Effect of oral vitamin D2 yearly bolus on hip fracture risk in elderly women: a community primary prevention study

BACKGROUND AND AIMS: Vitamin D deficiency is a well-known risk for hip fracture, and vitamin D insufficiency is so frequent in the elderly that population-wide preventive intervention would be useful. The objective of the study was to evaluate the efficacy of vitamin D bolus on hip fracture incidence in elderly women. METHODS: All women aged > 65 years registered at Health District 20 of the Regione Veneto, Italy, were eligible for this quasi-experimental, prospective community intervention study. A vial containing 400,000 IU vitamin D2 (Ostelin 800, Teofarma, Italy) was offered for oral administration to all women in the winters of 2000-2001 and 2001-2002. The only exclusion criteria for treatment were age and gender, and the control group included women who did not participate in the Health District initiative. Analysis of hip fracture incidence was carried out for 4 years, from 1999 to 2002. Patients with incident hip fracture were identified as soon as they were admitted to one of the 3 hospitals of the health district and interviewed regarding their participation in the vitamin D preventive intervention program. In 120 of the women (age range 68-90 years), serum concentrations of 25-OH vitamin D were measured from October to June, both before and 1 and 4 months after vitamin D administration. RESULTS: 23,325 and 24,747 women received the vitamin D bolus during winters 2000-2001 and 2001-2002 respectively, i.e. 45-47% of eligible women. The proportion of women who accepted the bolus declined with advancing age, from 50-55% in women aged 60-70 years to 22-26% in those aged > 90 years. The two-year intervention on the community decreased the incidence of fracture by 10% (p = 0.050) in comparison with the previous two years. The age-adjusted risk reduction (RR) of hip fracture during 2001 and 2002 in women who had received vitamin D, with respect to women who had not, decreased by 17% (p = 0.056) and 25% (p = 0.005) respectively. The RR was considerably greater and statistically significant over both 2001 and 2002 in the cohort aged > 75 years. 25-OH vitamin D concentrations, in the subset of women in whom it was measured, rose significantly (p < 0.0001) by 9 ng/ml over 4 months after administration. CONCLUSION: Despite several obvious limitations due to its nature, this study sufficiently documents that yearly vitamin D bolus supplements, given as primary prevention to elderly Caucasian women, may decrease the incidence of hip fracture. For its probable safety and excellent feasibility and cost-effectiveness, this primary intervention has a great potential for generalisability.     

Correlation between dopamine D(2) receptors in the ventral striatum and central processing of alcohol cues and craving

OBJECTIVE: Alcohol and other drugs of abuse stimulate dopamine release in the ventral striatum, which includes the nucleus accumbens, a core region of the brain reward system, and reinforce substance intake. Chronic alcohol intake is associated with down-regulation of central dopamine D(2) receptors, and delayed recovery of D(2) receptor sensitivity after detoxification is positively correlated with high risk for relapse. Prolonged D(2) receptor dysfunction in the ventral striatum may interfere with a dopamine-dependent error detection signal and bias the brain reward system toward excessive attribution of incentive salience to alcohol-associated stimuli. METHOD: Multimodal imaging, with the radioligand [(18)F]desmethoxyfallypride and positron emission tomography as well as functional magnetic resonance imaging (fMRI), was used to compare 11 detoxified male alcoholics with 13 healthy men. The authors measured the association of D(2)-like dopamine receptors in the ventral striatum with alcohol craving and central processing of alcohol cues. RESULTS: Activation of the medial prefrontal cortex and striatum by alcohol-associated stimuli, relative to activation by neutral visual stimuli, was greater in the detoxified alcoholics than in the healthy men. The alcoholics displayed less availability of D(2)-like receptors in the ventral striatum, which was associated with alcohol craving severity and with greater cue-induced activation of the medial prefrontal cortex and anterior cingulate as assessed with fMRI. DISCUSSION: In alcoholics, dopaminergic dysfunction in the ventral striatum may attribute incentive salience to alcohol-associated stimuli, so that alcohol cues elicit craving and excessive activation of neural networks associated with attention and behavior control.     

