Secondary biochemical and morphological consequences in lysosomal storage diseases

More than 50 hereditary lysosomal storage disorders (LSDs) are currently described. Most of these disorders are due to a deficiency of certain hydrolases/glycosidases and subsequent accumulation of nonhydrolyzable carbohydrate-containing compounds in lysosomes. Such accumulation causing hypertrophy of the lysosomal compartment is a characteristic feature of affected cells in LSDs. The investigation of biochemical and cellular parameters is of particular interest for understanding “life” of lysosomes in the normal state and in LSDs. This review highlights the wide spectrum of biochemical and morphological changes during developing LSDs that are extremely critical for many metabolic processes inside the various cells and tissues of affected persons. The data presented will help establish new complex strategies for metabolic correction of LSDs.     

Differential Gene Expression in the Liver of the African Lungfish,Protopterus annectens,after 6 Months of Aestivation in Air or 1 Day of Arousal from 6 Months of Aestivation

The African lungfish, Protopterus annectens, can undergo aestivation during drought. Aestivation has three phases: induction, maintenance and arousal. The objective of this study was to examine the differential gene expression in the liver of P. annectens after 6 months (the maintenance phase) of aestivation as compared with the freshwater control, or after 1 day of arousal from 6 months aestivation as compared with 6 months of aestivation using suppression subtractive hybridization. During the maintenance phase of aestivation, the mRNA expression of argininosuccinate synthetase 1 and carbamoyl phosphate synthetase III were up-regulated, indicating an increase in the ornithine-urea cycle capacity to detoxify ammonia to urea. There was also an increase in the expression of betaine homocysteine-S-transferase 1 which could reduce and prevent the accumulation of hepatic homocysteine. On the other hand, the down-regulation of superoxide dismutase 1 expression could signify a decrease in ROS production during the maintenance phase of aestivation. In addition, the maintenance phase was marked by decreases in expressions of genes related to blood coagulation, complement fixation and iron and copper metabolism, which could be strategies used to prevent thrombosis and to conserve energy. Unlike the maintenance phase of aestivation, there were increases in expressions of genes related to nitrogen, carbohydrate and lipid metabolism and fatty acid transport after 1 day of arousal from 6 months aestivation. There were also up-regulation in expressions of genes that were involved in the electron transport system and ATP synthesis, indicating a greater demand for metabolic energy during arousal. Overall, our results signify the importance of sustaining a low rate of waste production and conservation of energy store during the maintenance phase, and the dependence on internal energy store for repair and structural modification during the arousal phase, of aestivation in the liver of P. annectens.     

An Age-Wise Comparison of Human Airway Smooth Muscle Proliferative Capacity

We compared the proliferation of neonatal and adult airway smooth muscle cells (ASMC) with no/moderate lung disease, in glucose- (energy production by glycolysis) or glucose-free medium (ATP production from mitochondrial oxidative phosphorylations only), in response to 10% fetal calf serum (FCS) and PDGF-AA. In the presence of glucose, cell counts were significantly greater in neonatal vs. adult ASMC. Similarly, neonatal ASMC DNA synthesis in 10% FCS and PDGF-AA, and [Ca²⁺]i responses in the presence of histamine were significantly enhanced vs. adults. In glucose-free medium, cell proliferation was preserved in neonatal cells, unlike in adult cells, with concomitant increased porin (an indicator of mitochondrial activity) protein expression. Compared to adults, stimulated neonatal human ASMC are in a rapid and robust proliferative phase and have the capacity to respond disproportionately under abnormal environmental conditions, through increased mitochondrial biogenesis and altered calcium homeostasis.     

Oxidative Stress in Caenorhabditis elegans: Protective Effects of Spartin

Troyer syndrome is caused by a mutation in the SPG20 gene, which results in complete loss of expression of the protein spartin. We generated a genetic model of Troyer syndrome in worms to explore the locomotor consequences of a null mutation of the Caenorhabditis elegans SPG20 orthologue, F57B10.9, also known as spg-20. Spg-20 mutants showed decreased length, crawling speed, and thrashing frequency, and had a shorter lifespan than wild-type animals. These results suggest an age-dependent decline in motor function in mutant animals. The drug paraquat was used to induce oxidative stress for 4 days in the animals. We measured survival rate and examined locomotion by measuring crawling speed and thrashing frequency. After 4 days of paraquat exposure, 77% of wild-type animals survived, but only 38% of spg-20 mutant animals survived. Conversely, animals overexpressing spg-20 had a survival rate of 95%. We also tested lifespan after a 1 hour exposure to sodium azide. After a 24 hour recovery period, 87% of wild type animals survived, 57% of spg-20 mutant animals survived, and 82% of animals overexpressing spg-20 survived. In the behavioral assays, spg-20 mutant animals showed a significant decrease in both crawling speed and thrashing frequency compared with wild-type animals. Importantly, the locomotor phenotype for both crawling and thrashing was rescued in animals overexpressing spg-20. The animals overexpressing spg-20 had crawling speeds and thrashing frequencies similar to those of wild-type animals. These data suggest that the protein F57B10.9/SPG-20 might have a protective role against oxidative stress.     

