Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials.

BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.

Filling the knowledge gap of Middle American freshwater fish parasite biodiversity: metazoan parasite fauna of Nicaragua.

The heterogeneous landscape of Nicaragua harbours a large diversity of freshwater fishes. The great Nicaraguan lakes, Managua and Nicaragua, and several adjacent crater lakes harbour numerous endemic fish species. However, information about their parasite fauna is still fragmentary. Here, we surveyed the great Nicaraguan lakes and four crater lakes and provide data for 17 metazoan parasite taxa infecting seven fish host species. We also gathered all the published records from the literature on the parasites reported from Nicaraguan freshwater fishes, as well as those for Costa Rica and Panama to discuss the region of Lower Central America as a whole. With this information we built a parasite-host and a host-parasite checklist. With data from near 50% of the native and endemic freshwater fishes in Nicaragua, the parasite fauna comprises 101 taxa in 51 fish species allocated in 11 families. Cichlids are the most diverse group of fishes in this region and have been the most extensively surveyed for their metazoan parasites. Helminths are the best-represented groups of metazoan parasites, with 42 trematodes, five cestodes, 24 monogeneans, two acanthocephalans, 20 nematodes and one hirudinean. Additionally, freshwater fishes are parasitized by copepods, branchiurans and oribatid mites. Even though the inventory is not yet complete, the patterns of diversity uncovered revealed promising information about the origin, biogeography and evolutionary history of the Nicaraguan freshwater fish parasite fauna. More studies are necessary to complete our knowledge about the diversity, host association and distribution of metazoan parasites in Nicaragua and other Central American countries.

Diversity of Rhabdochona mexicana (Nematoda: Rhabdochonidae), a parasite of Astyanax spp. (Characidae) in Mexico and Guatemala, using mitochondrial and nuclear genes, with the description of a new species.

Among fish parasitic nematodes Rhabdochona is one of the most speciose genera, with c. 100 species. Twelve congeneric species occur in Mexican freshwater fishes, in a region located between the Nearctic and Neotropical biogeographical regions. Host association and biogeographical history have determined the high species richness of Rhabdochona in Mexico. One of these species, Rhabdochona mexicana, is highly specific to the characid genus Astyanax. Characids are a group of freshwater fish with Neotropical affinity. In this paper, we explore the genetic diversity of R. mexicana through samples obtained from populations of Astyanax spp. across river basins of Mexico and Guatemala. Sequences of one mitochondrial and two ribosomal genes were obtained from 38 individuals and analysed using Maximum Likelihood and Bayesian Inference analysis. Phylogenetic analyses using cox1, and a concatenated alignment of 18S + 28S + cox1 recovered two genetic lineages. One of them corresponded with R. mexicana sensu stricto; this lineage included three reciprocally monophyletic subgroups; the other lineage was highly divergent and represented a putative candidate species. A detailed morphological study was conducted to corroborate the molecular findings. We describe a new species herein and discuss the implications of using molecular tools to increase our knowledge about the diversity of a speciose genus such as Rhabdochona.

Microencapsulated feruloyl esterase-producing lactobacilli ameliorate lipid profile and glycaemia in high fat diet-induced obese mice.

The effect of oral administration of spray-dried microcapsules of feruloyl esterase (FE) producing Lactobacillus fermentum CRL1446 (Lf) and Lactobacillus johnsonii CRL1231 (Lj) on high fat diet-induced obese mice was investigated to evaluate whether these strains could be used as a biotherapeutic for obesity. Swiss albino mice were divided into a normal diet fed group receiving empty microcapsules (control), a high fat diet plus empty microcapsules (HFD group), HFD plus microcapsules with Lf (HFD-Lf group) and HDF plus microcapsules with Lj (HFD-Lj group). Microcapsules containing Lf or Lj at a dose of ~107 cells/day/mouse were given orally for 7 weeks. Body weight gain, adiposity index, plasma leptin, lipid profiles, glycaemia, insulinemia, oral glucose tolerance, intestinal FE, glutathione peroxidase and glutathione reductase (GR) activities were determined. Administration of lactobacilli (HFD-Lf and HFD-Lj groups) improved metabolic parameters (triglyceride, total cholesterol, low-density lipoprotein cholesterol levels) and cardiovascular risk indicators (37-46% decrease of atherogenic index), and reduced body weight gain (29-38%), adiposity index (42-62%), plasma leptin levels, liver weight and fat deposition in liver. Intestinal FE activities significantly increased in HFD-Lf (62%) and HFD-Lj group (48%), thus improving hepatic GR activity (42% increment) compared to HFD group. Moreover, L. johnsonii increased HDL-cholesterol and L. fermentum reduced blood glucose to levels similar to the control. These FE-producing lactobacilli have the potential to improve biomarkers involved in obesity by increasing intestinal FE activity.

