EU/US/CTAD Task Force: Lessons Learned from Recent and Current Alzheimer's Prevention Trials.

At a meeting of the EU/US/Clinical Trials in Alzheimer's Disease (CTAD) Task Force in December 2016, an international group of investigators from industry, academia, and regulatory agencies reviewed lessons learned from ongoing and planned prevention trials, which will help guide future clinical trials of AD treatments, particularly in the pre-clinical space. The Task Force discussed challenges that need to be addressed across all aspects of clinical trials, calling for innovation in recruitment and retention, infrastructure development, and the selection of outcome measures. While cognitive change provides a marker of disease progression across the disease continuum, there remains a need to identify the optimal assessment tools that provide clinically meaningful endpoints. Patient- and informant-reported assessments of cognition and function may be useful but present additional challenges. Imaging and other biomarkers are also essential to maximize the efficiency of and the information learned from clinical trials.

Development of gene therapies-lessons from nusinersen.

The nusinersen development and approval process provide important lessons regarding the pathway to marketing approval for gene therapies. These lessons emphasize rigorous clinical trial design, flexibility in trial design and analysis, a collaborative effort with regular communications between the drug developer and the Food and Drug Administration (FDA), and use of FDA's expedited programs. These lessons are critical to the development of gene therapies for the treatment of serious or life-threatening rare diseases.

Tongue-lip adhesion and tongue repositioning for obstructive sleep apnoea in Pierre Robin sequence: A systematic review and meta-analysis.

OBJECTIVE: To search for studies on tongue-lip adhesion and tongue repositioning used as isolated treatments for obstructive sleep apnoea in children with Pierre Robin sequence. METHODS: A systematic literature search of PubMed/Medline and three additional databases, from inception through to 8 July 2016, was performed by two authors. RESULTS: Seven studies with 90 patients (59 tongue-lip adhesion and 31 tongue repositioning patients) met the inclusion criteria. Tongue-lip adhesion reduced the mean (± standard deviation) apnoea/hypopnoea index from 30.8 ± 22.3 to 15.4 ± 18.9 events per hour (50 per cent reduction). The apnoea/hypopnoea index mean difference for tongue-lip adhesion was -15.28 events per hour (95 per cent confidence interval = -30.70 to 0.15; p = 0.05). Tongue-lip adhesion improved the lowest oxygen saturation from 75.8 ± 6.8 to 84.4 ± 7.3 per cent. Tongue repositioning reduced the apnoea/hypopnoea index from 46.5 to 17.4 events per hour (62.6 per cent reduction). Tongue repositioning improved the mean oxygen saturation from 90.8 ± 1.2 to 95.0 ± 0.5 per cent. CONCLUSION: Tongue-lip adhesion and tongue repositioning can improve apnoea/hypopnoea index and oxygenation parameters in children with Pierre Robin sequence and obstructive sleep apnoea.

Floral scent composition predicts bee pollination system in five butterfly bush (Buddleja, Scrophulariaceae) species.

Traditionally, plant-pollinator interactions have been interpreted as pollination syndrome. However, the validity of pollination syndrome has been widely doubted in modern studies of pollination ecology. The pollination ecology of five Asian Buddleja species, B. asiatica, B. crispa, B. forrestii, B. macrostachya and B. myriantha, in the Sino-Himalayan region in Asia, flowering in different local seasons, with scented inflorescences were investigated during 2011 and 2012. These five species exhibited diverse floral traits, with narrow and long corolla tubes and concealed nectar. According to their floral morphology, larger bees and Lepidoptera were expected to be the major pollinators. However, field observations showed that only larger bees (honeybee/bumblebee) were the primary pollinators, ranging from 77.95% to 97.90% of total visits. In this study, floral scents of each species were also analysed using coupled gas chromatography and mass spectrometry (GC-MS). Although the five Buddleja species emitted differentiated floral scent compositions, our results showed that floral scents of the five species are dominated by substances that can serve as attractive signals to bees, including species-specific scent compounds and principal compounds with larger relative amounts. This suggests that floral scent compositions are closely associated with the principal pollinator assemblages in these five species. Therefore, we conclude that floral scent compositions rather than floral morphology traits should be used to interpret plant-pollinator interactions in these Asian Buddleja species.

Insights into the pathophysiology of catch-up compared with non-catch-up growth in children born small for gestational age: an integrated analysis of metabolic and transcriptomic data.