Subgroups of Paediatric Acute Lymphoblastic Leukaemia Might Differ Significantly in Genetic Predisposition to Asparaginase Hypersensitivity

L-asparaginase (ASP) is a key element in the treatment of paediatric acute lymphoblastic leukaemia (ALL). However, hypersensitivity reactions (HSRs) to ASP are major challenges in paediatric patients. Our aim was to investigate genetic variants that may influence the risk to Escherichia coli-derived ASP hypersensitivity. Sample and clinical data collection was carried out from 576 paediatric ALL patients who were treated according to protocols from the Berlin—Frankfurt—Münster Study Group. A total of 20 single nucleotide polymorphisms (SNPs) in GRIA1 and GALNT10 genes were genotyped. Patients with GRIA1 rs4958351 AA/AG genotype showed significantly reduced risk to ASP hypersensitivity compared to patients with GG genotype in the T-cell ALL subgroup (OR = 0.05 (0.01–0.26); p = 4.70E-04), while no such association was found in pre-B-cell ALL. In the medium risk group two SNPs of GRIA1 (rs2055083 and rs707176) were associated significantly with the occurrence of ASP hypersensitivity (OR = 0.21 (0.09–0.53); p = 8.48E-04 and OR = 3.02 (1.36–6.73); p = 6.76E-03, respectively). Evaluating the genders separately, however, the association of rs707176 with ASP HSRs was confined only to females. Our results suggest that genetic variants of GRIA1 might influence the risk to ASP hypersensitivity, but subgroups of patients can differ significantly in this respect.     

Does the Neighborhood Area of Residence Influence Non-Attendance in an Urban Mammography Screening Program? A Multilevel Study in a Swedish City

MethodsWe analyze all women invited to mammography screening in 2005–09, residing in the city of Malmö, Sweden. Information regarding mammography screening attendance was linked to data on area of residence, demographic and socioeconomic characteristics available from Statistics Sweden. The influence of individual and neighborhood factors was assessed by multilevel logistic regression analysis with 29,901 women nested within 212 neighborhoods.ResultsThe prevalence of non-attendance among women was 18.3%. After adjusting for individual characteristics, the prevalence in the 212 neighborhoods was 3.6%. Neighborhood of residence had little influence on non-attendance. The multilevel analysis indicates that 8.4% of the total individual differences in the propensity of non-attendance were at the neighborhood level. However, when adjusting for specific individual characteristics this general contextual effect decreased to 1.8%. This minor effect was explained by the sociodemographic characteristic of the neighborhoods. The discriminatory accuracy of classifying women according to their non-attendance was 0.747 when considering only individual level variables, and 0.760 after including neighborhood level as a random effect.ConclusionOur results suggest that neighborhoods of residence in Malmö, Sweden (as defined by small-area market statistics (SAMS) areas) do not condition women’s participation in population based mammography screening. Thus, interventions should be directed to the whole city and target women with a higher risk of non-attendance.     

Electrocardiographic Screening for Prolonged QT Interval to Reduce Sudden Cardiac Death in Psychiatric Patients: A Cost-Effectiveness Analysis

ImportanceSudden cardiac death is a leading cause of mortality in psychiatric patients. Long QT (LQT) is common in this population and predisposes to Torsades-de-Pointes (TdP) and subsequent mortality.ObjectiveTo estimate the cost-effectiveness of electrocardiographic screening to detect LQT in psychiatric inpatients.ResultsIn the base-case scenario, the numbers of patients needed to screen were 1128 and 2817 to avoid one TdP and one death, respectively. The ICER of systematic ECG screening was $8644 (95%CI, 3144-82 498) per QALY. The probability of cost-effectiveness was 96% at a willingness-to-pay of $50 000 for one QALY. In sensitivity analyses, results were sensitive to the case-fatality of TdP episodes and to the TdP reduction following the diagnosis of LQT.

Conclusion and Relevance

In psychiatric hospitals, performing systematic ECG screening at admission help reduce the number of sudden cardiac deaths in a cost-effective fashion.     

The Customer Isn't Always Right—Conservation and Animal Welfare Implications of the Increasing Demand for Wildlife Tourism

Tourism accounts for 9% of global GDP and comprises 1.1 billion tourist arrivals per annum. Visits to wildlife tourist attractions (WTAs) may account for 20–40% of global tourism, but no studies have audited the diversity of WTAs and their impacts on the conservation status and welfare of subject animals. We scored these impacts for 24 types of WTA, visited by 3.6–6 million tourists per year, and compared our scores to tourists’ feedback on TripAdvisor. Six WTA types (impacting 1,500–13,000 individual animals) had net positive conservation/welfare impacts, but 14 (120,000–340,000 individuals) had negative conservation impacts and 18 (230,000–550,000 individuals) had negative welfare impacts. Despite these figures only 7.8% of all tourist feedback on these WTAs was negative due to conservation/welfare concerns. We demonstrate that WTAs have substantial negative effects that are unrecognised by the majority of tourists, suggesting an urgent need for tourist education and regulation of WTAs worldwide.