Vitamin D in Early Childhood and the Effect on Immunity to Mycobacterium tuberculosis

A potential role for vitamin D as a therapeutic immunomodulator in tuberculosis (TB) has been recognised for over 150 years, but has only recently returned to the centre of the research arena due to the increasing awareness of the global vitamin D deficiency epidemic. As early as birth a child is often deficient in vitamin D, which may not only affect their bone metabolism but also modulate their immune function, contributing to the increased susceptibility to many infections seen early in life. Recent studies have begun to explain the mechanisms by which vitamin D affects immunity. Antimicrobial peptides are induced in conjunction with stimulation of innate pattern recognition receptors enhancing immunity to particular infections. In contrast the role of vitamin D within the adaptive immune response appears to be more regulatory in function, perhaps as a mechanism to reduce unwanted inflammation. In this paper we focus on the effect of vitamin D on immunity to TB. Where much of the attention has been paid by past reviews to the role of vitamin D in adult TB patients, this paper, where possible, focuses on research in paediatric populations

Treatment Completion in a Cognitive Behaviour Therapy Service for Problem Gamblers: Clinical Outcome Study

Increased access to gambling is proving to be a great burden on the individuals who partake, their families and society in general. Despite growing evidence for the use of Cognitive-Behaviour Therapy (CBT) with problem gamblers, important questions remain unanswered regarding those individuals who do not respond to CBT. This paper compares gamblers who are considered 1) treatment completers, 2) drop-out following an initial assessment and, 3) drop-out after commencing treatment from a specialized CBT service. The results indicate a number of differences between the groups in regard to gambling severity and behaviour, demographic profile and variations in overall psychopathology

Specific antibodies against vaccine-preventable infections: a mother-infant cohort study

OBJECTIVES: To determine maternal and neonatal specific antibody levels to selected vaccine-preventable infections (pertussis, Haemophilus influenzae type b (Hib), tetanus and pneumococcus). DESIGN: Prospective cohort study. SETTING: A UK secondary care maternity unit (March 2011-January 2012). PARTICIPANTS: Mothers and infants within 72 h of delivery were eligible. Unwell individuals, mothers less than 18 years of age, and infants born at less than 36 weeks gestation, or weighing less than 2500 g, were excluded. HIV-infected mothers were included. 112 mother-infant pairs were recruited. Samples from 111 mothers and 109 infants (108 pairs) were available for analysis. OUTCOME MEASURES: Specific antibody levels were determined using standard commercial ELISAs. Specific antibody to pertussis antigens (PT and FHA) of >50 IU/ml, defined as 'positive' by the test manufacturer, were interpreted as protective. Antitetanus antibody titres >0.1 IU/ml and anti-Hib antibody titres >1 mg/l were regarded as protective. RESULTS: Only 17% (19/111) of women exhibited a protective antibody response against pertussis. 50% (56/111) of women had levels of antibody protective against Hib and 79% (88/111) against tetanus. There was a strong positive correlation between maternal-specific and infant-specific antibodies' responses against pertussis (rs=0.71, p<0.001), Hib (rs=0.80, p<0.001), tetanus (rs=0.90, p<0.001) and pneumococcal capsular polysaccharide (rs=0.85, p<0.001). Only 30% (33/109) and 42% (46/109) of infants showed a protective antibody response to pertussis and Hib, respectively. Placental transfer (infant:mother ratio) of specific IgG to pertussis, Hib, pneumococcus and tetanus was significantly reduced from HIV-infected mothers to their HIV-exposed, uninfected infants (n=12 pairs) compared with HIV-uninfected mothers with HIV-unexposed infants (n=96 pairs) by 58% (<0.001), 61% (<0.001), 28% (p=0.034) and 32% (p=0.035), respectively. CONCLUSIONS: Low baseline antibody levels against pertussis in this cohort suggest the recently implemented UK maternal pertussis immunisation programme has potential to be effective

Translation of MT-ATP6 pathogenic variants reveals distinct regulatory consequences from the co-translational quality control of mitochondrial protein synthesis

ddab314Pathogenic variants that disrupt human mitochondrial protein synthesis are associated with a clinically heterogeneous group of diseases. Despite an impairment in oxidative phosphorylation being a common phenotype, the underlying molecular pathogenesis is more complex than simply a bioenergetic deficiency. Currently, we have limited mechanistic understanding on the scope by which a primary defect in mitochondrial protein synthesis contributes to organelle dysfunction. Since the proteins encoded in the mitochondrial genome are hydrophobic and need co-translational insertion into a lipid bilayer, responsive quality control mechanisms are required to resolve aberrations that arise with the synthesis of truncated and misfolded proteins. Here, we show that defects in the OXA1L-mediated insertion of MT-ATP6 nascent chains into the mitochondrial inner membrane are rapidly resolved by the AFG3L2 protease complex. Using pathogenic MT-ATP6 variants, we then reveal discrete steps in this quality control mechanism and the differential functional consequences to mitochondrial gene expression. The inherent ability of a given cell type to recognize and resolve impairments in mitochondrial protein synthesis may in part contribute at the molecular level to the wide clinical spectrum of these disorders.Peer reviewe

