Dopamine D2 receptor availability is linked to hippocampal–caudate functional connectivity and episodic memory

D1 and D2 dopamine receptors (D1DRs and D2DRs) may contribute differently to various aspects of memory and cognition. The D1DR system has been linked to functions supported by the prefrontal cortex. By contrast, the role of the D2DR system is less clear, although it has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions. Here we present results from 181 healthy adults between 64 and 68 y of age who underwent comprehensive assessment of episodic memory, working memory, and processing speed, along with MRI and D2DR assessment with [¹¹C]raclopride and PET. Caudate D2DR availability was positively associated with episodic memory but not with working memory or speed. Whole-brain analyses further revealed a relation between hippocampal D2DR availability and episodic memory. Hippocampal and caudate D2DR availability were interrelated, and functional MRI-based resting-state functional connectivity between the ventral caudate and medial temporal cortex increased as a function of caudate D2DR availability. Collectively, these findings indicate that D2DRs make a specific contribution to hippocampus-based cognition by influencing striatal and hippocampal regions, and their interactions.Dopamine (DA) plays a key role in several cognitive processes (1–4). Reductions of D1 and D2 DA receptors (D1DRs and D2DRs) in aging (5–7) have been linked to age-related cognitive deficits (8, 9). The D1DR system has been related to functions supported by the prefrontal cortex (PFC), such as working memory and executive functions (10–12), which may reflect the relatively high density of D1DRs in the PFC (13). However, the role of D2DRs is far less clear. D2DRs are present in the PFC at very low densities (13), and evidence supporting a role for the D2DR system in working memory and executive functions is elusive (10). Pharmacological (14, 15) and PET studies assessing striatal D2DR availability (or binding potential to nondisplacable tissue uptake; BP_ND) with [¹¹C]raclopride (16, 17) have yielded mixed findings in relation to cognition. It has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions (10, 18, 19). Supporting these claims, positive links between D2DR BP_ND and episodic memory are commonly observed (20–23). PET imaging of hippocampal D2DR BP_ND also provides support for this hypothesis, although some studies indicate that hippocampal D2DRs may be related to both episodic memory and PFC-based executive functions (22, 23), including verbal working memory (24). Medial temporal lobe regions have been implicated in working memory (25, 26), and D2DR-mediated modulation may be exerted via hippocampal–cortical pathways (27). In addition, a [¹¹C]raclopride task-activation PET study demonstrated contributions of striatal D2DRs to a verbal working-memory task (11).Taken together, the specific role of the D2DR system in cognition remains unclear, likely due to the fact that past studies included small and age-heterogeneous samples and lacked comprehensive test batteries that allowed systematic comparison of the role of D2DRs in different cognitive functions. Here we present results from the Cognition, Brain, and Aging (COBRA) study that include assessment of episodic memory, working memory, and processing speed, in combination with [¹¹C]raclopride PET and MRI of 181 healthy adults between 64 and 68 y of age (28). The main analyses concerned caudate D2DR–cognition associations, as this striatal region has been implicated in cognitive functioning (11, 12, 29, 30). Subsequently, whole-brain analyses were conducted to examine extrastriatal (especially hippocampal) D2DRs in relation to cognition. Finally, resting-state functional connectivity patterns were analyzed in relation to D2DR BP_ND, with special focus on interactions between the ventral caudate (31) and medial temporal cortex regions (32, 33).     

The use of aluminium hydroxide as adjuvant modulates the specific antibody response—A Brown Norway rat study with native and denatured cow's milk allergens

