How mechanistic in silico modelling can improve our understanding of TB disease and treatment.

TB is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent. Decreasing the length of time for TB treatment is an important step towards the goal of reducing mortality. Mechanistic in silico modelling can provide us with the tools to explore gaps in our knowledge, with the opportunity to model the complicated within-host dynamics of the infection, and simulate new treatment strategies. Significant insight has been gained using this form of modelling when applied to other diseases - much can be learned in infection research from these advances.

Structure determination and crystal chemistry of large repeat mixed-layer hexaferrites.

Hexaferrites are an important class of magnetic oxides with applications in data storage and electronics. Their crystal structures are highly modular, consisting of Fe- or Ba-rich close-packed blocks that can be stacked in different sequences to form a multitude of unique structures, producing large anisotropic unit cells with lattice parameters typically >100 Šalong the stacking axis. This has limited atomic-resolution structure solutions to relatively simple examples such as Ba2Zn2Fe12O22, whilst longer stacking sequences have been modelled only in terms of block sequences, with no refinement of individual atomic coordinates or occupancies. This paper describes the growth of a series of complex hexaferrite crystals, their atomic-level structure solution by high-resolution synchrotron X-ray diffraction, electron diffraction and imaging methods, and their physical characterization by magnetometry. The structures include a new hexaferrite stacking sequence, with the longest lattice parameter of any hexaferrite with a fully determined structure.

Concentrations of oxidized linoleic acid derived lipid mediators in the amygdala and periaqueductal grey are reduced in a mouse model of chronic inflammatory pain.

Chronic pain is both a global public health concern and a serious source of personal suffering for which current treatments have limited efficacy. Recently, oxylipins derived from linoleic acid (LA), the most abundantly consumed polyunsaturated fatty acid in the modern diet, have been implicated as mediators of pain in the periphery and spinal cord. However, oxidized linoleic acid derived mediators (OXLAMs) remain understudied in the brain, particularly during pain states. In this study, we employed a mouse model of chronic inflammatory pain followed by a targeted lipidomic analysis of the animals' amygdala and periaqueductal grey (PAG) using LC-MS/MS to investigate the effect of chronic inflammatory pain on oxylipin concentrations in these two brain nuclei known to participate in pain sensation and perception. From punch biopsies of these brain nuclei, we detected twelve OXLAMs in both the PAG and amygdala and one arachidonic acid derived mediator, 15-HETE, in the amygdala only. In the amygdala, we observed an overall decrease in the concentration of the majority of OXLAMs detected, while in the PAG the concentrations of only the epoxide LA derived mediators, 9,10-EpOME and 12,13-EpOME, and one trihydroxy LA derived mediator, 9,10,11-TriHOME, were reduced. This data provides the first evidence that OXLAM concentrations in the brain are affected by chronic pain, suggesting that OXLAMs may be relevant to pain signaling and adaptation to chronic pain in pain circuits in the brain and that the current view of OXLAMs in nociception derived from studies in the periphery is incomplete.

Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice.

This corrects the article DOI: 10.1038/tp.2017.142.

Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice.

Late-onset Alzheimer's disease (AD) remains a medical mystery. Recent studies have linked it to impaired repair of aged neurons. Potential involvement of interleukin33 (IL33) in AD has been reported. Here we show that IL33, which was expressed by up to 75% astrocytes in the aged brains, was critical for repair of aged neurons. Mice lacking Il33 gene (Il33-/-) developed AD-like disease after 60-80 weeks, which was characterized by tau abnormality and a heavy loss of neurons/neurites in the cerebral cortex and hippocampus accompanied with cognition/memory impairment. We detected an abrupt aging surge in the cortical and hippocampal neurons at middle age (40 weeks). To counter the aging surge, wild-type mice rapidly upregulated repair of DNA double-strand breaks (DSBs) and autophagic clearance of cellular wastes in these neurons. Il33-/- mice failed to do so, but instead went on to develop rapid accumulation of abnormal tau, massive DSBs and abnormal autophagic vacuoles in these neurons. Thus, uncontrolled neuronal aging surge at middle age due to lack of IL33 resulted in neurodegeneration and late-onset AD-like symptome in Il33-/- mice. Our study also suggests that the aging surge is a time to search for biomarkers for early diagnosis of AD before massive neuron loss.

Accelerated discovery of two crystal structure types in a complex inorganic phase field.

