A live human parainfluenza type 3 virus vaccine is attenuated and immunogenic in young infants

BACKGROUND: Parainfluenza type 3 virus (PIV-3) infections cause lower respiratory tract illness in children throughout the world. A licensed PIV-3 vaccine is not yet available. METHODS: A live attenuated cold-adapted (ca) and temperature-sensitive (ts) PIV-3 vaccine, designated cp-45, was evaluated sequentially in open label studies in 20 adults and in placebo-controlled, double blind studies in 24 PIV-3-seropositive children, 52 PIV-3-seronegative infants and children and 49 infants 1 to 2 months old. A single dose of this intranasal vaccine was evaluated in adults [106 plaque-forming units (pfu)] and seropositive children, and 104 and 105 pfu were evaluated in seronegative children. In the infant study, two 104 pfu doses of vaccine were administered at 1- or 3-month intervals. Safety, infectivity, immunogenicity and phenotypic stability of the vaccine were evaluated in all cohorts. RESULTS: The cp-45 vaccine was well-tolerated in all age groups and infected 94% of vaccinated seronegative children and 94% of vaccinated infants. Although immunization with the first dose of cp-45 diminished the replication of a second dose in all infants, those immunized after 3 months shed vaccine virus more frequently than those immunized after 1 month (62% vs. 24%, respectively). Antibody responses to PIV-3 were readily detected in seronegative children with a variety of assays; however, the IgA response to the viral hemagglutinin-neuraminidase was the best measure of immunogenicity in young infants. Of 109 vaccine virus specimens recovered from nasal washes, 98 were ts and 11 were temperature-sensitive intermediate (tsi) viruses, with pinpoint plaques visible at 40 degrees C. tsi viruses appeared transiently at the time of peak viral replication, represented a very small proportion of the total virus shed and were not associated with changes in clinical status. ca revertants were not detected. CONCLUSIONS: The cp-45 vaccine is appropriately attenuated and immunogenic in infants as young as 1 month of age. Further development of this vaccine is warranted.     

Relationship between body mass index,serum cholesterol,leisure-time physical activity,and diet in a Mediterranean Southern-Europe population

The aim of the present study was to determine the relationship of BMI with other cardiovascular risk factors, leisure-time physical activity and diet. Participants were recruited in a cross-sectional population-based survey in a southern-Europe Mediterranean population (Spain); cardiovascular risk factors were measured, and leisure-time physical activity and diet intake were evaluated. Linear regression analysis adjusted for several confounders showed a significant, direct association of BMI and total cholesterol (P<0.005) and LDL-cholesterol (P<0.006), in men. HDL-cholesterol was inversely related to BMI in both sexes (P<0.0001). Higher BMI was more frequent in less-active men (P<0.04) but not in women. BMI increased significantly (P<0.0001) by 1.92 kg/m(2) with each 4.18 MJ consumed in men but not in women. Dietary intakes of carbohydrate (P<0.03), total fat (P<0.03) and saturated fatty acids (P<0.02) were directly associated with BMI in men but not in women, in whom protein intake was correlated (P<0.001) with BMI. Linear regression models including dietary components explained up to 10.6 and 21.1 % of BMI variability in men and women, respectively. Sex differences in the association of BMI with total cholesterol, and LDL-cholesterol, may account for the lower risk for CHD in women compared with men of similar BMI reported in the literature for the southern-Europe Mediterranean region. An increases of BMI may be more deleterious in populations in which it is accompanied by other risk factors such as a higher intake of total fat and, particularly, of saturated fatty acids, or lower leisure-time physical activity.     

