Dietary restriction of tyrosine and phenylalanine lowers tyrosinaemia associated with nitisinone therapy of alkaptonuria.

BACKGROUND: Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy. Recently, nitisinone treatment, which blocks HGA formation, has been effective in AKU patients. However, a consequence of nitisinone is elevated tyrosine that can cause keratopathy. The effect of tyrosine and phenylalanine dietary restriction was investigated in nitisinone-treated AKU mice, and in an observational study of dietary intervention in AKU patients. METHODS: Nitisinone-treated AKU mice were fed tyrosine/phenylalanine-free and phenylalanine-free diets with phenylalanine supplementation in drinking water. Tyrosine metabolites were measured pre-nitisinone, post-nitisinone, and after dietary restriction. Subsequently an observational study was undertaken in 10 patients attending the National Alkaptonuria Centre (NAC), with tyrosine >700μmol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine-free amino acid supplements. RESULTS: Elevated tyrosine (813μmol/L) was significantly reduced in nitisinone-treated AKU mice fed a tyrosine/phenylalanine-free diet in a dose responsive manner. At 3 days of restriction, tyrosine was 389.3μmol/L, 274.8μmol/L and 144.3μmol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine-free diet; at 3 days tyrosine was 757.3μmol/L, 530.2μmol/L and 656.2μmol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (p=0.002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine-free amino acid supplementation; 4 out of 10 patients achieved tyrosine <700μmol/L. CONCLUSION: Tyrosine/phenylalanine dietary restriction significantly reduced nitisinone-induced tyrosinaemia in mice, with phenylalanine restriction alone proving ineffective. Similarly, protein restriction significantly reduced circulating tyrosine in AKU patients

Commentary – ordering lab tests for suspected rheumatic disease

One of the least-appreciated advances in pediatric rheumatology over the past 25 years has been the delineation of the many ways in which children with rheumatic disease differ from adults with the same illnesses. Furthermore, we are now learning that paradigms that are useful in evaluating adults with musculoskeletal complaints have limited utility in children. Nowhere is that more true than in the use of commonly used laboratory tests, particularly antinuclear antibody (ANA) and rheumatoid factor (RF) assays. This short review will provide the practitioner with the evidence base that supports a more limited use of ANA and RF testing in children

A rapid response vaccine development strategy for newcastle disease in poultry

Poultry is a major source of protein in sub-Saharan Africa and many other lower-income regions. Newcastle disease virus (NCDV) comprises a significant threat toward poultry production. While NCDV vaccines are routinely used in developed countries, those used in sub-Saharan Africa are mostly imported and are not specific to locally circulating strains. Indeed, the lack of rapid, field-based NCDV detection and the absence of cost-effective production methods for pure, strain-specific vaccines hampers efficient poultry production throughout these regions. This remains a major problem for both subsistence and commercial farming.The aim for this study was firstly, to develop a field-based isothermal PCR assay for NCDV detection that employed a portable instrument and real-time data transfer application. Secondly,to use the nucleic acid sequence data obtained from field isolates to develop a protocol compatible with rapid emergency vaccine production for NCDV.To achieve this, the isothermal PCR detection assay was applied to field isolates from suspected NCDV outbreaks on commercial poultry farms in KwaZulu-Natal, South Africa, while for the vaccine development, the NCDV matrix gene of one of the isolates was sequenced and used to design primers for the recombinant cloning of this antigen into an adenoviral vector.This‘vaccine vector’ and a control adenoviral vector were each amplified in 293T cells and then used to infect both 293T cells as a production cell line and chicken embryo fibroblasts (CEF) as a preliminary model of the target host. Western blotting confirmed the successful expression of the V5epitopetagby the control vector in both cell lines, which established the compatibility of the adenovirus vector as an appropriate carrier of the target antigen. Mass spectrometry confirmed expression of the NCDV matrix protein by the vaccine vector in both cell lines. In conclusion, the improved turnaround time from detection to the production of the vaccine antigen was under6weeks.The approach described here provides a rapid and cost-effective protocol for both the pathogen detection on-site and the production of pure vaccine antigens specific to an emerging field strain of NCDV within lower-income regions.</jats:p

Barriers and motivators to gaining access to smoking cessation services amongst deprived smokers – a qualitative study

BACKGROUND: Smoking is strongly associated with disadvantage and is an important contributor to inequalities in health. Smoking cessation services have been implemented in the UK targeting disadvantaged smokers, but there is little evidence available on how to design services to attract this priority group. METHODS: We conducted focus groups with 39 smokers aged 21–75 from the most socio-economically deprived areas of Nottingham UK who had made an unsuccessful attempt to quit within the last year without using smoking cessation services, to identify specific barriers or motivators to gaining access to these services. RESULTS: Barriers to use of existing services related to fear of being judged, fear of failure, a perceived lack of knowledge about existing services, a perception that available interventions – particularly Nicotine Replacement Therapy – are expensive and ineffective, and negative media publicity about bupropion. Participants expressed a preference for a personalised, non-judgemental approach combining counselling with affordable, accessible and effective pharmacological therapies; convenient and flexible timing of service delivery, and the possibility of subsidised complementary therapies. CONCLUSION: We conclude that smokers from these deprived areas generally had low awareness of the services available to help them, and misconceptions about their availability and effectiveness. A more personalised approach to promoting services that are non-judgemental, and with free pharmacotherapy and flexible support may encourage more deprived smokers to quit smoking

Obesity and diabetes mellitus association in rural community of Katana, South Kivu, in Eastern Democratic Republic of Congo : Bukavu Observ Cohort study results