Analgesic, antiinflammatory and central depressor effects of the hydroalcoholic extract and fractions from Aeolanthus suaveolens

This work studied antinociceptive, antiedematogenic and central depressor effects of the hydroalcoholic extract (HAE) from Aeolanthus suaveolens and its fractions: hexane (ASHAE-H), ethyl acetate (ASHAE-A), aqueous (ASHAE-E) and precipitate (ASHAE-PPT) in experimental models in mice. The highest activity in the writhing test was presented by ASHAE-A followed by ASHAE-PPT and ASHAE-E and the lowest by ASHAE-H. In the formalin test the effect was manifested at both phases, although more intensely at the 2nd phase of the response. In this test, the most active fraction was ASHAE-PPT causing inhibitions of the order of 76 and 90% of the 2nd phase of the test at the doses of 10 and 100 mg/kg i.p., respectively. Naloxone reversed the effects of ASHAE-PPT in both phases of the test, suggesting the participation of the opioid system in the antinociceptive effect. On the other hand, the HAE effect on both phases of the formalin test was only partially reversed by naloxone, suggesting that the extract presents more than one active compound, and at least one, of a polar nature, acting through the opioid system. HAE and ASHAE-PPT presented antiinflammatory activity and were very effective in decreasing the mouse paw edema induced by carrageenan. All fractions significantly decreased locomotor activity in the open field test in mice. However, only the nonpolar fractions presented myorelaxant activity as demonstrated by the rota rod test.     

Cue-induced activation of the striatum and medial prefrontal cortex is associated with subsequent relapse in abstinent alcoholics

Rationale Animal experiments have provided evidence that the striatum and medial prefrontal cortex play a predominant role in the acquisition and maintenance of drug-seeking behavior.Objectives Alcohol-associated stimuli that were regularly paired with alcohol intake may become conditioned cues and elicit a motivational response that triggers relapse in alcohol-dependent patients.Methods We used functional magnetic resonance imaging and visual alcohol-associated and control cues to assess brain activation in ten abstinent alcoholics and control subjects. Patients were followed for 3 months, and alcohol intake was recorded.Results Alcohol-related versus neutral visual stimuli activated the putamen, anterior cingulate and adjacent medial prefrontal cortex in alcoholics compared with healthy controls. Cue-induced activation of these brain areas was pronounced in the five alcoholics who subsequently relapsed during the observation period. A multiple regression analysis showed that, in alcoholics, the amount of subsequent alcohol intake was associated with the intensity of cue-induced brain activation but not the severity of alcohol craving, amount of previous alcohol intake or duration of abstinence before scanning.Conclusions This pilot study showed that cue-induced activation of the anterior cingulate, medial prefrontal cortex and striatum may play a role in the attribution of incentive salience to alcohol-associated stimuli, thus increasing the motivational value and attentional processing of alcohol cues. Functional brain imaging may help to identify a group of alcoholics with an otherwise undetected high risk of relapse.     

Stable transformants of the azaphilone pigment-producing<Emphasis Type="Italic"> Monascus purpureus</Emphasis> obtained by protoplast transformation and<Emphasis Type="Italic"> Agrobacterium</Emphasis>-mediated DNA transfer

The high-level pigment-producing Monascus strain IBCC1 was characterized by random amplification of polymorphic DNA as M. purpureus. This technique allowed us to distinguish between M. purpureus and M. ruber strains. Transformation of Monascus species has not been previously reported. Protoplast formation and regeneration from M. purpureus IBCC1 was optimized by modification of growth media, lytic enzyme mixture, osmotic stabilizer and regeneration media. Of the Monascus transformants, 60% were found to be mitotically stable and retained the plasmid inserted in the chromosome after repeated sporulation cycles. Additionally, an Agrobacterium-mediated DNA transfer system was developed. The transformants obtained by Agrobacterium-mediated DNA transfer remained fully stable (98%) after four sporulation rounds and showed bands of hybridization corresponding to integration of the plasmid in different sites of the genome. The green fluorescent protein marker was well expressed in the M. purpureus transformants. The development of transformation systems is a basic tool for advanced genetic manipulation of the natural pigment producers, M. purpureus and M. ruber.Communicated by U. Kück     

