependency, and low performance when the MGV has varying velocities. In this study, a novel 3D path planning technique for multirotor UAVs is presented, the enhanced dynamic artificial potential field (ED-APF), where path planning is formulated as both a follow and cover problem with nongimbal sensors. The proposed technique adopts a vertical sinusoidal path for the UAV that adapts relative to the MGV's position and velocity, guided by the MGV's heading for reconnaissance and exploration of areas and routes ahead beyond the MGV sensors' range, thus extending the MGV's reconnaissance capabilities. The amplitude and frequency of the sinusoidal path are determined to maximize the required look-ahead visual coverage quality in terms of pixel density and quantity pertaining to the area covered. The ED-APF was tested and validated against the general artificial potential field techniques for various simulation scenarios using Robot Operating System (ROS) and Gazebo-supported PX4-SITL. It demonstrated superior performance and showed its suitability for reconnaissance and look-ahead support to MGVs in dynamic and obstacle-populated environments.

A novel approach to a rare case of non-islet cell hypoglycaemia.

SUMMARY: Insulin autoimmune syndrome (IAS) is a rare cause of non-islet cell hypoglycaemia. Treatment of this condition is complex and typically involves long-term use of glucocorticoids. Immunotherapy may provide an alternative in the management of this autoimmune condition through the suppression of antibodies production by B-lymphocyte depletion. We present a case of a 62-year-old male, with refractory hypoglycaemia initially presenting with hypoglycaemic seizure during an admission for acute psychosis. Biochemical testing revealed hypoglycaemia with an inappropriately elevated insulin and C-peptide level and no evidence of exogenous use of insulin or sulphonylurea. Polyethylene glycol precipitation demonstrated persistently elevated free insulin levels. This was accompanied by markedly elevated anti-insulin antibody (IA) titres. Imaging included CT with contrast, MRI, pancreatic endoscopic ultrasound and Ga 68-DOTATATE position emission tomography (DOTATATE PET) scan did not reveal islet cell aetiology for hyperinsulinaemia. Maintenance of euglycaemia was dependent on oral steroids and dextrose infusion. Complete resolution of hypoglycaemia and dependence on glucose and steroids was only achieved following treatment with plasma exchange and rituximab. LEARNING POINTS: Insulin autoimmune syndrome (IAS) should be considered in patients with recurrent hyperinsulinaemic hypoglycaemia in whom exogenous insulin administration and islet cell pathologies have been excluded. Biochemical techniques play an essential role in establishing high insulin concentration, insulin antibody titres, and eliminating biochemical interference. High insulin antibody concentration can lead to inappropriately elevated serum insulin levels leading to hypoglycaemia. Plasma exchange and B-lymphocyte depletion with rituximab and immunosuppression with high dose glucocorticoids are effective in reducing serum insulin levels and hypoglycaemia in insulin autoimmune syndrome (IAS). Based on our observation, the reduction in serum insulin level may be a better indicator of treatment efficacy compared to anti-insulin antibody (IA) titre as it demonstrated greater correlation to the frequency of hypoglycaemia and to hypoglycaemia resolution.

Neuraminidase activity and specificity of influenza A virus are influenced by haemagglutinin-receptor binding.

Influenza virus haemagglutinin (HA) and neuraminidase (NA) are involved in the recognition and modulation of sialic acids on the cell surface as the virus receptor. Although the balance between two proteins functions has been found to be crucial for viral fitness, the interplay between the proteins has not been well established. Herein we present evidence for interplay between influenza HA and NA, which may affect the balance between two glycoprotein functions. NA enzymatic activities against sialoglycans were promoted by the presence of HA, which is in accordance with the level of co-existing HA. Such activity enhancement was lost when the HA-receptor binding properties were abolished by low-pH treatment or by mutations at the HA receptor binding domain. Sialidase activities of NA-containing virus-like particles and native influenza viruses were detected using different NA-assays and sialic acid substrates. Most pronounced HA-mediated NA enhancement was found when intact virions were confronted with multivalent surface-anchored substrates, which mimics the physiological conditions on cell membranes. Using recombinant viruses with altered HA bindings preference between α2,3- and α2,6-linked sialic acids, we also found that NA function against different substrates is correlated with the HA-receptor specificity. The effect of HA-receptor specificities on NA functions, together with the HA-mediated NA enhancement, may play a role in virus evasion of the mucus barrier, as well as in cross-species adaptation. Our data also indicate the importance of using multivalent substrates in future studies of NA functions.

Serum anti-neuraminidase antibody responses in human influenza A(H1N1)pdm09 virus infections.

Haemagglutination inhibition (HAI) antibody titres are a correlate of protection for influenza virus infection, but several studies have also demonstrated the protective role of anti-neuraminidase (anti-NA) antibodies. However, there is limited data on anti-NA antibody responses in naturally occurring human influenza. We investigated anti-NA antibody responses to pandemic N1 and seasonal N1 in 18 RT-PCR-confirmed patients with naturally acquired pandemic influenza A (H1N1) 2009 disease detected as part of a prospective community study of influenza. There were increases in neuraminidase inhibition (NAI) antibody titres to both pandemic and seasonal N1 antigens, with greater fold increases in those who had low levels of anti-pandemic N1 titres in acute sera. Of 18 patients with pandemic H1N1 infection, fourfold increases in antibody were observed by HAI in 11 (61%) patients, by anti-pandemic N1 inhibition in 13 (72%) or either in 15 of them (83%). Prior seasonal H1N1 virus infections had elicited cross-reactive anti-pandemic N1 antibody titres in some people prior to the emergence of the 2009 pandemic H1N1 virus. Antibody responses to the anti-N1 pandemic 2009 virus and cross-reactive responses to anti-seasonal N1 antibody were seen in influenza A pandemic 2009 infections. NAI antibodies can complement HAI antibody in sero-diagnosis and sero-epidemiology.