Microbiota and host determinants of behavioural phenotype in maternally separated mice.

Early-life stress is a determinant of vulnerability to a variety of disorders that include dysfunction of the brain and gut. Here we exploit a model of early-life stress, maternal separation (MS) in mice, to investigate the role of the intestinal microbiota in the development of impaired gut function and altered behaviour later in life. Using germ-free and specific pathogen-free mice, we demonstrate that MS alters the hypothalamic-pituitary-adrenal axis and colonic cholinergic neural regulation in a microbiota-independent fashion. However, microbiota is required for the induction of anxiety-like behaviour and behavioural despair. Colonization of adult germ-free MS and control mice with the same microbiota produces distinct microbial profiles, which are associated with altered behaviour in MS, but not in control mice. These results indicate that MS-induced changes in host physiology lead to intestinal dysbiosis, which is a critical determinant of the abnormal behaviour that characterizes this model of early-life stress.

Impaired responses to gliadin and gut microbes of immune cells from mice with altered stress-related behavior and premature immune senescence.

Stress is associated with impaired communication between the nervous and immune systems leading to immunosenescence and increased disease risk. We investigated whether leukocytes from mice with altered stress-related behavior and premature immunosenescence, as well as from chronologically aged mice differently responded ex vivo to celiac disease (CD) triggers (gliadin) and intestinal bacteria by ELISA and flow cytometry and differed in microbiota composition. We found that altered stress-related behavior and premature immunosenescence led to alterations in T lymphocytes and cytokine release of immune cells basally and in response to peptic fragments of gliadin and commensal and pathogenic bacteria, possibly increasing susceptibility to CD in adulthood.

Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial.

The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.

Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women.

Obesity is associated with complications during pregnancy and increased health risks in the newborn. The objective of the present study was to establish possible relationships between gut microbiota, body weight, weight gain and biochemical parameters in pregnant women. Fifty pregnant women were classified according to their BMI in normal-weight (n 34) and overweight (n 16) groups. Gut microbiota composition was analysed by quantitative real-time PCR in faeces and biochemical parameters in plasma at 24 weeks of pregnancy. Reduced numbers of Bifidobacterium and Bacteroides and increased numbers of Staphylococcus, Enterobacteriaceae and Escherichia coli were detected in overweight compared with normal-weight pregnant women. E. coli numbers were higher in women with excessive weight gain than in women with normal weight gain during pregnancy, while Bifidobacterium and Akkermansia muciniphila showed an opposite trend. In the whole population, increased total bacteria and Staphylococcus numbers were related to increased plasma cholesterol levels. Increased Bacteroides numbers were related to increased HDL-cholesterol and folic acid levels, and reduced TAG levels. Increased Bifidobacterium numbers were related to increased folic acid levels. Increased Enterobacteriaceae and E. coli numbers were related to increased ferritin and reduced transferrin, while Bifidobacterium levels showed the opposite trend. Therefore, gut microbiota composition is related to body weight, weight gain and metabolic biomarkers during pregnancy, which might be of relevance to the management of the health of women and infants.

Shifts in clostridia, bacteroides and immunoglobulin-coating fecal bacteria associated with weight loss in obese adolescents.