New silver polypyridyl complexes: synthesis, characterization and biological activity on Leishmania mexicana

Leishmania parasites are the causal agents of leishmaniasis that currently threatens 350 million people in 88 different countries, in the absence of an effective drug. In order to continue the development of transition metal complexes with planar ligands that show interactions with DNA and activity against Leishmania parasites, the synthesis of the complexes [Ag(dpq)2]NO3 (1) and [Ag(dppz)2]NO3 (2), which were obtained by the reaction of silver nitrate with dpq and dppz, respectively, in a 1:2 molar ratio is reported. These complexes were characterized by elemental analysis and 1H-NMR, IR, and UV-vis spectroscopies. The most probable structure for these complexes is tetrahedral, with two molecules of ligand coordinated to the silver atom and a nitrate as a counter ion. Affinity studies of DNA vs. bovine albumin were carried out, and a strong interaction of the complexes with DNA was observed. Bioassays were undertaken in vitro on promastigotes of Leishmania (L.) mexicana exposed to the silver complexes for 48 h. At 10 micromol/L complex 2 induced a leishmanicidal effect (LD23), whilst complex 1 reduced the parasites growth rate by 55% (LD55). These findings suggest that biological activity could be associated with the interaction of the complexes with the parasitic DNA.     

Adjuvant properties of lipopolysaccharide from Neisseria meningitidis serogroup B detoxified and conjugated with tetanus toxoid

We evaluated the adjuvant properties and toxicity of purified Neisseria meningitidis serogroup B lipopolysaccharide (LPS) conjugated with tetanus toxoid (TT) using a new method of conjugation to obtain amine groups in the polysaccharide structure. The endotoxic activity of treated LPS was reduced 2400 times as determined by Limulus amoebocyte assay and no mortality was observed in Balb/c mice inoculated with detoxified LPS versus 100% mortality in native LPS inoculated mice. The conjugated LPS-TT elicited in mice higher anti-TT IgG2a and IgG1 than unconjugated TT. In addition, high levels of anti-LPS IgG and IgG subclasses were detected in sera. These results evidence the adjuvant activity of detoxified LPS and may suggest that the conjugation to TT changes the LPS immune response from thymus-independent to thymus-dependent.     

Genetic heterogeneity of autosomal dominant hypercholesterolemia in Mexico

BACKGROUND: Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) are relatively common lipid disorders caused by mutations of the low-density lipoprotein receptor (LDLR) and apolipoprotein B (apoB) genes, respectively. A third locus on chromosome 1p34.1-p32 was recently linked to FH and the responsible gene has been identified [protein convertase subtilisin/kexin type 9 (PCSK9)]. METHODS: We assessed the contribution of the LDLR, apoB, and PCSK9 genes as cause of FH in Mexico. Forty six unrelated probands, as well as 68 affected and 60 healthy relatives, were included. RESULTS: All index cases were diagnosed as having heterozygous autosomal dominant FH. Seventeen of the 46 index cases had LDLR gene mutations, four of which were novel (Fs92ter108, C268R, Q718X, and Fs736ter743); and only one patient had an apoB mutation (R3500Q). We sequenced the PCSK9 gene in the remainder of the 28 probands with no identified LDLR or APOB gene defects; however, no PCSK9 mutations were found, including one large kindred with positive linkage to the 1p34.1-32 locus (multipoint LOD score of 3.3) and two small pedigrees. Linkage was excluded from these three loci in at least four kindreds suggesting that other yet uncharacterized genes are involved. CONCLUSIONS: Our results underline substantial genetic heterogeneity for FH in the Mexican population.     

Serotonergic mechanisms: a potential link between affective disorders and cardiovascular risk

Cardiovascular disease and major depression are highly prevalent disorders in our society. Evidence has been found that confirms a reciprocal relationship between mechanisms of depression and those of cardiovascular pathology. This possible feedback between both pathologies is a subject of great concern. In recent years some studies suggest that platelets and serotonergic mechanisms could be involved in both conditions. The present review seeks a better understanding of the mechanisms that could link depression with an enhanced cardiovascular risk.     