A brief and unobtrusive instrument to detect simulation and exaggeration in patients with whiplash syndrome

The objective of this study was to develop and test a brief and unobtrusive instrument to detect exaggeration and simulation in whiplash syndrome. The instrument consists of eight scenarios with ten response options that have to be ordered according to how easy a behavior is to perform. Twenty-five simulating and 25 non-simulating patients with whiplash syndrome of grades 2 and 3 according to the Quebec Task Force classification as well as 25 simulating and 25 non-simulating controls completed the instrument. In a cross-validation study 20 controls and 20 patients participated. Malingering and exaggeration scores were determined for each subject and patient. The scores were summed up and compared across malingering and exaggerating subjects and controls and cut-off values were determined to classify the patients. T-tests and a discriminant analysis were used to determine classification accuracy. The instrument correctly identified 94% of the simulators and 84% of the exaggerators in both samples. This brief and unobtrusive instrument can detect exaggeration and simulation in whiplash syndrome.     

Diversity and evolution of the envelope gene of dengue virus type 1

The genetic diversity and phylogenetic relationships of a collection of strains of dengue virus type 1 (DV-1), isolated from different parts of the world, were investigated. Phylogenetic trees derived from the complete sequence of the E gene of 44 strains suggested the existence of five genetic types defined by a maximum nucleotide divergence within each group of 6%. The 22 strains from America were classified into a single genetic type that included strains associated either with classical dengue or hemorrhagic dengue episodes. Using a maximum likelihood procedure based on a single rate with dated tips model and substitution rates calculated at the third codon position, evolution of the five DV-1 genotypes was shown to conform to a molecular clock. The average rate of evolution was estimated to be approximately 16.2 x 10(-4) substitutions/third codon position site/year. Using this estimate, divergence among the DV-1 genotypes was calculated to have occurred approximately 100 years ago. Very low average value of the ratio of nonsynonymous-to-synonymous nucleotide substitutions, relative to the respective sites (0.046), indicated that the evolution of the E gene of the DV-1 is subject mostly to purifying selection.     

Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs.

Metabotropic glutamate (mGlu) receptors have been considered as potential targets for neuroprotective drugs, but the lack of specific drugs has limited the development of neuroprotective strategies in experimental models of acute or chronic central nervous system (CNS) disorders. The advent of potent and centrally available subtype-selective ligands has overcome this limitation, leading to an extensive investigation of the role of mGlu receptor subtypes in neurodegeneration during the last 2 years. Examples of these drugs are the noncompetitive mGlu1 receptor antagonists, CPCCOEt and BAY-36-7620; the noncompetitive mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)pyridine, SIB-1893, and SIB-1757; and the potent mGlu2/3 receptor agonists, LY354740 and LY379268. Pharmacologic blockade of mGlu1 or mGlu5 receptors or pharmacologic activation of mGlu2/3 or mGlu4/7/8 receptors produces neuroprotection in a variety of in vitro or in vivo models. MGlu1 receptor antagonists are promising drugs for the treatment of brain ischemia or for the prophylaxis of neuronal damage induced by synaptic hyperactivity. MGlu5 receptor antagonists may limit neuronal damage induced by a hyperactivity of N-methyl-d-aspartate (NMDA) receptors, because mGlu5 and NMDA receptors are physically and functionally connected in neuronal membranes. A series of observations suggest a potential application of mGlu5 receptor antagonists in chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer disease. MGlu2/3 receptor agonists inhibit glutamate release, but also promote the synthesis and release of neurotrophic factors in astrocytes. These drugs may therefore have a broad application as neuroprotective agents in a variety of CNS disorders. Finally, mGlu4/7/8 receptor agonists potently inhibit glutamate release and have a potential application in seizure disorders. The advantage of all these drugs with respect to NMDA or AMPA receptor agonists derives from the evidence that mGlu receptors do not "mediate," but rather "modulate" excitatory synaptic transmission. Therefore, it can be expected that mGlu receptor ligands are devoid of the undesirable effects resulting from the inhibition of excitatory synaptic transmission, such as sedation or an impairment of learning and memory.     