OBJECTIVE: To evaluate the effects of a multidisciplinary obesity treatment programme on fecal microbiota composition and immunoglobulin-coating bacteria in overweight and obese adolescents and their relationship to weight loss. DESIGN: Longitudinal intervention study based on both a calorie-restricted diet (calorie reduction=10-40%) and increased physical activity (calorie expenditure=15-23 kcal/kg body weight per week) for 10 weeks. PARTICIPANTS: Thirty-nine overweight and obese adolescents (BMI mean 33.1 range 23.7-50.4; age mean 14.8 range, 13.0-16.0). MEASUREMENTS: BMI, BMI z-scores and plasma biochemical parameters were measured before and after the intervention. Fecal microbiota was analyzed by fluorescent in situ hybridization. Immunoglobulin-coating bacteria were detected using fluorescent-labelled F(ab')2 antihuman IgA, IgG and IgM. RESULTS: Reductions in Clostridium histolyticum and E. rectale-C. coccoides proportions significantly correlated with weight and BMI z-score reductions in the whole adolescent population. Proportions of C. histolyticum, C. lituseburense and E. rectale-C. coccoides dropped significantly whereas those of the Bacteroides-Prevotella group increased after the intervention in those adolescents who lost more than 4 kg. Total fecal energy was almost significantly reduced in the same group of adolescents but not in the group that lost less than 2.5 kg. IgA-coating bacterial proportions also decreased significantly in participants who lost more than 6 kg after the intervention, paralleled to reductions in C. histolyticum and E. rectale-C. coccoides populations. E. rectale-C. coccoides proportions also correlated with weight loss and BMI z-score reduction in participants whose weight loss exceeded 4 kg. CONCLUSIONS: Specific gut bacteria and an associated IgA response were related to body weight changes in adolescents under lifestyle intervention. These results suggest interactions between diet, gut microbiota and host metabolism and immunity in obesity.

Models for experimental infection of dogs fed with tissue from fetuses and neonatal cattle naturally infected with Neospora caninum.

Three models were designed to investigate the development and enteroepithelial phase of Neospora caninum in dogs, and to induce oocyst production by the parasite. In the first model, three dogs were fed raw fetal bovine tissue on two occasions. The bovine fetal tissue had been stored at 4 degrees C for 14 days and 16 days, respectively, and had tested positive for neosporosis using histopathology and immunohistochemistry. In the second model, nine dogs from the beginning of the experiment until euthanasia were fed portions of tissue from bovine fetuses that been stored at 4 degrees C for between 1 and 2 days. Three fetuses had tested positive for neosporosis using histopathology and immunohistochemistry. In the third model, three dogs were fed pieces of raw tissue from two neonatal calves that had not received colostrum, and which had tested positive for antibodies against N. caninum. The brains of these calves were positive for neosporosis by histopathology and immunohistochemistry. In all three models, none of the dogs excreted oocysts of N. caninum, developed intestinal parasites or seroconverted.

Transgenic plants of blue grama grass, Bouteloua gracilis (H.B.K.) Lag. ex Steud., from microprojectile bombardment of highly chlorophyllous embryogenic cells.

For the first time, the production of transgenic plants of the forage grass blue grama, Bouteloua gracilis [H.B.K.] Lag. ex Steud., is reported. Transgenic plants containing a gus Colon, two colons nptll fusion driven by a double CaMV35S promoter were obtained by microprojectile bombardment of the highly chlorophyllous embryogenic cell line 'TIANSJ98'. Transformed B. gracilis cell lines resisted a lethal concentration of 160 mg/l of kanamycin for at least 8 months. Chlorophyll development and growth rate were used as useful criteria for discriminating transformed from non-transformed clones. Stable integration of the transgene in the blue grama genome was demonstrated by PCR and Southern-hybridization analysis. Expression of the NPTll protein in transgenic plants grown under greenhouse conditions was confirmed indirectly by spraying kanamycin (150-250 mg/l) on plant foliage, and directly by ELISA immunological tests. Control plants sprayed with kanamycin showed foliar necrosis and reduced growth (tillering) compared to plants containing the transgene. NPTll was found in transgenic plants in levels ranging between 12.6 and 29.6 ng/mg FW of cells, as determined by ELISA reactions.

[Antibiotic treatment of pneumococcal meningitis (author's transl)]. / Tratamiento antibiótico de la meningitis neumocócicas.

Pneumococcal meningitis, which represents the third in frequency among the purulent forms of meningitis, continues to be, in spite of antibiotic therapy, a serious problem due to its high mortality rate, which reaches 50 per cent in patients of advanced age. The antibiotic treatment of choice is penicillin G, using chloramphenicol as the substitute antibiotic and the cephalosporins in other instances. This article is a review of the cases of pneumococcal meningitis which were admitted to our hospital in the period between 1969-1977, placing especial stress on the therapy followed. Our experience in the treatment of 28 patients affected with this condition indicates therapeutic success in 45 per cent of the cases treated with penicillin G, and a rate of 70 per cent using cephaloridine. In view of these results we believe that cephaloridine should be considered an important alternative antibiotic in the therapy of pneumococcal meningitis.