The discovery of new materials is hampered by the lack of efficient approaches to the exploration of both the large number of possible elemental compositions for such materials, and of the candidate structures at each composition. For example, the discovery of inorganic extended solid structures has relied on knowledge of crystal chemistry coupled with time-consuming materials synthesis with systematically varied elemental ratios. Computational methods have been developed to guide synthesis by predicting structures at specific compositions and predicting compositions for known crystal structures, with notable successes. However, the challenge of finding qualitatively new, experimentally realizable compounds, with crystal structures where the unit cell and the atom positions within it differ from known structures, remains for compositionally complex systems. Many valuable properties arise from substitution into known crystal structures, but materials discovery using this approach alone risks both missing best-in-class performance and attempting design with incomplete knowledge. Here we report the experimental discovery of two structure types by computational identification of the region of a complex inorganic phase field that contains them. This is achieved by computing probe structures that capture the chemical and structural diversity of the system and whose energies can be ranked against combinations of currently known materials. Subsequent experimental exploration of the lowest-energy regions of the computed phase diagram affords two materials with previously unreported crystal structures featuring unusual structural motifs. This approach will accelerate the systematic discovery of new materials in complex compositional spaces by efficiently guiding synthesis and enhancing the predictive power of the computational tools through expansion of the knowledge base underpinning them.

Redox-controlled potassium intercalation into two polyaromatic hydrocarbon solids.

Alkali metal intercalation into polyaromatic hydrocarbons (PAHs) has been studied intensely after reports of superconductivity in a number of potassium- and rubidium-intercalated materials. There are, however, no reported crystal structures to inform our understanding of the chemistry and physics because of the complex reactivity of PAHs with strong reducing agents at high temperature. Here we present the synthesis of crystalline K2Pentacene and K2Picene by a solid-solid insertion protocol that uses potassium hydride as a redox-controlled reducing agent to access the PAH dianions, and so enables the determination of their crystal structures. In both cases, the inserted cations expand the parent herringbone packings by reorienting the molecular anions to create multiple potassium sites within initially dense molecular layers, and thus interact with the PAH anion π systems. The synthetic and crystal chemistry of alkali metal intercalation into PAHs differs from that into fullerenes and graphite, in which the cation sites are pre-defined by the host structure.

Exposure to Perinatal Infections and Bipolar Disorder: A Systematic Review.

Bipolar disorder (BD) is a debilitating psychiatric disorder and a growing global public health issue. Notwithstanding BD has been conceptualized as a neuroprogressive illness, there are some evidences to suggest a role for neurodevelopmental pathways in the patho-etiology of this disorder. Evidences on the associations between perinatal infections and risk for bipolar disorder have been inconsistent across studies. Here, we performed a systematic review of observational studies on the relationship between exposure to perinatal pathogens and bipolar disorder. A computerized literature search of the PubMed, Embase, and PsyINFO databases till January 31(st), 2015 was performed. Twenty-three studies ultimately met inclusion criteria. Studies investigated exposure to several pathogens namely Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Herpes simplex virus-1 (HSV-1), Herpes simplex virus-2 (HSV-2), Human herpesvirus 6 (HHV-6), Toxoplasma gondii, Influenza, and Varicella zoster virus (VZV). Overall, studies provided mixed evidences. Thus, contrary to schizophrenia, the role of perinatal infections as risk factors for BD remain inconclusive. Larger studies with a prospective design would be necessary to elucidate the role of previous exposure to infectious agents as a potential risk factor for BD.

Designing switchable polarization and magnetization at room temperature in an oxide.

Ferroelectric and ferromagnetic materials exhibit long-range order of atomic-scale electric or magnetic dipoles that can be switched by applying an appropriate electric or magnetic field, respectively. Both switching phenomena form the basis of non-volatile random access memory, but in the ferroelectric case, this involves destructive electrical reading and in the magnetic case, a high writing energy is required. In principle, low-power and high-density information storage that combines fast electrical writing and magnetic reading can be realized with magnetoelectric multiferroic materials. These materials not only simultaneously display ferroelectricity and ferromagnetism, but also enable magnetic moments to be induced by an external electric field, or electric polarization by a magnetic field. However, synthesizing bulk materials with both long-range orders at room temperature in a single crystalline structure is challenging because conventional ferroelectricity requires closed-shell d(0) or s(2) cations, whereas ferromagnetic order requires open-shell d(n) configurations with unpaired electrons. These opposing requirements pose considerable difficulties for atomic-scale design strategies such as magnetic ion substitution into ferroelectrics. One material that exhibits both ferroelectric and magnetic order is BiFeO3, but its cycloidal magnetic structure precludes bulk magnetization and linear magnetoelectric coupling. A solid solution of a ferroelectric and a spin-glass perovskite combines switchable polarization with glassy magnetization, although it lacks long-range magnetic order. Crystal engineering of a layered perovskite has recently resulted in room-temperature polar ferromagnets, but the electrical polarization has not been switchable. Here we combine ferroelectricity and ferromagnetism at room temperature in a bulk perovskite oxide, by constructing a percolating network of magnetic ions with strong superexchange interactions within a structural scaffold exhibiting polar lattice symmetries at a morphotropic phase boundary (the compositional boundary between two polar phases with different polarization directions, exemplified by the PbZrO3-PbTiO3 system) that both enhances polarization switching and permits canting of the ordered magnetic moments. We expect this strategy to allow the generation of a range of tunable multiferroic materials.

