Lysosomal storage disorders: A review of the musculoskeletal features

The lysosomal storage disorders are a collection of progressive, multisystem disorders that frequently present in childhood. Their timely diagnosis is paramount as they are becoming increasingly treatable. Musculoskeletal manifestations often occur early in the disease course, hence are useful as diagnostics clues. Non‐inflammatory joint stiffness or pain, carpal tunnel syndrome, trigger fingers, unexplained pain crises and short stature should all prompt consideration of a lysosomal storage disorder. Recurrent ENT infections, hepatosplenomegaly, recurrent hernias and visual/hearing impairment – especially when clustered together – are important extra‐skeletal features. As diagnostic and therapeutic options continue to evolve, children with lysosomal storage disorders and their families are facing more sophisticated options for screening and treatment. The aim of this article is to highlight the paediatric presentations of lysosomal storage disorders, with an emphasis on the musculoskeletal features.     

Characterization of HDL and lipoproteins intermediate to LDL and HDL in the serum of pedigreed baboons fed an atherogenic diet

A lipoprotein species with ultracentrifugal flotation rates (F0(1.20) 9-28) intermediate to high density lipoproteins (HDL, F0(1.20) 0-9) and low density lipoproteins (LDL, F0(1.20) 28-56) found in the plasma of certain pedigreed baboons fed an atherogenic diet was studied by gradient gel electrophoresis (GGE) and ultracentrifugal techniques. These lipoproteins were found to be heterogeneous in size (125-220 A) and hydrated density (1.028-1.080 g/ml). The major apolipoprotein in all density subfractions of the F0(1.20) 9-28 lipoproteins exhibited the molecular weight (2.8 X 10(4) daltons) and immunochemical properties of apolipoprotein A-I (apoA-I). Protein corresponding to apolipoprotein E (apoE, 3.5 X 10(4) daltons) was observed primarily in the less dense subspecies of F0(1.20) 9-28 lipoproteins. Some low molecular weight (1.8 X 10(4), 1.3 X 10(4), and 1.1 X 10(4) daltons) apolipoproteins were also detected. At low serum F0(1.20) 9-28 lipoprotein concentrations, only the smaller, more dense, protein-rich species were present; at higher F0(1.20) 9-28 concentrations, the larger, less dense species were observed in addition to the small species. The HDL of pedigreed baboons in families with and without serum F0(1.20) 9-28 lipoproteins were also characterized. The HDL of both groups of progeny consisted of a similar set of 5 subpopulations designated HDL-I through HDL-V determined by GGE. HDL-I, consisting of material 100-125 A in size, was the major HDL subpopulation. ApoA-I was the major protein moiety in all HDL subpopulations; none contained apoE. Baboons in families with F0(1.20) 9-28 lipoproteins had more HLD-I (292 +/- 80 mg/dl vs. 235 +/- 55 mg/dl) and less HDL-II (86 +/- 22 mg/dl vs. 135 +/- 34 mg/dl) than baboons in families without F0(1.20) 9-28 lipoproteins; both groups showed identical total HDL concentrations (446 +/- 90 mg/dl and 444 +/- 49 mg/dl, respectively). Among those baboons in families with F0(1.20) 9-28 lipoproteins, there was an inverse correlation between F0(1.20) 9-28 concentration and total HDL, HDL-I and HDL-II concentrations, indicating a possible metabolic relationship between these HDL subpopulations and the F0(1.20) 9-28 species.     

Elimination of extrachromosomally amplified MYC genes from human tumor cells reduces their tumorigenicity.

Oncogene amplification has been observed in a broad spectrum of human tumors and has been associated with a poor prognosis for patients with several different types of malignancies. Importantly, at biopsy, the amplified genes localize to acentric extrachromosomal elements such as double-minute chromosomes (DMs) in the vast majority of cases. We show here that treatment of several human tumor cell lines with low concentrations of hydroxyurea accelerates the loss of their extrachromosomally amplified oncogenes. The decreases in MYC copy number in a human tumor cell line correlated with a dramatic reduction in cloning efficiency in soft agar and tumorigenicity in nude mice. No effect on gene copy number or tumorigenicity was observed for a closely related cell line containing the same number of chromosomally amplified MYC genes. One step involved in the accelerated loss of extrachromosomal elements is shown to involve their preferential entrapment of DMs within micronuclei. The data suggest that agents that accelerate the loss of extrachromosomally amplified genes could provide valuable tools for moderating the growth of a large number of human neoplasms.     