There is a need for efficient methods to treat food allergy; however, no immunotherapeutic method has yet been satisfactory due to the high rate of unpredictable severe reactions and the limited efficacy. Therefore, modified versions of food allergens have been suggested as alternatives to the parent proteins for immunotherapy. The aim of the study was to compare the inherent allergenicity of the native and denatured version of the cow's milk proteins β-lactoglobulin and α-lactalbumin, and to study the impact of the use of Al(OH)₃ as an adjuvant. Brown Norway rats were immunized intraperitoneally with either native or denatured β-lactoglobulin or α-lactalbumin, with or without the use of Al(OH)₃ as adjuvant. Antibody responses were analysed in various ways by means of different ELISAs. Both the immunogenicity and the sensitizing capacity of the cow's milk allergens were influenced by their globular folding, with the native version being more allergenic than the denatured counterpart. The native folded proteins mainly raised antibodies against conformational epitope, whereas the denatured versions predominantly raised antibodies against linear epitopes. Most interestingly, the study showed that the use of Al(OH)₃, besides increasing immunogenicity and sensitizing capacity of the cow's milk allergens, caused a modification of the specificity of the antibodies raised against the native version of the proteins. Adsorption of the native forms of the allergens to Al(OH)₃ caused a significant greater proportion of antibodies raised against linear epitopes, stressing that the adsorption induced a partly unfolding of the proteins. This may have implications for IT safety and efficacy.     

Real-Time Whole-Genome Sequencing for Routine Typing,Surveillance, and Outbreak Detection of Verotoxigenic Escherichia coli

Fast and accurate identification and typing of pathogens are essential for effective surveillance and outbreak detection. The current routine procedure is based on a variety of techniques, making the procedure laborious, time-consuming, and expensive. With whole-genome sequencing (WGS) becoming cheaper, it has huge potential in both diagnostics and routine surveillance. The aim of this study was to perform a real-time evaluation of WGS for routine typing and surveillance of verocytotoxin-producing Escherichia coli (VTEC). In Denmark, the Statens Serum Institut (SSI) routinely receives all suspected VTEC isolates. During a 7-week period in the fall of 2012, all incoming isolates were concurrently subjected to WGS using IonTorrent PGM. Real-time bioinformatics analysis was performed using web-tools (www.genomicepidemiology.org) for species determination, multilocus sequence type (MLST) typing, and determination of phylogenetic relationship, and a specific VirulenceFinder for detection of E. coli virulence genes was developed as part of this study. In total, 46 suspected VTEC isolates were characterized in parallel during the study. VirulenceFinder proved successful in detecting virulence genes included in routine typing, explicitly verocytotoxin 1 (vtx1), verocytotoxin 2 (vtx2), and intimin (eae), and also detected additional virulence genes. VirulenceFinder is also a robust method for assigning verocytotoxin (vtx) subtypes. A real-time clustering of isolates in agreement with the epidemiology was established from WGS, enabling discrimination between sporadic and outbreak isolates. Overall, WGS typing produced results faster and at a lower cost than the current routine. Therefore, WGS typing is a superior alternative to conventional typing strategies. This approach may also be applied to typing and surveillance of other pathogens.     

The significance of early breastfeeding experiences on breastfeeding self‐efficacy one week postpartum

Many new mothers do not reach their breastfeeding goals. Breastfeeding self‐efficacy is a modifiable determinant influenced by prior and new breastfeeding experiences. More knowledge about factors associated with early breastfeeding experiences and breastfeeding self‐efficacy would allow us to qualify breastfeeding counselling and increase breastfeeding duration. This study aimed to identify prevalence and factors associated with early negative breastfeeding experience, low breastfeeding self‐efficacy in the first week postpartum, and drop in self‐efficacy from late pregnancy to early postpartum period. A prospective longitudinal study was performed in Denmark from 2013 to 2014, including 2, 804 mothers. Results showed that 1 week postpartum almost 10% of mothers had negative breastfeeding experiences, 36% had low breastfeeding self‐efficacy, and 26% drop in self‐efficacy from pregnancy. Negative breastfeeding experiences were significantly associated with epidural analgesia, interrupted skin‐to‐skin contact immediately postpartum, short previous breastfeeding duration, and lacking social support. Low breastfeeding self‐efficacy was associated with low breastfeeding intention, short previous breastfeeding duration, and negative breastfeeding experiences in the first week postpartum. Finally, significant associations of drop in breastfeeding self‐efficacy from late pregnancy were no or short education, early negative breastfeeding experiences, prior short breastfeeding duration, and low general breastfeeding self‐efficacy in pregnancy. Negative breastfeeding experiences in the first week postpartum is crucial for maternal breastfeeding self‐efficacy 1 week following birth. It is important to identify and support mothers at risk of negative breastfeeding experiences in the first week following birth and address factors that might increase the probability of early successful breastfeeding experiences.     