Small for gestational age (SGA) children exhibiting catch-up (CU) growth have a greater risk of cardiometabolic diseases in later life compared with non-catch-up (NCU) SGA children. The aim of this study was to establish differences in metabolism and gene expression profiles between CU and NCU at age 4-9 years. CU children (n=22) had greater height, weight and body mass index standard deviation scores along with insulin-like growth factor-I (IGF-I) and fasting glucose levels but lower adiponectin values than NCU children (n=11; all P<0.05). Metabolic profiling demonstrated a fourfold decrease of urine myo-inositol in CU compared with NCU (P<0.05). There were 1558 genes differentially expressed in peripheral blood mononuclear cells between the groups (P<0.05). Integrated analysis of data identified myo-inositol related to gene clusters associated with an increase in insulin, growth factor and IGF-I signalling in CU children (P<0.05). Metabolic and transcriptomic profiles in CU SGA children showed changes that may relate to cardiometabolic risk.

Why decision making may not require awareness.

Newell & Shanks (N&S) argue against the idea that any significant role for unconscious influences on decision making has been established by research to date. Inasmuch as this conclusion applies to the idea of an "intelligent cognitive unconscious," we would agree. Our concern is that the article could lead the unwary to conclude that there are no unconscious influences on decision making - and never could be. We give reasons why this may not be the case.

Acute effects of prostaglandin E1 and E2 on vascular reactivity and blood flow in situ in the chick chorioallantoic membrane.

The chick chorioallantoic membrane (CAM) subserves gas exchange in the developing embryo and shell-less culture affords a unique opportunity for direct observations over time of individual blood vessels to pharmacologic interventions. We tested a number of lipids including prostaglandins PGE(1&2) for vascular effects and signaling in the CAM. Application of PGE(1&2) induced a decrease in the diameter of large blood vessels and a concentration-dependent, localized, reversible loss of blood flow through small vessels. The loss of flow was also mimicked by misoprostol, an agonist for 3 of 4 known PGE receptors, EP(2-4), and by U46619, a thromboxane mimetic. Selective receptor antagonists for EP(3) and thromboxane each partially blocked the response. This is a first report of the effects of prostaglandins on vasoreactivity in the CAM. Our model allows the unique ability to examine simultaneous responses of large and small vessels in real time and in vivo.

Electrically conductive, immobilized bioanodes for microbial fuel cells.

The power densities of microbial fuel cells with yeast cells as the anode catalyst were significantly increased by immobilizing the yeast in electrically conductive alginate electrodes. The peak power densities measured as a function of the electrical conductivity of the immobilized electrodes show that although power increases with rising electrical conductivity, it tends to saturate beyond a certain point. Changing the pH of the anode compartment at that point seems to further increase the power density, suggesting that proton transport limitations and not electrical conductivity will limit the power density from electrically conductive immobilized anodes.

Microarray karyotyping of maltose-fermenting Saccharomyces yeasts with differing maltotriose utilization profiles reveals copy number variation in genes involved in maltose and maltotriose utilization.

AIMS: We performed an analysis of maltotriose utilization by 52 Saccharomyces yeast strains able to ferment maltose efficiently and correlated the observed phenotypes with differences in the copy number of genes possibly involved in maltotriose utilization by yeast cells. METHODS AND RESULTS: The analysis of maltose and maltotriose utilization by laboratory and industrial strains of the species Saccharomyces cerevisiae and Saccharomyces pastorianus (a natural S. cerevisiae/Saccharomyces bayanus hybrid) was carried out using microscale liquid cultivation, as well as in aerobic batch cultures. All strains utilize maltose efficiently as a carbon source, but three different phenotypes were observed for maltotriose utilization: efficient growth, slow/delayed growth and no growth. Through microarray karyotyping and pulsed-field gel electrophoresis blots, we analysed the copy number and localization of several maltose-related genes in selected S. cerevisiae strains. While most strains lacked the MPH2 and MPH3 transporter genes, almost all strains analysed had the AGT1 gene and increased copy number of MALx1 permeases. CONCLUSIONS: Our results showed that S. pastorianus yeast strains utilized maltotriose more efficiently than S. cerevisiae strains and highlighted the importance of the AGT1 gene for efficient maltotriose utilization by S. cerevisiae yeasts. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results revealed new maltotriose utilization phenotypes, contributing to a better understanding of the metabolism of this carbon source for improved fermentation by Saccharomyces yeasts.

