Effect of Whey-Derived Lactopeptide ß-Lactolin on Memory in Healthy Adults: An Integrated Analysis of Data from Randomized Controlled Trials.

CONTEXT: Epidemiological studies have shown that consumption of dairy products reduces the risk of dementia and cognitive decline in older individuals. Tryptophan-tyrosine-related ß-lactopeptides and their representative ß-lactolin of glycine-threonine-tryptophan-tyrosine tetra-peptide have been identified as agents in dairy products, which improve cognitive function as well as memory function via the activation of the dopaminergic system in a mouse model of amnesia. Previous clinical trials have shown that supplementation with ß-lactolin improves memory retrieval in healthy older adults. Specifically, ß-lactolin improved the scores in some neuropsychological tests. However, the effects of ß-lactolin on memory function have not been clarified. OBJECTIVES: The aim of this study was to evaluate the effect of ß-lactolin on memory function using statistical methods. DATA SOURCES: We searched the Web of Science, Cochrane Library, and JDream III until November 2021 to identify relevant randomized controlled trials for integrated analysis. DATA SYNTHESIS: Three randomized controlled trials evaluating the effect of ß-lactolin on memory in healthy adults were selected for the integrated analysis. The results showed that the score of cued recall among the neuropsychological tests in the ß-lactolin group was significantly higher than that in the placebo group (g=0.33; 95% CI: 0.10, 0.55). In addition, the total memory score was higher but this difference was not significant (g=0.17; 95% CI: -0.09, 0.43). CONCLUSIONS: Taken together, these results suggest that supplementation with ß-lactolin improves cued recall in healthy older adults.

Polyunsaturated fatty acid deficiency during neurodevelopment in mice models the prodromal state of schizophrenia through epigenetic changes in nuclear receptor genes.

The risk of schizophrenia is increased in offspring whose mothers experience malnutrition during pregnancy. Polyunsaturated fatty acids (PUFAs) are dietary components that are crucial for the structural and functional integrity of neural cells, and PUFA deficiency has been shown to be a risk factor for schizophrenia. Here, we show that gestational and early postnatal dietary deprivation of two PUFAs-arachidonic acid (AA) and docosahexaenoic acid (DHA)-elicited schizophrenia-like phenotypes in mouse offspring at adulthood. In the PUFA-deprived mouse group, we observed lower motivation and higher sensitivity to a hallucinogenic drug resembling the prodromal symptoms in schizophrenia. Furthermore, a working-memory task-evoked hyper-neuronal activity in the medial prefrontal cortex was also observed, along with the downregulation of genes in the prefrontal cortex involved in oligodendrocyte integrity and the gamma-aminobutyric acid (GABA)-ergic system. Regulation of these genes was mediated by the nuclear receptor genes Rxr and Ppar, whose promoters were hyper-methylated by the deprivation of dietary AA and DHA. In addition, the RXR agonist bexarotene upregulated oligodendrocyte- and GABA-related gene expression and suppressed the sensitivity of mice to the hallucinogenic drug. Notably, the expression of these nuclear receptor genes were also downregulated in hair-follicle cells from schizophrenia patients. These results suggest that PUFA deficiency during the early neurodevelopmental period in mice could model the prodromal state of schizophrenia through changes in the epigenetic regulation of nuclear receptor genes.

A novel conditional platelet depletion mouse model reveals the importance of platelets in protection against Staphylococcus aureus bacteremia.

BACKGROUND: Platelets are critical cells for maintaining vascular hemostasis, but their activities in other processes are becoming apparent. Specifically, the ability of platelets to recognize and respond to infectious agents is an important area of investigation. To understand the physiologic roles of platelets in vivo, most researchers have used antibody-mediated platelet depletion, which has certain limitations. OBJECTIVE: To develop an optimal system with which to study the contribution of platelets to protection against S. aureus blood infection. METHODS: Here, we describe a novel experimental model of conditional platelet depletion based on the Cre-recombinase cell ablation system. With this technology, the simian diphtheria toxin receptor was expressed in platelet factor 4-positive cells (megakaryocytes and platelets). RESULTS: Systemic administration of diphtheria toxin every 48 h resulted in reduced platelet numbers that became undetectable after 6 days. Although platelets were depleted, no other blood cells were affected. With this newly developed model, the functional contributions of platelets to protection against Staphylococcus aureus bacteremia was examined. Platelet-depleted mice succumbed to infection more rapidly than wild-type mice, and had a significantly higher bacterial burden in kidneys, elevated levels of serum markers of kidney damage, and increased levels of cytokines indicative of septic shock. CONCLUSIONS: Here, we illustrate a new mouse model for conditional platelet depletion, and implicate platelets as important participants in the immune response to bacterial blood infections.