Avoiding overshoot: why and how

Overshooting global temperature goals is risky. New research from the ENGAGE project shows the long-term economic benefits of scenarios that avoid overshoot and points out the investments needed to make it happen

Stakeholder engagement in climate change solutions

Workshops bringing scientists together with stakeholders from various backgrounds have shown the importance of dialogue for co-designing climate pathways and highlighted the need for physical meetings and capacity building. To find and implement solutions to climate change and other complex problems that society faces, requires constructive dialogue between the research community and a wide range of other stakeholders. Since 2019, the ENGAGE project has developed and used a carefully designed stakeholder engagement process to co-design climate mitigation pathways through open discussions about a range of topics using a combination of surveys, visual tools, and presentations

Mechanism of membrane-tethered mitochondrial protein synthesis

Mitochondrial ribosomes (mitoribosomes) are tethered to the mitochondrial inner membrane to facilitate the cotranslational membrane insertion of the synthesized proteins. We report cryo-electron microscopy structures of human mitoribosomes with nascent polypeptide, bound to the insertase oxidase assembly 1-like (OXA1L) through three distinct contact sites. OXA1L binding is correlated with a series of conformational changes in the mitoribosomal large subunit that catalyze the delivery of newly synthesized polypeptides. The mechanism relies on the folding of mL45 inside the exit tunnel, forming two specific constriction sites that would limit helix formation of the nascent chain. A gap is formed between the exit and the membrane, making the newly synthesized proteins accessible. Our data elucidate the basis by which mitoribosomes interact with the OXA1L insertase to couple protein synthesis and membrane delivery.Peer reviewe

Characterisation and outcome of idiopathic pyogranulomatous lymphadenitis in 64 English springer spaniel dogs

Objectives To describe the history, clinicopathological abnormalities, diagnostic imaging findings, lymph node cytological/histological appearance, treatment and outcome of English springer spaniels diagnosed with idiopathic pyogranulomatous lymphadenitis. Materials and Methods In this retrospective UK‐based multicentre study, 64 dogs were recruited from 10 referral centres, 32 first‐opinion practices and three histopathology/cytology laboratories, between 2010 and 2016. Results The median age at presentation was 6 years (range: 0.17 to 11.75). Neutered females were frequently affected. Pyrexia (83.8%), peripheral lymphadenomegaly (78.4%), dermatological lesions (72.9%), lethargy (67.6%), hyporexia (54%), diarrhoea (29.7%), coughing (24.3%), epistaxis, sneezing or nasal discharge (21.6%), ocular signs (21.6%) and vomiting (16.2%) were reported in dogs for which the history and physical examination records were available. Popliteal (45.3%), superficial cervical (35.9%) and submandibular (37.5%) lymphadenomegaly were frequently reported. Haematology and serum biochemistry revealed non‐specific changes. When undertaken, testing for infectious diseases was negative in all cases. Lymph node cytology, histopathology or both demonstrated mixed inflammatory (27%), pyogranulomatous (24%), neutrophilic (20%) or granulomatous (11%) lymphadenitis. Treatment details were available for 38 dogs, with 34 receiving prednisolone for a median duration of 15 weeks (range: 1 to 28 weeks). A good to excellent clinical response was reported in all but one case. Ten dogs relapsed after discontinuing prednisolone. Clinical Significance Idiopathic pyogranulomatous lymphadenitis should be considered as a differential diagnosis for lymphadenopathy and pyrexia in English springer spaniels. The characteristics of the disease, absence of identifiable infectious aetiology and response to glucocorticoid therapy suggest an immune‐mediated aetiology

A novel mitochondrial ATP6 frameshift mutation causing isolated complex V deficiency, ataxia and encephalomyopathy

We describe a novel frameshift mutation in the mitochondrial ATP6 gene in a 4-year-old girl associated with ataxia, microcephaly, developmental delay and intellectual disability. A heteroplasmic frameshift mutation in the MT-ATP6 gene was confirmed in the patient's skeletal muscle and blood. The mutation was not detectable in the mother's DNA extracted from blood or buccal cells. Enzymatic and oxymetric analysis of the mitochondrial respiratory system in the patients' skeletal muscle and skin fibroblasts demonstrated an isolated complex V deficiency. Native PAGE with subsequent immunoblotting for complex V revealed impaired complex V assembly and accumulation of ATPase subcomplexes. Whilst northern blotting confirmed equal presence of ATP8/6 mRNA, metabolic S-35-labelling of mitochondrial translation products showed a severe depletion of the ATP6 protein together with aberrant translation product accumulation. In conclusion, this novel isolated complex V defect expands the clinical and genetic spectrum of mitochondrial defects of complex V deficiency. Furthermore, this work confirms the benefit of native PAGE as an additional diagnostic method for the identification of OXPHOS defects, as the presence of complex V subcomplexes is associated with pathogenic mutations of mtDNA. (C) 2017 Elsevier Masson SAS. All rights reserved.Peer reviewe