Differential predictions about future negative events in seasonal and non-seasonal depression.

BACKGROUND: Previous research indicates that individuals with seasonal depression (SD) do not exhibit the memory biases for negative self-referent information that characterize non-seasonal depression (NSD). The current study extended this work by examining processing of self-referent emotional information concerning potential future events in SD. METHOD: SD and NSD patients, along with never-depressed controls, completed a scenario-based measure of likelihood estimation for future positive and negative events happening either to the self or to another person. RESULTS: SD patients estimated future negative events as more likely to happen to both the self and others, relative to controls. In contrast, in the NSD sample this bias was specific to self-referred material. There were no group differences for positive events. CONCLUSIONS: These data provide further evidence that the self-referent bias for processing negative information that characterizes NSD can be absent in SD, this time in the domain of future event processing.

Case of fulminant leptospirosis in a renal transplant patient.

We present a case of fulminant leptospirosis that was acquired in the suburban area by a 48-year-old male renal transplant recipient. He developed acute renal and hepatic failure with profound jaundice. Spirochetes were identified on liver biopsy. Weil's disease was suspected, and the diagnosis was further supported by a positive serum Leptospira interrogans icterohaemorrhagiae antibody titer. Unfortunately, he suffered from recurrent lower gastrointestinal bleeding, had a prolonged hospital course, and eventually succumbed to overwhelming sepsis. This case is the third report to our knowledge of leptospirosis in a renal transplant recipient in the English literature.

Epidemiology and outcomes of community-associated methicillin-resistant Staphylococcus aureus infection.

Over a 2-year period (2003 to 2005) patients with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and community-acquired methicillin-susceptible Staphylococcus aureus (CA-MSSA) infections were prospectively identified. Patients infected with CA-MRSA (n = 102 patients) and CA-MSSA (n = 102 patients) had median ages of 46 and 53 years, respectively; the most common sites of infection in the two groups were skin/soft tissue (80 and 93%, respectively), respiratory tract (13 and 6%, respectively), and blood (4 and 1%, respectively). Fourteen percent of patients with CA-MRSA infections and 3% of patients with CA-MSSA infections had household contacts with similar infections (P < 0.01). Among the CA-MRSA isolates, the pulsed-field gel electrophoresis (PFGE) groups detected were USA300 (49%) and USA100 (13%), with 27 PFGE groups overall; 71% of the isolates were staphylococcal chromosome cassette mec (SCCmec) type IV, 29% were SCCmec type II, and 54% had the Panton-Valentine leucocidin (PVL) gene. Among the CA-MSSA isolates there were 33 PFGE groups, with isolates of the USA200 group comprising 11%, isolates of the USA600 group comprising 11%, isolates of the USA100 group comprising 10%, and isolates of the PVL type comprising 10%. Forty-six and 18% of the patients infected with CA-MRSA and CA-MSSA, respectively, were hospitalized (P < 0.001). Fifty percent of the patients received antibiotic therapy alone, 5% received surgery alone, 30% received antibiotics and surgery, 3% received other therapy, and 12% received no treatment. The median durations of antibiotic therapy were 12 and 10 days in the CA-MRSA- and CA-MSSA-infected patients, respectively; 48 and 56% of the patients in the two groups received adequate antimicrobial therapy, respectively (P < 0.001). The clinical success rates of the initial therapy in the two groups were 61 and 84%, respectively (P < 0.001); recurrences were more common in the CA-MRSA group (recurrences were detected in 18 and 6% of the patients in the two groups, respectively [P < 0.001]). CA-MRSA was an independent predictor of clinical failure in multivariate analysis (odds ratio, 3.4; 95% confidence interval, 1.7 to 6.9). In the community setting, the molecular characteristics of the S. aureus strains were heterogeneous. CA-MRSA infections were associated with a more adverse impact on outcome than CA-MSSA infections.

Trisomy of chromosome 18 in the baboon (Papio hamadryas anubis).