Effect of environment on the long-term consequences of chronic pain.

Much evidence from pain patients and animal models shows that chronic pain does not exist in a vacuum but has varied comorbidities and far-reaching consequences. Patients with long-term pain often develop anxiety and depression and can manifest changes in cognitive functioning, particularly with working memory. Longitudinal studies in rodent models also show the development of anxiety-like behavior and cognitive changes weeks to months after an injury causing long-term pain. Brain imaging studies in pain patients and rodent models find that chronic pain is associated with anatomical and functional alterations in the brain. Nevertheless, studies in humans reveal that lifestyle choices, such as the practice of meditation or yoga, can reduce pain perception and have the opposite effect on the brain as does chronic pain. In rodent models, studies show that physical activity and a socially enriched environment reduce pain behavior and normalize brain function. Together, these studies suggest that the burden of chronic pain can be reduced by nonpharmacological interventions.

Nephronophthisis and retinal degeneration in tmem218-/- mice: a novel mouse model for Senior-Løken syndrome?

Mice deficient in TMEM218 (Tmem218(-/-) ) were generated as part of an effort to identify and validate pharmaceutically tractable targets for drug development through large-scale phenotypic screening of knockout mice. Routine diagnostics, expression analysis, histopathology, and electroretinogram analyses completed on Tmem218(-/-) mice identified a previously unknown role for TMEM218 in the development and function of the kidney and eye. The major observed phenotypes in Tmem218(-/-) mice were progressive cystic kidney disease and retinal degeneration. The renal lesions were characterized by diffuse renal cyst development with tubulointerstitial nephropathy and disruption of tubular basement membranes in essentially normal-sized kidneys. The retinal lesions were characterized by slow-onset loss of photoreceptors, which resulted in reduced electroretinogram responses. These renal and retinal lesions are most similar to those associated with nephronophthisis (NPHP) and retinitis pigmentosa in humans. At least 10% of NPHP cases present with extrarenal conditions, which most often include retinal degeneration. Senior-Løken syndrome is characterized by the concurrent development of autosomal recessive NPHP and retinitis pigmentosa. Since mutations in the known NPHP genes collectively account for only about 30% of NPHP cases, it is possible that TMEM218 could be involved in the development of similar ciliopathies in humans. In reviewing all other reported mouse models of NPHP, we suggest that Tmem218(-/-) mice could provide a useful model for elucidating the pathogenesis of cilia-associated disease in both the kidney and the retina, as well as in developing and testing novel therapeutic strategies for Senior-Løken syndrome.

Skin- and gut-homing molecules on human circulating γδ T cells and their dysregulation in inflammatory bowel disease.

Changes in phenotype and function of γδ T cells have been reported in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Dysregulation of lymphocyte migration plays a key role in IBD pathogenesis; however, data on migratory properties of γδ T cells are scarce. Human circulating γδ T cells from healthy controls (n = 27), patients with active CD (n = 15), active UC (n = 14) or cutaneous manifestations of IBD (n = 2) were characterized by flow cytometry. Circulating γδ T cells in healthy controls were CD3(hi) and expressed CD45RO. They expressed gut-homing molecule ß7 but not gut-homing molecule corresponding chemokine receptors (CCR)9, or skin-homing molecules cutaneous lymphocyte-associated antigen (CLA) and CCR4, despite conventional T cells containing populations expressing these molecules. CCR9 expression was increased on γδ T cells in CD and UC, while skin-homing CLA was expressed aberrantly on γδ T cells in patients with cutaneous manifestations of IBD. Lower levels of CD3 expression were found on γδ T cells in CD but not in UC, and a lower proportion of γδ T cells expressed CD45RO in CD and UC. Enhanced expression of gut-homing molecules on circulating γδ T cells in IBD and skin-homing molecules in cutaneous manifestations of IBD may be of clinical relevance.

Recurrent malignant peripheral nerve sheath tumour in a patient with neurofibromatosis Type 1: a case report.