Adequacy of essential fatty acid, vitamin D and vitamin E intake: Implications for the 'core' and 'extras' food group concept of the Australian Guide to Healthy Eating

Objective: To assess the implications of new recommendations for essential fatty acids, vitamin D and vitamin E on the classification of margarines and vegetable oils as ‘extras’ in the current Australian Guide to Healthy Eating. Design: The role of margarines and vegetable oils as sources of essential fatty acids, vitamin D and vitamin E was examined in two ways. First, data from the 1995 National Nutrition Survey were assessed and, second, sample diets conforming to the Australian Guide to Healthy Eating were modelled and analysed. Subjects: For the assessment of national intake, subjects were a representative sample of 13 858 Australians, surveyed in the 1995 National Nutrition Survey. Main outcome measures: Relative contributions of margarines and oils, the ‘core’ food groups and ‘extras’ categories of the Australian Guide to Healthy Eating to intakes of essential fatty acids and vitamins D and E; changes in nutrient profiles of baseline diets conforming to the Australian Guide to Healthy Eating with or without varying amounts of margarines and oils. Results: ‘Core’ foods and ‘extras’ contributed similar amounts of essential fatty acids and vitamins D and E to the Australian diet, margarines and oils being the major contributor among ‘extras’. The simulated low‐fat, low‐saturated‐fat baseline diets generally failed to meet the adequate intakes for n‐3 and n‐6 polyunsaturates and vitamin D, and vitamin E in some instances. The addition of 25 g of sunflower margarine, but not comparable amounts of canola margarine, olive oil and butter, markedly increased the ratio of polyunsaturated to saturated fatty acids and generally delivered the adequate intakes, vitamin D being the exception. Conclusion: The inclusion of margarines and vegetable oils in diets based on the current Australian Guide to Healthy Eating, and guidance on choice among these foods, is required to provide adequate intakes of linoleic acid, α‐linolenic acid and vitamins D and E and to achieve fatty acid profiles consistent with the prevention of chronic disease.     

A non-living nasal influenza vaccine can induce major humoral and cellular immune responses in humans without the need for adjuvants

Twenty-eight healthy adult volunteers were immunized intranasally with an inactivated whole-virus influenza vaccine based on the strain A/New Caledonia/20/99 (H1N1), either in saline or mixed with formaldehyde-inactivated Bordetella pertussis as a mucosal adjuvant, or in a thixotropic vehicle with mucoadhesive properties. After four doses, all groups of vaccinees developed significant IgG- and IgA-antibody responses, measured by ELISA, in respectively serum and nasal secretions. None of the volunteers had demonstrable hemagglutination inhibition (HAI) antibodies in serum before being immunized, whereas more than 80% of them reached HAI titers>or=40, considered protective, after immunizations. In addition, cellular immune responses, measured as significant increases in CD4+ T-cell proliferation and granzyme B-producing cytotoxic T-cells, were detected against the vaccine strain as well as against heterologous virus strains (H3N2). However, no additive effect on these responses could be demonstrated with use of B. pertussis or the thixotropic substance in the present vaccines. It appeared, actually, that the mucoadhesive vehicle containing the thixotropic substance was less efficient than were the two other formulations. An influenza vaccine made as a simple particulate formulation of inactivated virus, and given repeatedly onto the nasal mucosa, may thus be an attractive alternative to currently available vaccines.     