Background: Factual data exploring the relationship between obesity and diabetes mellitus prevalence from rural areas of sub-Saharan Africa remain scattered and are unreliable. To address this scarceness, this work reports population study data describing the relationship between the obesity and the diabetes mellitus in the general population of the rural area of Katana (South Kivu in the Democratic Republic of the Congo). Methods: A cohort of three thousand, nine hundred, and sixty-two (3962) adults (>15 years old) were followed between 2012 and 2015 (or 4105 person-years during the observation period), and data were collected using the locally adjusted World Health Organization's (WHO) STEPwise approach to Surveillance (STEPS) methodology. The hazard ratio for progression of obesity was calculated. The association between diabetes mellitus and obesity was analyzed with logistic regression. Results: The diabetes mellitus prevalence was 2.8 % versus 3.5 % for obese participants and 7.2 % for those with metabolic syndrome, respectively. Within the diabetes group, 26.9 % had above-normal waist circumference and only 9.8 % were obese. During the median follow-up period of 2 years, the incidence of obesity was 535/100,000 person-years. During the follow-up, the prevalence of abdominal obesity significantly increased by 23 % (p < 0.0001), whereas the increased prevalence of general obesity (7.8 %) was not significant (p = 0.53). Finally, diabetes mellitus was independently associated with age, waist circumference, and blood pressure but not body mass index. Conclusion: This study confirms an association between diabetes mellitus and abdominal obesity but not with general obesity. On the other hand, the rapid increase in abdominal obesity prevalence in this rural area population within the follow-up period calls for the urgent promoting of preventive lifestyle measures

A case of panuveitis with hypopyon due to presumed ocular leishmaniasis in a HIV patient.

BACKGROUND: Post-kala-azar dermal leishmaniasis is a well-known immunologic cutaneous reaction. There are few case reports of ocular leishmaniasis. It is a sight-threatening condition that needs to be rapidly recognized and treated to avoid permanent visual loss. Ocular leishmaniasis panuveitis can present with severe inflammation in patients with highly active anti-retroviral therapy (HAART)-induced immune reconstitution syndrome. FINDINGS: A case of a 40-year-old man, human immunodeficiency virus (HIV) positive on HAART, with a presumed diagnosis of ocular leishmaniasis, is presented. He had a past history of visceral leishmaniasis and was referred to the uveitis service with rapidly worsening panuveitis and counting fingers vision in both eyes. On empirical anti-leishmania therapy and systemic steroids, the visual acuity of the left eye improved to 6/9 but remained poor in the right eye. Based on the medical history, improvement with therapy and the exclusion of other common infections, a presumed diagnosis of ocular leishmaniasis-related panuveitis was made. CONCLUSIONS: A major immune reaction against lingering parasites may play a key role in the pathogenesis of this sight-threatening and rapidly progressive condition. Both the infection and the immune reaction should be treated

Mesozoic retroposons reveal parrots as the closest living relatives of passerine birds

The relationships of passerines (such as the well-studied zebra finch) with non-passerine birds is one of the great enigmas of avian phylogenetic research, because decades of extensive morphological and molecular studies yielded highly inconsistent results between and within data sets. Here we show the first application of the virtually homoplasy-free retroposon insertions to this controversy. Our study examined ~200,000 retroposon-containing loci from various avian genomes and retrieved 51 markers resolving early bird phylogeny. Among these, we obtained statistically significant evidence that parrots are the closest and falcons the second-closest relatives of passerines, together constituting the Psittacopasserae and the Eufalconimorphae, respectively. Our new and robust phylogenetic framework has substantial implications for the interpretation of various conclusions drawn from passerines as model organisms. This includes insights of relevance to human neuroscience, as vocal learning (that is, birdsong) probably evolved in the psittacopasseran ancestor, >30 million years earlier than previously assumed

Understanding voltage decay in lithium-excess layered cathode materials through oxygen-centred structural arrangement

Lithium-excess 3d-transition-metal layered oxides (Li1+xNiyCozMn1-x-y-zO2, &gt; 250 mAh g(-1)) suffer from severe voltage decay upon cycling, which decreases energy density and hinders further research and development. Nevertheless, the lack of understanding on chemical and structural uniqueness of the material prevents the interpretation of internal degradation chemistry. Here, we discover a fundamental reason of the voltage decay phenomenon by comparing ordered and cation-disordered materials with a combination of X-ray absorption spectroscopy and transmission electron microscopy studies. The cation arrangement determines the transition metal-oxygen covalency and structural reversibility related to voltage decay. The identification of structural arrangement with de-lithiated oxygen-centred octahedron and interactions between octahedrons affecting the oxygen stability and transition metal mobility of layered oxide provides the insight into the degradation chemistry of cathode materials and a way to develop high-energy density electrodes

FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation

FUsed in Sarcoma (FUS) is a multifunctional RNA binding protein (RBP). FUS mutations lead to its cytoplasmic mislocalization and cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Here, we use mouse and human models with endogenous ALS-associated mutations to study the early consequences of increased cytoplasmic FUS. We show that in axons, mutant FUS condensates sequester and promote the phase separation of fragile X mental retardation protein (FMRP), another RBP associated with neurodegeneration. This leads to repression of translation in mouse and human FUS-ALS motor neurons and is corroborated in vitro, where FUS and FMRP copartition and repress translation. Last, we show that translation of FMRP-bound RNAs is reduced in vivo in FUS-ALS motor neurons. Our results unravel new pathomechanisms of FUS-ALS and identify a novel paradigm by which mutations in one RBP favor the formation of condensates sequestering other RBPs, affecting crucial biological functions, such as protein translation