Trisomy 18 is usually a lethal chromosomal abnormality and is the second most common autosomal trisomy in humans, with an incidence of 1:8000 live births. It is commonly associated with abnormalities of the lower and upper extremities, having the frequency of 95% and 65%, respectively. A newborn female olive baboon (Papio hamadryas anubis) was diagnosed with intrauterine growth retardation and severe arthrogryposis-like congenital joint deformities. Cytogenetic analysis including G-banding and fluorescence in situ hybridization (FISH) revealed that the congenital abnormalities were associated with chromosomal mosaicism for trisomy 18. Genetic analysis with microsatellites from chromosome 18 confirmed the maternal origin of the extra chromosome 18. This is the first report of trisomy 18 in the baboon, which may be a promising animal model of human disease.

Spatial trends and factors affecting variation of organochlorine contaminants levels in Canadian Arctic beluga (Delphinapterus leucas).

Organochlorine pesticides and PCBs were analysed in blubber from beluga (Delphinapterus leucas), or white whales, collected at 15 sites in the Canadian Arctic between 1993 and 2001. The objective of the study was to define and interpret the spatial trends of major organic contaminants in northern beluga in terms of sources and transport pathways, and the biological factors influencing accumulation. When compared on a lipid weight basis, the concentrations of beta-HCH, cis-CHL and SigmaCHL, cis-nonachlor, heptachlor epoxide and p,p'-DDT were significantly higher in males than females at all five sites in the eastern Arctic where the two sexes were harvested. The differences were attributed to losses from the females during fetal development and lactation as reported in previous studies. Major compounds increased with age in males at most sites, however the lack of a significant increase with age at some sites was in part due to high organochlorine concentrations in young year classes (2-5 years), particularly at eastern sites such as Iqaluit and Pangnirtung. Lower concentrations of SigmaHCH and SigmaDDT compounds in young males in 2001 relative to 1995 at Hendrickson Island could be due to declining levels in the environment, changes in the diet, or differences in organochlorine loads transferred from the female after birth. Age-corrected least square mean concentrations in males showed significantly higher levels of many compounds, such as p,p'-DDE and SigmaCHB, at south Baffin Island sites than those in the west. Two notable exceptions were HCBz and beta-HCH which were higher in the west. Methoxyclor was detected in males at Sanikiluaq (58 ng g-1) and in both sexes at Kimmirut, but at no other sites. Principal component analysis grouped the 16 sites into five major groupings based on the similarity of normalised organochlorine pesticide and PCB levels. Sites from the western Arctic were grouped by higher proportions of HCBz, beta-HCH and gamma-HCH and higher chlorinated PCBs. Endosulfan and alpha-HCH comprised a larger proportion of total organochlorine residues in the northern Hudson Bay sites, while methoxychlor, chlordane compounds and octachlorobiphenyls were enriched at Sanikiluaq in eastern Hudson Bay. The analysis showed that the relative amounts of several key compounds are similar in the beluga stocks over large spatial areas (i.e. eastern versus western sites), however, some stocks have distinct fingerprints which can be used to differentiate them from adjacent stocks. Ratios of major HCH isomers largely corresponded with air and surface water measurements conducted during the 1990s, but low alpha-/beta- and alpha-/gamma-HCH ratios in all three western Arctic collections indicate rapid losses of the alpha-isomer from the food web, proportionately higher beta- and gamma-isomers in the Beaufort Sea, or a combination of the two processes. Chlordane residue patterns generally correspond to those from previous studies, however, interpretation of spatial trends are difficult due to the aging of the probable sources in the south, possible atmospheric input from new sources and complex transport pathways.

Concentrations of mercury in tissues of beluga whales (Delphinapterus leucas) from several communities in the Canadian Arctic from 1981 to 2002.