Imbalanced chordal force distribution causes acute ischemic mitral regurgitation: mechanistic insights from chordae tendineae force measurements in pigs

BACKGROUND: Ischemic mitral regurgitation is caused by an imbalance of the entire mitral-ventricular complex. This interaction is mediated through the chordae tendineae force distribution, which may perturb several elements of the mitral valve apparatus. Our objective was to investigate the association between the mitral valvular 3-dimensional geometric perturbations and chordae tendineae force redistribution in a porcine model of acute ischemic mitral regurgitation. METHODS: In 9 pigs, acute ischemic mitral regurgitation was induced by repeated microembolization of the left circumflex coronary artery. Mitral leaflet coaptation geometry was determined by 2-dimensional echocardiography and reconstructed 3-dimensionally. Leading edge chordal forces were measured by dedicated miniature force transducers at control and during ischemic mitral regurgitation. RESULTS: During acute ischemic mitral regurgitation, there was a decreased tension of the primary chorda from the ischemic posterior left ventricular wall to the anterior leaflet (0.295 +/- 0.063 N vs 0.336 +/- 0.071 N [control]; P < .05). The tension of the chorda from the nonischemic anterior left ventricular wall to the anterior leaflet increased (0.375 +/- 0.066 N vs 0.333 +/- 0.071 N [control]; P < .05). In accordance, relative leaflet prolapse was observed at the ischemic commissural side, whereas there was an increase in the leaflet surface area at the nonischemic commissural side, indicating localized leaflet tethering. CONCLUSIONS: Acute ischemic mitral regurgitation due to posterior left ventricular wall ischemia was associated with focal chordal and leaflet tethering at the nonischemic commissural portion of the mitral valve and a paradoxical decrease of the chordal forces and relative prolapse at the ischemic site of the anterior mitral valve leaflet.     

Reference Values for Valve Circumferences and Ventricular Wall Thicknesses of Fetal and Neonatal Hearts

To evaluate valvular stenosis, cardiac dilation, and/or cardiac hypertrophy, measurements of valve circumference and ventricular wall thickness are of importance. To establish reference values in fetuses and neonates, we reviewed pathology reports at Women and Infants Hospital from 1978 through 2002 and found measurements in 776 cases that were suitable for analysis. Gestational ages (GA) ranged from 15 to 42 wk. The tabulated data include the mean, standard deviation, and 10th and 90th percentile values for foot length, body weight, body length, heart weight, valve measurements, and ventricular wall thicknesses for each week of GA. In cases in which clinical dating is not reliable, we estimated the GA by the mean value nearest that of the observed foot length. All linear measurements increased in a linear fashion throughout the second and third trimesters of development. The circumferences of cardiac valves at all ages, in descending order of magnitude, are: tricuspid, mitral, pulmonary, and aortic. Mean left ventricular (LV) wall thickness is greater than mean right ventricular (RV) wall thickness throughout gestation. The tables offer a means of determining valvular stenosis, or cardiac dilation and/or hypertrophy, based on various gestational ages.     

Positive pivot shift after ACL reconstruction predicts later osteoarthrosis: 63 patients followed 5-9 years after surgery

BACKGROUND: Rupture of the anterior cruciate ligament (ACL) may cause osteoarthrosis (OA) and functional impairment. We wanted to find out whether the degree of knee stability obtained after ACL reconstruction correlates with radiographic and clinical outcome. PATIENTS AND METHODS: We examined 63 patients 2 and 5-9 years after anterior cruciate ligament (ACL) reconstruction. Knee stability was assessed 2 years after surgery by recording AP laxity using radiostereometric technique (RSA) and by performing the pivot shift test. Degeneration of the knee joint was evaluated with bone scintigraphy, and radiographically. Functional outcome was assessed with Lysholm score, Tegner activity scale and with the one-leg hop test. RESULTS: Radiographic signs of osteoarthrosis at the most recent follow-up (5-9 years) did not correlate with knee stability. Patients with positive pivot shift test 2 years after surgery showed increased scintigraphic activity of the subchondral bone at the most recent follow-up, and inferior subjective functional outcome 2 years after surgery. Knees having had meniscus resections had more often OA. Radiographical signs of OA were associated with higher scintigraphic uptake in the operated knee relative to the contralateral knee. INTERPRETATION: The ability to obliterate the pivoting by ACL reconstruction appears to be more important than normalizing the AP laxity in order to prevent later OA.