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.     

Subthalamic stimulation activates internal pallidus: evidence from cGMP microdialysis in PD patients

Parkinson's disease patients benefit from deep brain stimulation (DBS) in subthalamic nucleus (STN), but the basis for this effect is still disputed. In this intraoperative microdialysis study, we found elevated cGMP extracellular concentrations in the internal segment of the globus pallidus, despite negligible changes in glutamate levels, during a clinically effective STN-DBS. This supports the view that a clinically beneficial effect of STN-DBS is paralleled by an augmentation (and not an inactivation) of the STN output onto the GPi.     

The contribution of statistical parametric mapping in the assessment of precuneal and medial temporal lobe perfusion by 99mTc-HMPAO SPECT in mild Alzheimer's and Lewy body dementia

AIM: To assess the role of 99mTc-hexamethylpropyleneamine oxime single-photon emission computed tomography (99mTc-HMPAO SPECT) imaging of the precuneus and medial temporal lobe in the individual patient with mild Alzheimer's disease and dementia with Lewy bodies (DLB) using statistical parametric mapping and visual image interpretation. METHODS: Thirty-four patients with mild late-onset Alzheimer's disease, 20 patients with early-onset Alzheimer's disease, 15 patients with DLB and 31 healthy controls were studied. All patients fulfilled appropriate clinical criteria; the DLB patients also had evidence of dopaminergic presynaptic terminal loss on 123I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane imaging. 99mTc-HMPAO SPECT brain scans were acquired on a multidetector gamma camera and images were assessed separately by visual interpretation and with SPM99. RESULTS: Statistical parametric maps were significantly more accurate than visual image interpretation in all disease categories. In patients with mild late-onset Alzheimer's disease, statistical parametric mapping demonstrated significant hypoperfusion to the precuneus in 59% and to the medial temporal lobe in 53%. Seventy-six per cent of these patients had a defect in either location. No controls had precuneal or medial temporal lobe hypoperfusion (specificity, 100%). Statistical parametric mapping also demonstrated 73% of patients with DLB to have precuneal abnormalities, but only 6% had medial temporal lobe involvement. CONCLUSION: These findings illustrate the capability of statistical parametric mapping to demonstrate reliable abnormalities in the majority, but not all, patients with either mild Alzheimer's disease or DLB. Precuneal hypoperfusion is not specific to Alzheimer's disease and is equally likely to be found in DLB. In this study, medial temporal hypoperfusion was significantly more common in Alzheimer's disease than in DLB. Statistical parametric maps appear to be considerably more reliable than simple visual interpretation of 99mTc-HMPAO images for these regions.     

Reproductive health history of lesbians: implications for care

OBJECTIVE: Parity and hormonal contraceptives modify the risk of reproductive cancers and cardiovascular disease. However, clinicians may not obtain reproductive histories from patients who self-identify as lesbian. We report lifetime pregnancy-related outcomes and hormonal contraception for 392 women who reported sexual activity with another woman in the preceding year. STUDY DESIGN: Among self-referred volunteers, previous pregnancy, pregnancy outcome, contraceptive use, and sexual identity were assessed with self-administered questionnaire. RESULTS: One in 4 subjects had been pregnant, and more than 50% of the women had used oral contraceptives (mean duration, 40 months). Sixteen percent of all subjects and 63% of those who had been pregnant previously reported having 1 or more induced abortions. The most common pregnancy outcome for women younger than 25 years was induced abortion (59% of pregnancies). Identifying as "lesbian" or "bisexual" predicted neither the duration of oral contraceptive use nor a report of induced abortion. CONCLUSION: Previous pregnancy, induced abortion, and hormonal contraceptive use are common among women who report sex with women, regardless of self-identification as lesbian.     

Alcohol consumption and acute myocardial infarction: a benefit of alcohol consumed with meals?

BACKGROUND: The apparent favorable effect of alcohol on the risk of acute myocardial infarction (MI) may be related to its hypoinsulinemic effect when consumed with meals. We studied how the timing of alcohol consumption in relation to meals might affect the risk of MI in a population with relatively high regular alcohol consumption. METHODS: We conducted a case-control study between 1995 and 1999 in Milan, Italy. Cases were 507 subjects with a first episode of nonfatal acute MI, and controls were 478 patients admitted to hospitals for other acute diseases. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by multiple logistic regression models. RESULTS: Compared with nondrinkers, an inverse trend in risk was observed when alcohol was consumed during meals only (for > or =3 drinks per day: OR = 0.50; 95% CI = 0.30-0.82). In contrast, no consistent trend in risk was found for subjects drinking outside of meals (for > or =3 drinks per day: 0.98; 0.49-1.96). The pattern of risk was similar when we considered people who drank only wine. CONCLUSIONS: Alcohol drinking during meals was inversely related with risk of acute MI, whereas alcohol drinking outside meals only was unrelated to risk.     

Bone loss induced by dietary magnesium reduction to 10% of the nutrient requirement in rats is associated with increased release of substance P and tumor necrosis factor-alpha

Dietary Mg intake has been linked to osteoporosis. Previous studies have demonstrated that severe Mg deficiency [0.04% of nutrient requirement (NR)] results in osteoporosis in rodent models. We assessed the effects of more moderate dietary Mg restriction (10% of NR) on bone and mineral metabolism over a 6-mo experimental period in rats. At 2, 4 and 6 mo, serum Mg, Ca, parathyroid hormone (PTH), 1,25-dihydroxy-vitamin D, alkaline phosphatase, osteocalcin and urine pyridinoline were measured. Femurs and tibiae were collected for measurement of mineral content, microcomputerized tomography, histomorphometry, and immunocytochemical localization. By 2 mo, profound Mg deficiency had developed as assessed by marked hypomagnesemia and up to a 51% reduction in bone Mg content. These features continued through 6 mo of study. Serum Ca was slightly but significantly higher in Mg-deficient rats than in controls at all time points. At 2 mo, serum PTH was elevated in Mg-deficient rats but was significantly decreased at 6 mo in contrast to control rats in which PTH rose. Serum 1,25-dihydroxy-vitamin D was significantly lower than in controls at 4 and 6 mo. A significant fall in both serum alkaline phosphatase and osteocalcin suggested decreased osteoblast activity. Histomorphometry demonstrated decreased bone volume and trabecular thickness. This was confirmed by microcomputerized tomography analysis, which also showed that trabecular volume, thickness and number were significantly lower in Mg-deficient rats. Increased bone resorption was suggested by an increase in osteoclast number over time compared with controls as well as surface of bone covered by osteoclasts and eroded surface, but there was no difference in osteoblast numbers. The increased bone resorption may be due to an increase in TNF-alpha because immunocytochemical localization of TNF-alpha in osteoclasts was 199% greater than in controls at 2 mo, 75% at 4 mo and 194% at 6 mo. The difference in TNF-alpha may be due to substance P, which was 250% greater than in controls in mononuclear cells at 2 mo and 266% at 4 mo. These data demonstrated that a Mg intake of 10% of NR in rats causes bone loss that may be secondary to the increased release of substance P and TNF-alpha.