Late infantile metachromatic leucodystrophy (MLD)

A typical case of late infantile MLD is presented with all available clinical, morphological and biochemical results. The diagnostical value of the different parameters is evaluated and the pathogenesis of the disorder discussed. In spite of successful experimental enzyme substitution in cultured MLD fibroblasts with restitution of function by added Arylsulfatase, the therapeutic possibilities for the fatal disease in the patients are extremely limited.     

What information do breast cancer screening programmes provide to Italian women?

BACKGROUNDS: The necessity for building transparent communications on screening, both on risks and benefits, is shared by different sides. There is a general agreement that women cannot express informed participation in a screening programme unless they are given sufficient and adequate information. In the screening context, invitation letters and leaflets often represent the principal source of information. METHODS: The invitation letters and leaflets used by 60 Italian breast cancer screening programmes were collected and evaluated through a score sheet developed to verify what kind of information is provided to women. RESULTS: Fifty-three programmes (88.3%) answered and 47 (78.3%) were included in the analysis because of completeness of the material. Nearly all the programmes provide satisfactory practical information and explanations about the test and the screening aims. Few programmes mention the possibility of some discomfort during the exam (34.0%), quality assessment and operator training (10.6%), double reading (6.4%), radiation risk (6.4%) and data confidentiality (6.4%). 68.1% provide information about recall but none describes what a further assessment involves. Epidemiological and numerical information are present only occasionally. CONCLUSION: Although satisfactorily disclosing some practical information, Italian invitation letters and leaflets remain inadequate in managing side effects and risks. If accurate information has the potential to enable women to make an informed choice, the information inviting them to perform screening test must be improved. Further researcher is needed to evaluate different decision aids to meet women's desires for balanced information. KEY POINTS: Women cannot express informed participation in a breast screening programme unless they are given balanced information both on benefits and adverse effects. Current information screening tools often omit relevent data, fail to give information about pros and cons and ignore uncertainties. Despite these considerations, how much information should be given and how this should be framed remains still to be defined. Further evalutions of different ways of presenting information and women's information needs are urgently required.     

Dietary magnesium reduction to 25% of nutrient requirement disrupts bone and mineral metabolism in the rat

Low dietary magnesium (Mg) may be a risk factor for osteoporosis. In animals, severe Mg deficiency (0.04% of nutrient requirement [NR]) results in bone loss. We have also found that a more moderate dietary Mg restriction (10% of NR) also resulted in loss of bone. We now report the effect of Mg intake of 25% NR on bone and mineral metabolism in the rat. Serum Mg, Ca, PTH, 1,25(OH)2-vitamin D, alkaline phosphatase, osteocalcin, and pyridinoline were measured at 2, 4, and 6 months in control and Mg-deficient animals. Femurs and tibias were collected for mineral content, micro-computerized tomography, histomorphometry, and immunocytochemical localization. Profound Mg deficiency developed as assessed by marked hypomagnesemia and 27% reduction in bone Mg content. Serum calcium was not significantly different between groups. Mg depletion resulted in a significantly lower serum PTH concentrations. Serum 1,25(OH)2-vitamin D was also significantly lower. No difference was noted in markers of bone turnover. Histomorphometry and micro-computerized tomography demonstrated decreased bone volume and trabecular thickness. No difference was observed for osteoclast or osteoblast number. Inflammatory cytokines may contribute to bone loss. We found that immunocytochemical localization of TNFalpha in osteoclasts was increased 138-150%. This increase in TNFalpha may be due to increased substance P as it was found to be elevated from 179% to 432%. These data demonstrate that Mg intake of 25% NR in the rat causes lower bone mass which may be related to increased release of substance P and TNFalpha.     

Effect of starch on the cariogenic potential of sucrose

Since in vitro and animal studies suggest that the combination of starch with sucrose may be more cariogenic than sucrose alone, the study assessed in situ the effects of this association applied in vitro on the acidogenicity, biochemical and microbiological composition of dental biofilm, as well as on enamel demineralization. During two phases of 14 d each, fifteen volunteers wore palatal appliances containing blocks of human deciduous enamel, which were extra-orally submitted to four groups of treatments: water (negative control, T1); 2 % starch (T2); 10 % sucrose (T3); and 2 % starch+10 % sucrose (T4). The solutions were dripped onto the blocks eight times per day. The biofilm formed on the blocks was analysed with regard to amylase activity, acidogenicity, and biochemical and microbiological composition. Demineralization was determined on enamel by cross-sectional microhardness. The greatest mineral loss was observed for the association starch+sucrose (P<0.05). Also, this association resulted in the highest lactobacillus count in the biofilm formed (P<0.05). In conclusion, the findings suggest that a small amount of added starch increases the cariogenic potential of sucrose.     

Acceptability of five nonoxynol-9 spermicides

OBJECTIVE: To examine the acceptability of five nonoxynol-9 (N-9) spermicides. METHODS: We analyzed data from a randomized trial of five products, including three gels containing different amounts of N-9 per dose, a film and a suppository. In the trial, 1536 participants were asked to use the assigned spermicide for 7 months and to complete questionnaires 4 weeks after admission and at discontinuation. RESULTS: Overall, 43% of participants liked their spermicide "very much." This proportion was higher in the three gel groups than in the suppository and film groups. Difficulty with insertion, messiness and discontent with timing of insertion were common complaints in all groups. After adjustment for selected baseline factors, acceptability on the first questionnaire was not related to duration or consistency of subsequent spermicide use or to subsequent time to pregnancy. CONCLUSIONS: In this study, all five spermicides were considered acceptable by most users. Acceptability did not appear to influence spermicide use or pregnancy risk.     