Serum levels of hepatocyte growth factor and epiregulin are associated with the prognosis on anti-EGFR antibody treatment in KRAS wild-type metastatic colorectal cancer.

BACKGROUND: Ligands of transmembrane receptor tyrosine kinases have important roles in cell proliferation, survival, migration and differentiation in solid tumours. We conducted this study to evaluate the relationship between concentration of serum ligands and prognosis of patients with metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) antibodies. METHODS: Between August 2008 and August 2011, serum samples were obtained from KRAS wild-type patients who met the inclusion criteria and received an anti-EGFR antibody treatment. Serum concentration of ligands was measured by an enzyme-linked immunosorbent assay, and somatic mutations of KRAS, BRAF, PIK3CA and BRAF were analysed by direct sequencing. RESULTS: A total of 103 patients were enrolled in the present study. At the pretreatment serum levels, patients with high levels of hepatocyte growth factor (HGF) had shorter progression-free survival (PFS) and overall survival (OS) compared with those with low levels of HGF (median PFS: 6.4 months vs 4.4 months; P<0.001, median OS: 15.3 months vs 8.0 months; P<0.001, respectively). Patients with high levels of epiregulin (EREG) also had shorter PFS and OS compared with those with low levels of EREG (median PFS: 6.6 months vs 4.9 months; P=0.016, median OS: 13.8 months vs 7.4 months; P=0.048, respectively). In addition, patients whose serum levels of ligands were elevated at progressive disease had shorter PFS and OS compared with other patients. CONCLUSIONS: Our study indicated that high levels of HGF and EREG were associated with resistance to treatment with anti-EGFR antibodies in KRAS wild-type patients with mCRC. Our findings will contribute to the newly combination therapy on the treatment of anti-EGFR antibodies.

Impact of excision repair cross-complementing gene 1 (ERCC1) on the outcomes of patients with advanced gastric cancer: correlative study in Japan Clinical Oncology Group Trial JCOG9912.

BACKGROUND: Since the best chemotherapy regimen for each patient with advanced gastric cancer is uncertain, we aimed to identify molecular prognostic or predictive biomarkers from biopsy specimens in JCOG9912, a randomized phase III trial for advanced gastric cancer. PATIENTS AND METHODS: Endoscopic biopsy specimens from primary lesions were collected in 445 of 704 randomized patients in JCOG9912. We measured the mRNA expression of excision repair cross-complementing group 1 (ERCC1), thymidylate synthase, dihydropyrimidine dehydrogenase, and five other genes, then, categorized them into low and high groups relative to the median, and examined whether gene expression was associated with efficacy end point. RESULTS: Multivariate analyses showed that high ERCC1 expression [HR 1.37; 95% confidence interval (CI) 1.08-1.75; P = 0.010], performance status ≥ 1 (HR 1.45; 95% CI 1.13-1.86; P = 0.004), and number of metastatic sites ≥ 2 (HR 1.66; 95% CI 1.28-1.86; P < 0.001) were associated with a poor prognosis, and recurrent disease (versus unresectable; HR 0.75; 95% CI 0.56-1.00; P = 0.049) was associated with a favorable prognosis. None of these molecular factors were a predictive marker for choosing irinotecan plus cisplatin or 5-fluorouracil rather than S-1. CONCLUSION: These correlative analyses suggest that ERCC1 is an independent prognostic factor for overall survival in the first-line treatment of gastric cancer. CLINICAL TRIAL NUMBER: C000000062, www.umin.ac.jp.

Anomalous enhancement in the infrared phonon intensity of a one-dimensional uneven peanut-shaped C60 polymer.

