Therapeutic potential of lipase inhibitor orlistat in Alzheimer’s disease

Emerging evidences indicate that elevated cholesterol and triglyceride levels precede Alzheimer’s disease (AD) pathology. High caloric intake based on saturated fat raises hyperlipidaemia and also promotes AD pathology. As a result, strategy that limits the absorption of dietary fat and attenuates hyperlipidemia could be a useful medication for protective treatment of AD. As an active site-directed inhibitor of digestive lipases, orlistat effectively reduces dietary fat absorption and decreases total cholesterol and triglyceride levels in plasma. Orlistat also potently inhibits lipoprotein lipase, monoacylglycerol lipase and diacylglycerol lipase, which are also involved in AD causation. Taken together, orlistat inhibits lipases activities, thereby reduces dietary fat intake and ameliorates hyperlipidemia, which indicates a therapeutic potential of orlistat in protecting against AD pathology.     

Possibilities and potential roles of the functional peptides based on enamel matrix proteins in promoting the remineralization of initial enamel caries

Dental caries is the most common oral diseases, and it gives a serious threat to oral and general health. Fluoride, a classic anti-caries agent, has a profound effect on caries prevention and treatment. However, fluorosis and fluoride-resistant strains limit the further application of fluoride treatment. Therefore, it is still of significant benefit to seek alternatives, bringing more effective anti-caries agents. The potential role of enamel matrix proteins(EMPs) in promoting the regeneration of periodontal tissue and inducing bone have been proved. EMPs have been successfully applied in the field of periodontal disease and dental implants in recent years. Previous researches revealed that enamel matrix proteins had an important role in the synthesis of hydroxyapatite in vitro. Some experiments about the degeneration or removal of EMP suggest that enamel matrix proteins are related to the occurrence and development of caries. Based on evidences illustrated by these experiments, this paper hypothesizes that functional peptides based on the function and structure of EMPs could promote remineralization of enamel caries, which could perform as a suitable treatment to enamel caries. The hypothesis may lead a new direction in the study on the prevention and treatment of enamel caries, and further study of the anti-caries mechanisms of EMP will enable researchers to find out the most effective anti-caries peptides, which could be developed into a bionics anti-cariogenic agent.     

It’s a Bird,It’s a Plane,It’s … Fidelity Measurement in the Real World

[Clin Psychol Sci Prac 18: 142–147, 2011] In psychotherapy research, fidelity instruments were originally developed as manipulation checks in experimental tests of treatment efficacy. The purposes of fidelity measurement are expanding as consumers, administrators, and payers seek to determine the extent to which the interventions purchased are actually received. Emerging purposes for fidelity measurement are described, as are challenges to developing a single instrument that can adequately meet multiple purposes, and that is both effective (psychometrically sound) and efficient (feasibly used in routine care). Examples are provided of efforts to balance these attributes of fidelity measurement, to measure fidelity at multiple levels of the practice context, and to index and evaluate the effects of additional program parameters on client outcomes in routine care.     

Allergenicity of goat’s milk in children with cow’s milk allergy

BACKGROUND: Cow's milk allergy (CMA) is a common disease of infancy and childhood. An appropriate cow's milk (CM) substitute is necessary for feeding babies with CMA. CM substitutes are soy formulas and casein- or whey-based extensively hydrolyzed formulas. In several countries, including Italy, goat's milk (GM) formulas are available, and some physicians recommend them for feeding babies with CMA. OBJECTIVE: We sought to investigate, in vitro and in vivo, the allergenicity of GM in 26 children with proven IgE-mediated CMA. METHODS: All the children underwent skin tests with CM and GM; detection of specific serum IgE to CM and GM; and double-blind, placebo-controlled, oral food challenges (DBPCOFCs) with fresh CM, GM, and, as placebo, a soy formula (Isomil, Abbott, Italy). CAP inhibition and immunoblotting inhibition assays were also carried out in 1 of 26 and 4 of 26 children with positive RAST results to both CM and GM, respectively. RESULTS: All the children had positive skin test responses and CAP results to both CM and GM, all had positive DBPCOFC results to CM, and 24 of 26 had positive DBPCOFCs to GM. In CAP inhibition tests, preincubation of serum with CM or GM strongly inhibited IgE either to CM or to GM. In immunoblotting inhibition assays, preincubation with CM completely extinguished reactivity to GM, whereas GM partially inhibited reactivity to CM. CONCLUSIONS: These data strongly indicate that GM is not an appropriate CM substitute for children with IgE-mediated CMA. A warning on the lack of safety of GM for children with CMA should be on the label of GM formulas to prevent severe allergic reactions in babies with CMA.     