Beluga whales have been hunted for food by Native People in the Canadian Arctic since prehistoric time. Here we report the results of analyses of total mercury in samples of liver, kidney, muscle and muktuk from collections over the period 1981-2002. We compare these results with human consumption guidelines and examine temporal and geographic variation. Liver has been analyzed more frequently than other organs and it has been used as the indicator organ. Mercury accumulates in the liver of the whales over time so that the whale ages are usually linked statistically to their levels of mercury in liver. Virtually all the samples of 566 animals analyzed contained mercury in liver at concentrations higher than the Canadian consumption guideline of 0.5 microg g-1 (wet weight) for fish. (There is no regulatory guideline for concentrations in marine mammals in Canada.) Samples from locations in the Mackenzie Delta in the western Canadian Arctic and from Pangnirtung in the eastern Canadian Arctic were obtained more often than from other location and these offered the best chances to determine whether levels have changed over time. Statistical outlier points were removed and the regressions of (ln) mercury in liver on age were used to calculate the level of mercury in whales of age 13.1 years in order to compare age-adjusted levels at different locations. These age-adjusted levels and also the slopes of regressions suggested that levels have increased in the Mackenzie Delta over the sampling period although not in a simple linear fashion. Other locations had fewer collections, generally spread over fewer years. Some of them indicated differences between sampling times but we could not establish whether these differences were simply temporal variation or whether they were segments of a consistent trend. For example, the levels in whales from Arviat were considerably higher in 1999 than in 1984 but we have only two samples. Similarly, samples from Iqaluit in 1994 exceeded considerably those in 1993 and the interval seems too short to reflect any regional temporal trend and more likely represent an extreme case of year-to-year variation. Previous analyses of data from geographically distinct groups had suggested that whales in the western Canadian Arctic had higher levels of mercury than those from the eastern Canadian Arctic. The present analysis suggests that such regional differences have diminished and are no longer statistically significant. No site has indicated significant decreases in more recent samples. The levels of total mercury in the most analyzed organs fell in the order of liver (highest levels), kidney, muscle and muktuk (lowest level). While muktuk had the lowest level of the organs most frequently analyzed, it is the preferred food item from these whales and it still exceeded the consumption guideline in most instances.

Expression and anti-bacterial activity of human parotid secretory protein (PSP).

Parotid secretory protein (PSP) is an abundant protein in mouse and rat parotid glands. A related sequence (C20orf70) was identified on human chromosome 20. The goal of this study was to determine if PSP is expressed in the human parotid gland. The cDNA for human PSP was amplified from a human parotid cDNA sample. A peptide antibody, raised to the C-terminal peptide of PSP, identified the protein in human parotid tissue by immunofluorescence microscopy. Immunoaffinity chromatography suggested that PSP was expressed in human saliva. PSP is related to bactericidal/permeability-increasing protein (BPI). To test if PSP exhibits anti-bacterial activity, epitope-tagged PSP was expressed in rat GH4C1 cells. The secretion medium exhibited bacteristatic or bactericidal effects on Pseudomonas aeruginosa in a colony-forming assay when compared with secretion medium from GH4C1 cells that did not express PSP. These results suggest that PSP is expressed in the human parotid gland and saliva, where it functions as a BPI-like anti-bacterial protein.

Multicenter evaluation of ethambutol susceptibility testing of mycobacterium tuberculosis by agar proportion and radiometric methods.

Reproducibility of ethambutol (EMB) susceptibility test results for Mycobacterium tuberculosis has always been difficult for a variety of reasons, including the narrow range between the critical breakpoint for EMB resistance and the MIC for susceptible strains, borderline results obtained with the BACTEC 460TB method, the presence of microcolonies determined using the agar proportion (AP) method, and a lack of agreement between these two testing methods. To assess the frequency of these problems, M. tuberculosis drug susceptibility data were collected in a multicenter study involving four laboratories. Resistant, borderline, and susceptible isolates were shared among the laboratories to measure interlaboratory test agreement. Half of isolates determined by BACTEC 460TB to be resistant were determined to be susceptible by the AP method. Isolates determined to be resistant to EMB by both BACTEC 460TB and AP methods were almost always resistant to isoniazid. Results from isolates tested by the BACTEC 460TB method with an EMB concentration of 3.75 micro g/ml in addition to the standard 2.5 micro g/ml did not show improved agreement by the AP method. While these results do not indicate that the AP method is more accurate than the BACTEC 460TB method, laboratories should not report EMB monoresistance based on BACTEC 460TB results alone. Monoresistance to EMB should only be reported following confirmation by the AP method. Microcolonies could not be confirmed as resistant by the BACTEC 460TB method or by repeat testing with the AP method and do not appear to be indicative of resistance.

Bovine tuberculosis in Michigan wildlife.

White-tailed deer in Michigan are now recognized as a reservoir host of bovine tuberculosis (TB). It has been determined that the most likely cause of bovine TB infection in the deer is from congregating in artificially high numbers at feed sites. The presence of a wildlife reservoir of TB in Michigan poses a serious threat to the control and eradication programs that are now in their final stages in the United States.