A one-dimensional (1D) uneven peanut-shaped C(60) polymer formed from electron-beam (EB)-induced polymerization of C(60) molecules showed an anomalous increase in two characteristic infrared (IR) peak intensities, which are respectively due to the radial and tangential motion of the 1D polymer, when compared to the IR peaks of pristine C(60) films. This anomaly was analyzed on the basis of the vibrational van Hove singularity (VHS), using an extended thin-shell elastic model fully considering the effects of periodic radius modulation inherent to the 1D uneven peanut-shaped C(60) polymer. We succeeded in explaining the enhancement in the tangential peak intensity by VHS, whereas the origin to cause that in the radial peak intensity is still unclear.

Structural evolution in the neutron-rich nuclei ¹°6Zr and ¹°8Zr.

The low-lying states in ¹°6Zr and ¹°8Zr have been investigated by means of ß-γ and isomer spectroscopy at the radioactive isotope beam factory (RIBF), respectively. A new isomer with a half-life of 620 ± 150 ns has been identified in ¹°8Zr. For the sequence of even-even Zr isotopes, the excitation energies of the first 2⁺ states reach a minimum at N = 64 and gradually increase as the neutron number increases up to N = 68, suggesting a deformed subshell closure at N = 64. The deformed ground state of ¹°8Zr indicates that a spherical subshell gap predicted at N = 70 is not large enough to change the ground state of ¹°8Zr to the spherical shape. The possibility of a tetrahedral shape isomer in ¹°8Zr is also discussed.

ß-decay half-lives of very neutron-rich Kr to Tc isotopes on the boundary of the r-process path: an indication of fast r-matter flow.

The ß-decay half-lives of 38 neutron-rich isotopes from (36)Kr to (43)Tc have been measured; the half-lives of (100)Kr, (103-105)Sr, (106-108)Y, (108-110)Zr, (111,112)Nb, (112-115)Mo, and (116,117)Tc are reported here. The results when compared with previous standard models indicate an overestimation in the predicted half-lives by a factor of 2 or more in the A≈110 region. A revised model based on the second generation gross theory of ß decay better predicts the measured half-lives and suggests a more rapid flow of the rapid neutron-capture process (r-matter flow) through this region than previously predicted.

Tau aggregation is a therapeutic target for Alzheimer's disease.

Based on the amyloid hypothesis, studies for AD therapy have been mostly focused on removing ß-amyloid. Recent results of amyloid immunotherapy raised the question whether ß-amyloid is sufficient target for AD therapy. Neurofibrillary tangles (NFTs), which contain hyperphosphorylated tau, are another pathological hallmark of AD. NFTs are observed in entorhinal cortex, limbic, and neocortex over the course of clinical progression. NFTs are associated with synapse and neuron loss, suggesting that the process of NFT formation is involved in brain dysfunction. During NFT formation, tau forms a variety of different aggregation species, including tau oligomers, granules, and fibrils. Analysis of different human tau-expressing mouse lines reveals that soluble hyperphosphorylated tau, which includes tau oligomer, is involved in synapse loss, whereas granular tau formation is involved in neuronal loss. Therefore, inhibition of tau aggregation and tau phosphorylation is expected to prevent synapse loss and neuron loss, and may slow or halt the progressive dementia in AD.

Tau oligomerization: a role for tau aggregation intermediates linked to neurodegeneration.

Intracellular accumulation of filamentous tau proteins is a defining feature of neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and frontotemporal dementia with Parkinsonism linked to chromosome 17, all known collectively as tauopathies. Tau protein is a member of microtubule (MT)-associated proteins. Tau is a highly soluble and natively unfolded protein dominated by a random coil structure in solution. It is believed that aberrant modifications of tau, including phosphorylation, truncation, and conformational changes, induce filamentous aggregation. However, the mechanism underlying the conversion of tau protein from a soluble state to one of insoluble aggregates still remains elusive. The importance of tau aggregation intermediates (e.g. tau dimer, tau multimer, and granular tau oligomer) in disease pathogenesis was suggested by recent studies. Here, we review the latest developments in tracking the structural changes of tau protein and discuss the utility improving our understanding of tau aggregation pathway leading to human tauopathies.

Multifocal granulomatous hepatitis caused by Actinobacillus pleuropneumoniae serotype 2 in slaughter pigs.

In a survey of 66 894 slaughter pigs, 11 animals from three farms were found to have multifocal granulomatous lesions in the liver, caused by Actinobacillus pleuropneumoniae serotype 2. The lesions consisted of epithelioid cells and multinucleated giant cells, with asteroid bodies and discernible gram-negative bacteria. Lymph nodes and spleen were occasionally affected. The results suggested that haematogenous spread had occurred from pre-existing pulmonary infections.