Recall of drug utilization depends on subtle structural questionnaire characteristics

Objective To test the hypothesis that questionnaire organization affects the recall of antimalarial drugs utilization. Setting Maputo, Mozambique. Methods Treatment of last malaria episode was assessed using two alternative versions (A and B) of a questionnaire, which differed only by the order each proposed drug was presented in the response options (version A: quinine and most frequently used drugs presented first; version B: less frequently used drugs first and quinine at the end). Questionnaires A or B were randomly assigned to each of 32 classes in a private University in Maputo, Mozambique. Within each classroom all subjects received the same questionnaire version, and a similar number of participants fulfilled questionnaires A (n = 249) and B (n = 255). Main outcome measures Recall of the antimalarial drugs utilization in a previous malaria episode. Results Mefloquine and clindamycin were not used by any subject in the last malaria episode. The overall recall of quinine utilization was higher with questionnaire A (19.5% vs. 11.6%, P = 0.006) and the use of artemisinine/artesunate was reported more frequently by subjects inquired with questionnaire B (16.5% vs. 7.3%, P = 0.012). When considering subjects reporting more than one malaria episode, the recall of quinine utilization was higher with questionnaire A (20.0% vs. 6.4%, P = 0.004), and the use of artemisinine/artesunate was reported more frequently by subjects inquired with questionnaire B (18.3% vs. 8.8%, P = 0.069). No differences were observed among those having had only one malaria episode, neither for quinine (22.2% vs. 20.0%, P = 0.807) or artemisinine/artesunate (5.0% vs. 6.7%, P = 0.701). Conclusion The structure of the questionnaire used to collect self-reported information about antimalarial treatments influences the recall, even when close ended questions asking for specific drugs are used. Among subjects having been treated for malaria more than once, the first antimalarial drugs being asked were more likely to be selected.     

Selective blockade of metabotropic glutamate receptor subtype 5 is neuroprotective

We have used potent and selective non-competitive antagonists of metabotropic glutamate receptor subtype 5 (mGlu5) -- 2-methyl-6-phenylethynylpyridine (MPEP), [6-methyl-2-(phenylazo)-3-pyridinol] (SIB-1757) and [(E)-2-methyl-6-(2-phenylethenyl)pyridine] (SIB-1893) - to examine whether endogenous activation of this particular metabotropic glutamate receptor subtype contributes to neuronal degeneration. In cortical cultures challenged with N-methyl-D-aspartate (NMDA), all three mGlu5 receptor antagonists were neuroprotective. The effect of MPEP was highly specific because the close analogue, 3-methyl-6-phenylethynylpyridine (iso-MPEP), which did not antagonize heterologously expressed mGlu5 receptors, was devoid of activity on NMDA toxicity. Neuroprotection by mGlu5 receptor antagonists was also observed in cortical cultures challenged with a toxic concentration of beta-amyloid peptide. We have also examined the effect of mGlu5 receptor antagonists in in vivo models of excitotoxic degeneration. MPEP and SIB-1893 were neuroprotective against neuronal damage induced by intrastriatal injection of NMDA or quinolinic acid. These results indicate that mGlu5 receptors represent a suitable target for novel neuroprotective agents of potential application in neurodegenerative disorders.