Age of diabetes diagnosis and diabetes duration associate with glycated haemoglobin

An earlier age of diagnosis (r = −0.28, p < 0.0001) and longer duration of type 2 diabetes (r = 0.26, p < 0.0001) were each found to correlate with higher HbA1c level, on analysis of a diabetes centre database in people under regular shared care. When combined, these biological variables strongly associate with the current HbA1c level.     

Too Fit To Fracture: exercise recommendations for individuals with osteoporosis or osteoporotic vertebral fracture

Summary

A consensus process was conducted to develop exercise recommendations for individuals with osteoporosis or vertebral fractures. A multicomponent exercise program that includes balance and resistance training is recommended.

Introduction

The aim was to develop consensus on exercise recommendations for older adults: (1) with osteoporosis and (2) with osteoporotic vertebral fracture(s).

Methods

The Grading of Recommendations Assessment, Development, and Evaluation method was used to evaluate the quality of evidence and develop recommendations. Outcomes important for decision making were nominated by an expert panel and patient advocates. They included falls, fractures, bone mineral density (BMD), and adverse events for individuals with osteoporosis/vertebral fractures, and pain, quality of life, and function for those with vertebral fracture. Meta-analyses evaluating the effects of exercise on the outcomes were reviewed. Observational studies or clinical trials were reviewed when meta-analyses were not available. Quality ratings were generated, and informed the recommendations.

Results

The outcome for which evidence is strongest is falls. Point estimates of the effects of exercise on falls, fractures, and BMD vary according to exercise type. There is not enough evidence to quantify the risks of exercise in those with osteoporosis or vertebral fracture. Few trials of exercise exist in those with vertebral fracture. The exercise recommendations for exercise in individuals with osteoporosis or osteoporotic vertebral fracture are conditional. The panel strongly recommends a multicomponent exercise program including resistance and balance training for individuals with osteoporosis or osteoporotic vertebral fracture. The panel recommends that older adults with osteoporosis or vertebral fracture do not engage in aerobic training to the exclusion of resistance or balance training.

Conclusions

The consensus of our international panel is that exercise is recommended for older adults with osteoporosis or vertebral fracture, but our recommendations are conditional.     

Causes of metabolic syndrome and obesity-related co-morbidities Part 1: A composite unifying theory review of human-specific co-adaptations to brain energy consumption

One line summary

Metabolic syndrome and obesity-related co-morbidities are largely explained by co-adaptations to the energy use of the large human brain in the cortico-limbic-striatal and NRF2 systems.

The medical, research and general community is unable to effect significantly decreased rates of central obesity and related type II diabetes mellitus (TIIDM), cardiovascular disease (CVD) and cancer. All conditions seem to be linked by the concept of the metabolic syndrome (MetS), but the underlying causes are not known. MetS markers may have been mistaken for causes, thus many treatments are destined to be suboptimal.The current paper aims to critique current paradigms, give explanations for their persistence, and to return to first principles in an attempt to determine and clarify likely causes of MetS and obesity related comorbidities. A wide literature has been mined, study concepts analysed and the basics of human evolution and new biochemistry reviewed. A plausible, multifaceted composite unifying theory is formulated.The basis of the theory is that the proportionately large, energy-demanding human brain may have driven co-adaptive mechanisms to provide, or conserve, energy for the brain. A ‘dual system’ is proposed. 1) The enlarged, complex cortico-limbic-striatal system increases dietary energy by developing strong neural self-reward/motivation pathways for the acquisition of energy dense food, and (2) the nuclear factor-erythroid 2-related factor 2 (NRF2) cellular protection system amplifies antioxidant, antitoxicant and repair activity by employing plant chemicals, becoming highly energy efficient in humans.The still-evolving, complex human cortico-limbic-striatal system generates strong behavioural drives for energy dense food procurement, including motivating agricultural technologies and social system development. Addiction to such foods, leading to neglect of nutritious but less appetizing ‘common or garden’ food, appears to have occurred. Insufficient consumption of food micronutrients prevents optimal human NRF2 function. Inefficient oxidation of excess energy forces central and non-adipose cells to store excess toxic lipid. Oxidative stress and metabolic inflammation, or metaflammation, allow susceptibility to infectious, degenerative atherosclerotic cardiovascular, autoimmune, neurodegenerative and dysplastic diseases.Other relevant human-specific co-adaptations are examined, and encompass the unusual ability to store fat, certain vitamin pathways, the generalised but flexible intestine and microbiota, and slow development and longevity.This theory has significant past and future corollaries, which are explored in a separate article by McGill, A-T, in Archives of Public Health, 72: 31.