Pulmonary aspiration: new therapeutic approaches in the experimental model

BACKGROUND: Acute lung injury caused by gastric aspiration is a frequent occurrence in unconscious patients. Acute respiratory distress syndrome in association with gastric aspiration carries a mortality of up to 30% and accounts for up to 20% of deaths associated with anesthesia. Although the clinical condition is well known, knowledge about the exact inflammatory mechanisms is still incomplete. This study was performed to define the role of alveolar macrophages in this inflammatory response. In addition, potentially modifying effects of intratracheally applied nuclear factor kappaB inhibitor pyrrolidine dithiocarbamate were investigated. METHODS: Rat alveolar macrophages were depleted by intratracheal administration of clodronate liposomes, and lung injury was evaluated 6 h after instillation of 0.1N hydrochloric acid. In a second set of experiments, pyrrolidine dithiocarbamate was intratracheally instilled 3 h after hydrochloric acid application, and injury parameters were determined. RESULTS: Depletion of alveolar macrophages resulted in decreased production of inflammatory mediators in acid aspiration (23-80% reduction of messenger RNA or protein of inflammatory mediators; P < 0.05) and consequently also in diminished neutrophil recruitment (36% fewer neutrophils; P < 0.01). Treatment with pyrrolidine dithiocarbamate was highly effective in decreasing neutrophil recruitment (66%; P < 0.01) and vascular permeability (80%; P < 0.001). CONCLUSIONS: These data suggest that alveolar macrophages play an essential role in the inflammatory response of acid-induced lung injury. For the first time, attenuation of acid-induced lung injury with an inhibitor, applied after the onset of injury, is shown.     

Spatial learning with unilateral and bilateral hippocampal networks

This study investigated the ability of animals to learn both reference memory and delayed matching-to-place variants of the watermaze after large lesions of the hippocampus that deliberately spared only small remnants of the structure. Groups were created that had differing blocks of residual tissue in the septal pole of the hippocampus (15% or 30% of total volume), located either unilaterally (30 or 50% on one side, 0% on the other) or bilaterally (30 + 30%). These groups were capable of learning the reference memory task, as indexed by normal spatially focused searching in a probe trial, but their rate of learning was slower than that of sham-lesioned rats. An impairment in the rate of learning was also seen in the delayed match-to-place task, where one-trial memory was observed only at the shortest (5 s) intertrial interval in the lesioned groups with the largest sparing. In both tasks performance was proportional to the volume of hippocampus spared and independent of whether this was unilaterally or bilaterally located. The findings are compatible with distributed processing accounts of hippocampal memory storage.     

Bicistronic lentiviral vector corrects beta-hexosaminidase deficiency in transduced and cross-corrected human Sandhoff fibroblasts

Sandhoff disease is an autosomal recessive neurodegenerative disease characterized by a GM2 ganglioside intralysosomal accumulation. It is due to mutations in the beta-hexosaminidases beta-chain gene, resulting in a beta-hexosaminidases A (alphabeta) and B (betabeta) deficiency. Mono and bicistronic lentiviral vectors containing the HEXA or/and HEXB cDNAs were constructed and tested on human Sandhoff fibroblasts. The bicistronic SIV.ASB vector enabled a massive restoration of beta-hexosaminidases activity on synthetic substrates and a 20% correction on the GM2 natural substrate. Metabolic labeling experiments showed a large reduction of ganglioside accumulation in SIV.ASB transduced cells, demonstrating a correct recombinant enzyme targeting to the lysosomes. Moreover, enzymes secreted by transduced Sandhoff fibroblasts were endocytosed in deficient cells via the mannose 6-phosphate pathway, allowing GM2 metabolism restoration in cross-corrected cells. Therefore, our bicistronic lentivector supplying both alpha- and beta-subunits of beta-hexosaminidases may provide a potential therapeutic tool for the treatment of Sandhoff disease.     

A coiled-coil interaction mediates cauliflower mosaic virus cell-to-cell movement

The function of the virion-associated protein (VAP) of cauliflower mosaic virus (CaMV) has long been only poorly understood. VAP is associated with the virion but is dispensable for virus morphogenesis and replication. It mediates virus transmission by aphids through simultaneous interaction with both the aphid transmission factor and the virion. However, although insect transmission is not fundamental to CaMV survival, VAP is indispensable for spreading the virus infection within the host plant. We used a GST pull-down technique to demonstrate that VAP interacts with the viral movement protein through coiled-coil domains and surface plasmon resonance to measure the interaction kinetics. We mapped the movement protein coiled-coil to the C terminus of the protein and proved that it self-assembles as a trimer. Immunogold labeling/electron microscopy revealed that the VAP and viral movement protein colocalize on CaMV particles within plasmodesmata. These results highlight the multifunctional potential of the VAP protein conferred by its efficient coiled-coil interaction system and show a plant virus possessing a surface-exposed protein (VAP) mediating viral entry into host cells.     

CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy

We tested the efficacy and safety of glutamine (0.6 gm/kg/day) and creatine (5 gm/day) in 50 ambulant boys with Duchenne muscular dystrophy in a 6-month, double-blind, placebo-controlled clinical trial. Drug efficacy was tested by measuring muscle strength manually (34 muscle groups) and quantitatively (10 muscle groups). Timed functional tests, functional parameters, and pulmonary function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease-modifying effect of creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were well tolerated.