Gastroprotective activity of sesquiterpene derivatives from Fabiana imbricata

An infusion or decoction of the aerial parts of Fabiana imbricata (Solanaceae) is used in traditional medicine in Chile and Argentina as a digestive and diuretic agent. The main sesquiterpene of the plant was identified as 11-hydroxy-4-amorphen-15-oic acid. At doses of 25, 50 and 100 mg/kg, the compound showed a dose-dependent gastroprotective effect in HCl/EtOH-induced gastric lesions in mice reducing the lesions by 68% at 100 mg/kg. Seven derivatives of the terpene were prepared and their gastroprotective effect was assessed in HCl/EtOH-induced gastric lesions in mice. The cytotoxicity of the products was evaluated in fibroblasts and AGS cells. At 100 mg/kg, 11-hydroxy-4-amorphen-15-p-toluidinamide presented the best gastroprotective effect reducing the gastric lesions by 80%, showing a similar effect to lansoprazole at 20 mg/kg. The compound, however, presented higher cytotoxicity than other derivatives with the IC50 ranging between 110 and 145 microm in AGS cells and fibroblasts, respectively. Most compounds proved to be non-toxic showing cytotoxicity values higher than 1000 microm. The spectroscopic data of six 11-hydroxy-4-amorphen-15-oic acid derivatives are presented here for the first time.     

AtFtsH6 is involved in the degradation of the light-harvesting complex II during high-light acclimation and senescence

Degradation of the most abundant membrane protein on earth, the light-harvesting complex of Photosystem II (LHC II), is highly regulated under various environmental conditions, e.g., light stress, to prevent photochemical damage to the reaction center. We identified the LHC II degrading protease in Arabidopsis thaliana as a Zn(2+)-dependent metalloprotease, activated by the removal of unknown extrinsic factors, similar to the proteolytic activity directed against Lhcb3 in barley. By using a reversed genetic approach, the chloroplast-targeted protease FtsH6 was identified as being responsible for the degradation. T-DNA KO A. thaliana mutants, lacking ftsH6, were unable to degrade either Lhcb3 during dark-induced senescence or Lhcb1 and Lhcb3 during highlight acclimation. The A. thaliana ftsH6 gene has a clear orthologue in the genome of Populus trichocarpa. It is likely that FtsH6 is a general LHC II protease and that FtsH6-dependent LHC II proteolysis is a feature of all higher plants.     

Economic analysis of galantamine,a cholinesterase inhibitor,in the treatment of patients with mild to moderate Alzheimer's disease in the Netherlands

BACKGROUND: The economic impact of dementia on the Dutch health and social services is substantial. OBJECTIVE: To predict the long-term economic impact of galantamine, a cholinesterase inhibitor, in the treatment of Dutch patients with mild to moderate Alzheimer's disease. METHOD: A pharmacoeconomic model was used to predict long-term outcomes. It has two components: an initial module based on clinical trials of galantamine and a subsequent module that predicts when a patient will deteriorate to a level where full time care (FTC) is needed. The analyses take a broad perspective that includes all formal (paid) care, not just those covered by the Dutch health care system. Direct cost estimates were based on resource use profiles of patients with Alzheimer's disease in the Netherlands. Key inputs were tested in sensitivity analyses. RESULTS: After 10.5 years all patients are predicted to require FTC. For every hundred patients starting treatment on galantamine at the mild to moderate stage, it is predicted that 18 person-years of FTC will be avoided (14.4 discounted) and about 5 quality-adjusted years of life will be gained (3.9 discounted). Net savings for those starting treatment with galantamine are estimated at NLG 3,050 (1,676 UDS). The cost of galantamine accounts for only about 5.0% of the total cost of care for treated Alzheimer's patients. The direction of these results remained unchanged when input values and assumptions were tested in sensitivity analyses. CONCLUSIONS: The cholinesterase inhibitor galantamine is expected to bring savings in the direct cost of caring for patients with Alzheimer's disease in the Netherlands.     

Multigeneration reproduction study of policosanol in rats

The hypocholesterolaemic drug policosanol was administered to Sprague-Dawley rats of both sexes throughout three successive generations at concentrations of 0, 5, 50 and 500 mg/kg bw/day by gavage. for each generation two litters were reared until they were at least 3 weeks old. No clinical signs which could be related to the administration of the test substance were observed in the F₀, F_1b and F_2b parents. There were no differences among groups in the number of animals that conceived, the number of pups born live or dead, the rate of male to female pups, the number of pups that survived until weaning and the pups' body weights through the lactancy. The following test showed no treatment-related effects on F3b offspring: righting on a surface, air righting, corneal, pirmal and pain reflexes, auditory startle and visual placing. The results of the present study did not demonstrate any deleterious effects on the fertility, reproductive performance or development of rats administered policosanol at levels of up to 500 mg/kg bw/day over three successive generations.