Complementary distributions of amyloid-beta and neprilysin in the brains of dogs and cats.

Neprilysin is an amyloid-beta-degrading enzyme localized in the brain parenchyma. The involvement of neprilysin in the pathogenesis of Alzheimer's disease has recently received much attention. We examined the localization of neprilysin and amyloid-beta, as well as the activity of neprilysin, in the brains of dogs and cats of various ages to clarify the relationship between neprilysin activity and amyloid-beta deposition. The distribution of neprilysin was almost identical in dogs and cats, being high in the striatum, globus pallidus, and substantia nigra, but very low in the cerebral cortex. The white matter and hippocampus were negative. Neprilysin activity in the brain regions in dogs and cats was ranked from high to low as follows: thalamus/striatum > cerebral cortex > hippocampus > white matter. Amyloid-beta deposition was first detected at 7 and 10 years of age in dogs and cats, respectively, and both the quantity and frequency of deposition increased with age. In both species, amyloid-beta deposition appeared in the cerebral cortex and the hippocampus. In summary, the localization of neprilysin and neprilysin activity, and that of amyloid-beta, were complementary in the brains of dogs and cats.

Stress and glucocorticoid footprints in the brain-the path from depression to Alzheimer's disease.

Increasingly, stress is recognized as a trigger of depressive episodes and recent evidence suggests a causal role of stress in the onset and progression of Alzheimer's disease (AD) pathology. Besides aging, sex is an important determinant of prevalence rates for both AD and mood disorders. In light of a recent meta-analysis indicating that depressed subjects have a higher likelihood of developing AD, a key message in this article will be that both depression and AD are stress-related disorders and may represent a continuum that should receive more attention in future neurobiological studies. Accordingly, this review considers some of the cellular mechanisms that may be involved in regulating this transition threshold. In addition, it highlights the importance of addressing the question of how aging and sex interplay with stress to influence mood and cognition, with a bias towards consideration of neuroplastic events in particular brain regions, as the basis of AD and depressive disorders.

Chemosensitivity of patients with recurrent esophageal cancer receiving perioperative chemotherapy.

Perioperative chemotherapy (CT) and chemoradiotherapy are widely used for advanced esophageal cancer. We evaluated the chemosensitivity of patients displaying recurrent esophageal cancer after esophagectomy with perioperative CT. From the database at National Cancer Center Hospital in Tokyo, we extracted recurrent esophageal cancer cases after perioperative CT and evaluated the effectiveness of the first CT against the recurrent disease according to the duration between termination of the original perioperative CT and recurrence with treatment-free intervals (TFIs) 6 months. Systemic CT for their recurrent disease was performed for 30 esophageal cancer patients after perioperative CT. All patients received 5-fluorouracil and cisplatin as perioperative CT, with relapses occurring at TFIs 6 months in 19 patients (all received platinum-containing regimens). The response rate of patients experiencing a recurrence at TFIs 6 months was 0 and 37% (P = 0.029), the median progression-free survival was 2.8 and 4.8 months (log-rank P = 0.001) and the median overall survival was 6.1 and 10.2 months (log-rank P = 0.012), respectively. Recurrence at the TFI

Granulomatous lymphadenitis and pneumonia associated with Actinobacillus porcitonsillarum in a slaughter pig.

Multiple coalescing granulomatous foci were detected in the pulmonary hilar and mediastinal lymph nodes and lung of a slaughtered pig aged 6 months. Haemolytic, Gram-negative bacilli were isolated from the lymph nodes. The isolate (strain TO17214) strongly cross-reacted with sera against Actinobacillus pleuropneumoniae serotype 12 in slide agglutination tests. Comparative 16S rDNA gene sequencing analysis identified strain TO17214 as Actinobacillus porcitonsillarum. Histologically, extensive inflammation took the form of large granulomas consisting of epithelioid cells and multinucleated giant cells in the lymph nodes and lung, and Gram-negative bacilli were discernible in the centres of the lesions. Immunohistochemically, the organisms cross-reacted with polyclonal antibodies against A. pleuropneumoniae serotypes 12 and 2. The results indicated that A. porcitonsillarum, previously considered non-pathogenic, can induce multifocal granulomatous lymphadenitis accompanied by pneumonia in the growing-finishing pig.