Oropharyngeal epignathus with partial facial duplication: report of a rare case.

Foetal oral teratoma or epignathus is a rare benign condition that originates in the oropharyngeal region. The term 'teratoma' refers to a mass composed of poorly organized tissues derived from each of the three germ layers. Epignathus may occur when one twin ceases development during gestation and becomes vestigial to the fully formed dominant twin. The reported incidence of epignathus is approximately 1:35,000 to 1:200,000 live births. A unique case of partial facial duplication with gross histological and radiological evidence of partial duplication of the facial elements and organs is presented herein. The affected newborn baby underwent urgent surgery due to breathing difficulties. The mass was excised successfully and the infant made an uneventful recovery. The resected specimen included two developing faces, each composed of a developing mandible and maxilla with developing tooth buds. Tissues from all three germ layers were present. In such cases, the treatment option is exclusively surgical, and complete resection is curative in most cases during the early neonatal period.

Cardiovascular risk assessment in type 2 diabetes mellitus: comparison of the World Health Organization/International Society of Hypertension risk prediction charts versus UK Prospective Diabetes Study risk engine.

INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) are at higher risk of developing cardiovascular diseases, and assessment of their cardiac risk is important for preventive strategies. PURPOSE: The Ministry of Health of Sri Lanka has recommended World Health Organization/International Society of Hypertension (WHO/ISH) charts for cardiac risk assessment in individuals with T2DM. However, the most suitable cardiac risk assessment tool for Sri Lankans with T2DM has not been studied. This study was designed to evaluate the performance of two cardiac risk assessments tools; WHO/ISH charts and UK Prospective Diabetes Study (UKPDS) risk engine. METHODS: Cardiac risk assessments were done in 2,432 patients with T2DM attending a diabetes clinic in Southern Sri Lanka using the two risk assessment tools. Validity of two assessment tools was further assessed by their ability to recognize individuals with raised low-density lipoprotein (LDL) and raised diastolic blood pressure in a cohort of newly diagnosed T2DM patients (n=332). RESULTS: WHO/ISH charts identified 78.4% of subjects as low cardiac risk whereas the UKPDS risk engine categorized 52.3% as low cardiac risk (P<0.001). In the risk categories of 10%-<20%, the UKPDS risk engine identified higher proportions of patients (28%) compared to WHO/ISH charts (7%). Approximately 6% of subjects were classified as low cardiac risk (<10%) by WHO/ISH when UKPDS recognized them as cardiac risk of >20%. Agreement between the two tools was poor (κ value =0.144, P<0.01). Approximately 82% of individuals categorized as low cardiac risk by WHO/ISH had higher LDL cholesterol than the therapeutic target of 100 mg/dL. CONCLUSION: There is a significant discrepancy between the two assessment tools with WHO/ISH risk chart recognizing higher proportions of patients having low cardiac risk than the UKPDS risk engine. Risk assessment by both assessment tools demonstrated poor sensitivity in identifying those with treatable levels of LDL cholesterol and diastolic blood pressure.

Beta-endorphin 1-31 biotransformation and cAMP modulation in inflammation.

A large body of evidence now exists for the immune cell expression, production, and the release of beta-endorphin (BE 1-31) within inflamed tissue. The inflammatory milieu is characterised by increased acidity, temperature and metabolic activity. Within these harsh conditions BE 1-31 is even more susceptible to increased enzymatic degradation over that of plasma or other non-injured tissue. To elucidate the biotransformation pathways of BE 1-31 and provide an insight to the impact of inflamed tissue environments, BE 1-31 and three of its major N-terminal fragments (BE 1-11, BE 1-13 and BE 1-17) were incubated in inflamed tissue homogenates at pH 5.5 for 2 hrs. In addition, the potency of BE 1-31 and five main N--terminal fragments (BE 1-9, BE 1-11, BE 1-13, BE 1-17, BE 1-20) was assessed at mu-opioid receptors (MOR), delta-opioid receptors (DOR), and kappa-opioid receptors (KOR). Opioid receptor potency was investigated by examining the modulation of forskolin induced cAMP accumulation. The majority of the N-terminal fragment of BE 1-31 had similar efficacy to BE 1-31 at MOR. The shortest of the major N-terminal fragments (BE 1-9), had partial agonist activity at MOR but possessed the highest potency of all tested peptides at DOR. There was limited effect for BE 1-31 and the biotransformed peptides at KOR. Major N-terminal fragments produced within inflamed tissue have increased presence within inflamed tissue over that of the parent molecule BE 1-31 and may therefore contribute to BE 1-31 efficacy within disease states that involve inflammation.