Malignant peripheral nerve sheath tumour (MPNST) is a rare, albeit well-described, complication of neurofibromatosis. We report a 58-year-old patient with known neurofibromatosis Type 1 (NF-1) who presented with an aggressive recurrent malignant peripheral nerve sheath tumour and spinal cord compression 5 weeks after undergoing tumour excision with thoracic (T)6-7 laminectomy. The case and literature review are instructive to those following NF-1 patients with regards to screening for, and management of, malignant conversion of plexiform neurofibroma.

Amitriptyline modifies the visceral hypersensitivity response to acute stress in the irritable bowel syndrome.

BACKGROUND: Acute physical stress causes alteration in gut autonomic function and visceral hypersensitivity in patients with irritable bowel syndrome (IBS). We have developed a model to measure this stress response. AIM: To assess whether treatment with a drug effective in treating IBS (amitriptyline) alters the response to acute stress in IBS patients. METHODS: Nineteen patients with IBS were given amitriptyline 25-50 mg. Patients underwent physical stress (cold pressor) test at baseline and after 3 months of treatment. Physiological parameters measured were: stress perception; systemic autonomic tone [heart rate (HR) and blood pressure (BP)]; gut specific autonomic innervation [rectal mucosal blood flow (RMBF)] and visceral sensitivity (rectal electrosensitivity). RESULTS: Fourteen of 19 (74%) patients improved symptomatically after 3 months of amitriptyline. Acute stress induced increased perception of stress and systemic autonomic tone and reduced RMBF in symptomatic responders and nonresponders (P > 0.05 for all). All nonresponders but only 3 of 14 responders continued to exhibit stress-induced reduced pain threshold at 3 months (change from baseline -31% vs. +2%, P < 0.03 respectively). CONCLUSION: In this open study, amitriptyline appears to decrease stress-induced electrical hypersensitivity; this effect is independent of autonomic tone. The gut response to acute stress deserves further study as a model to study drug efficacy in IBS.

Quality of care for women presenting with benign breast conditions.

The aim of the study was to investigate the management of women with benign breast problems. A consecutive sample of women (n = 194) was assessed who presented to public or private sector providers. The main reasons for referral were breast lumps (62%); 56% of women who attended the public sector did not receive any recommendation compared to 40% who attended the private sector and clinical/general practitioner reviews were recommended to more women in the private sector (54%). Reasons for the discrepancy between public and private patients require further investigation.

IgA multiple myeloma presenting as non-obstructive jaundice.

Multiple myeloma can occasionally present with jaundice. The underlying process may be pancreatic head myeloma infiltration causing obstructive jaundice or hepatic amyloid deposition resulting in cholestatic jaundice. A rare case of myeloma presenting as jaundice due to hepatic myeloma infiltration is reported.

Referral patterns to a district general hospital gastroenterology outpatient clinic: implications for the 'two-week target'.

We defined the pattern and appropriateness of GPs' new-patient referrals to a large district general hospital gastroenterology department, and assessed the implications for workload in the context of the recently introduced 'two-week target'. Prospective data were collected on all new referrals over a two-month period and 426 new appointments were included, from which data were available on 390. Only six referrals were deemed inappropriate. Sixty-nine patients had a functional disorder, and GPs were less likely to diagnose this group at referral than the gastroenterologist was after the initial consultation. Nineteen per cent of all GP referrals were classified as urgent and 6% of these had a malignancy. Fifty per cent of patients with malignancy were not perceived as meriting an urgent referral by the GP Gastroenterology outpatient facilities are already overstretched and the implementation of the two-week target will add considerable strain to the current resources, with little gain in identifying malignancy.

A case of weak muscles.

BACKGROUND: Gut involvement in inflammatory myositis is rare but causes significant morbidity and mortality. CASE REPORT: A case of eosinophilic gastroenteritis and polymyositis occurring in the same patient is described. The interface of visceral and striated muscle involvement is discussed. The pathophysiology of eosinophilic gastroenteritis and the spectrum of gastrointestinal involvement in inflammatory myositis are also discussed. RESULTS: Both gastrointestinal and skeletal muscle symptoms improved with immunosuppression, suggesting a possible common underlying mechanism.

Outcome of treatment for limb and limb girdle sarcomas at the Royal Marsden Hospital.

AIMS: In this study we aimed to determine local recurrence, mortality an d amputation rates in patients presenting with limb and limb girdle soft tissue sarcomas. METHOD: A review of all 439 patients presenting with p rimary or recurrent soft tissue sarcomas of limb and limb girdle to the Royal Marsden Hospital between 1989 and 1995 was carried out. RESULTS: The local recurrence rate was 15.5% and the mortality rate was 30%, with a median follow up of 3.2 years and an overall amputation rate of 4.8%. CONCLUSION: The outcome of limb and limb girdle sarcomas in this study i s comparable to those reported elsewhere.