Molecular chaperone-mediated tau protein metabolism counteracts the formation of granular tau oligomers in human brain.

Intracellular accumulation of filamentous tau proteins is a defining feature of neurodegenerative diseases termed tauopathies. The pathogenesis of tauopathies remains largely unknown. Molecular chaperones such as heat shock proteins (HSPs), however, have been implicated in tauopathies as well as in other neurodegenerative diseases characterized by the accumulation of insoluble protein aggregates. To search for in vivo evidence of chaperone-related tau protein metabolism, we analyzed human brains with varying degrees of neurofibrillary tangle (NFT) pathology, as defined by Braak NFT staging. Quantitative analysis of soluble protein levels revealed significant positive correlations between tau and Hsp90, Hsp40, Hsp27, alpha-crystallin, and CHIP. An inverse correlation was observed between the levels of HSPs in each specimen and the levels of granular tau oligomers, the latter of which were isolated from brain as intermediates of tau filaments. We speculate that HSPs function as regulators of soluble tau protein levels, and, once the capacity of this chaperone system is saturated, granular tau oligomers form virtually unabated. This is expressed pathologically as an early sign of NFT formation. The molecular basis of chaperone-mediated protection against neurodegeneration might lead to the development of therapeutics for tauopathies. (c) 2007 Wiley-Liss, Inc.

Declarative memory consolidation in humans: a prospective functional magnetic resonance imaging study.

Retrieval of recently acquired declarative memories depends on the hippocampus, but with time, retrieval is increasingly sustainable by neocortical representations alone. This process has been conceptualized as system-level consolidation. Using functional magnetic resonance imaging, we assessed over the course of three months how consolidation affects the neural correlates of memory retrieval. The duration of slow-wave sleep during a nap/rest period after the initial study session and before the first scan session on day 1 correlated positively with recognition memory performance for items studied before the nap and negatively with hippocampal activity associated with correct confident recognition. Over the course of the entire study, hippocampal activity for correct confident recognition continued to decrease, whereas activity in a ventral medial prefrontal region increased. These findings, together with data obtained in rodents, may prompt a revision of classical consolidation theory, incorporating a transfer of putative linking nodes from hippocampal to prelimbic prefrontal areas.

Successful declarative memory formation is associated with ongoing activity during encoding in a distributed neocortical network related to working memory: a magnetoencephalography study.

The aim of the present study was to investigate the spatio-temporal characteristics of the neural correlates of declarative memory formation as assessed by the subsequent memory effect, i.e. the difference in encoding activity between subsequently remembered and subsequently forgotten items. Different operations could account for these effects. In particular, it has been proposed that successful memory formation depends on the organization of the information at the time of encoding, an operation accomplished by the working memory system. Consequently, functional magnetic resonance imaging studies have already shown that the very same regions that are involved in certain working memory processes are also involved in declarative memory formation. Here, we used magnetoencephalography to investigate whether the subsequent memory effects in these regions are present throughout picture stimulus presentation, postulating ongoing working memory operations as an effective factor. The results showed that subsequent memory effects began to appear after about 300 ms post stimulus onset over bilateral temporal areas and left parietal regions and were sustained throughout the recording epoch (1000 ms). Roughly parallel to these effects, we identified a left frontal subsequent memory effect, which, however, was less sustained than the other effects. In addition, we revealed a late subsequent memory effect over the right occipital region, which has not been described previously in the event-related potential literature. These sustained subsequent memory effects are suggestive of working memory processes that may enable deep semantic and perceptual processing. Additionally, contextually constrained visual perception after top-down modulation may account for a more efficient encoding of the complex scene.

Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100.

To examine the regulation of amyloid secretion in more detail, Abeta sandwich ELISAs with high sensitivity and specificity were developed. Using this technique, we measured Abeta secreted from COS7 cells transiently transfected with APP C100 in the presence of LiCl, a potent glycogen synthase kinase (GSK)-3beta inhibitor. We found that both Abetax-40 and Abetax-42 secretion were reduced by LiCl treatment in a dose-dependent manner. Diminished amyloid secretion was associated with GSK-3beta activity. These results suggest that GSK-3beta might function as a possible mediator for regulating both amyloid deposition and tau pathology in Alzheimer's disease (AD), and that lithium should be re-evaluated as a candidate reagent for preventing AD pathology.