Alzheimer’s disease

This article reviews the clinical and neuropathological features of Alzheimer’s disease, its known genetic and non-genetic risk factors, procedures used to make the diagnosis and rule out other reversible and non-reversible forms of dementia, and the treatment strategies used to help patients and their families cope with the problem. In addition, it considers how neuroimaging techniques promise to characterize the brain changes which precede the onset of cognitive impairment in persons at risk for Alzheimer’s disease and identify treatments to prevent the onset of dementia.     

Harnessing the potential of dystrophin‐related proteins for ameliorating Duchenne’s muscular dystrophy

Duchenne’s muscular dystrophy (DMD) is a fatal disease caused by mutations in the DMD gene that lead to quantitative and qualitative disturbances in dystrophin expression. Dystrophin is a member of the spectrin superfamily of proteins. Dystrophin itself is closely related to three proteins that constitute a family of dystrophin‐related proteins (DRPs): the chromosome 6‐encoded DRP or utrophin, the chromosome‐X encoded, DRP2 and the chromosome‐18 encoded, dystrobrevin. These proteins share sequence similarity and functional motifs with dystrophin. Current attempts at somatic gene therapy of DMD face numerous technical problems. An alternative strategy for DMD therapy, that circumvents many of these problems, has arisen from the demonstration that the DRP utrophin can functionally substitute for the missing dystrophin and its overexpression can rescue dystrophin‐deficient muscle. Currently, a promising avenue of research consists of identifying molecules that would increase the expression of utrophin and the delivery of these molecules to dystrophin‐deficient tissues as a means of DMD therapy. In this review, we will focus on DRPs from the perspective of strategies and issues related to upregulating utrophin expression for DMD therapy. Additionally, we will address the techniques used for anatomical, biochemical and physiological evaluation of the potential benefits of this and other forms of DMD therapy in dystrophin‐deficient animal models.     

ECT for Parkinson’s disease

Parkinson’s disease (PD) is a chronic, progressive, degenerative disorder that affects over five million people worldwide. Pharmacotherapy with dopamine enhancing medications is the mainstay of treatment. Neurosurgical techniques, ranging from pallidotomy to deep brain stimulation (DBS) are used in refractory patients. Another treatment, electroconvulsive therapy (ECT), has repeatedly been shown to have beneficial effects in PD, but has never gained acceptance as a clinical treatment option. We review the literature on the use of ECT in PD, pointing out that ECT has beneficial effects on both the core motor symptoms of PD as well as the commonly occurring psychiatric co-morbidities. ECT is hypothesized to act in PD by enhancing dopamine neurotransmission, including increasing sensitivity of dopamine receptors. The beneficial effects of ECT in PD persist for variable periods. Maintenance ECT has been used to increase the length of benefit. The stigma surrounding ECT has likely been responsible for its lack of use in PD. We suggest that ECT has a role in the treatment of PD, both in patients with PD alone, or PD with co-occurring depression.     

Chemokines and Alzheimer’s disease

In recent years, increasing attention has been focused on chemokines as inflammatory mediators in the CNS. The limited number of studies that have investigated chemokine and chemokine receptor expression in Alzheimer’s disease (AD) brain and in cell culture models seem to support a role for inflammation in AD pathogenesis. Here we provide a review of these studies, but in addition, point out the possible role of chemokines as communication molecules between neurons and microglia. Understanding neuron-microglia interactions is essential for understanding AD pathogenesis, and disturbances in chemokine-mediated intercellular communication may contribute toward a generalized impairment of microglial cell function.     

全光纤OCT量化检出早期釉质龋的研究

目的评价全光纤光学相干断层成像（全光纤OCT）检出早期牙釉质人工龋的敏感性。方法在新鲜拔除的7颗离体人恒牙釉质光滑面制备2mm×3mm实验窗．选用pH4．5的化学酸蚀液在开窗区制备0～120h早期脱矿人工龋模型．采用自行研发的口腔全光纤OCT系统检测离体人恒牙早期牙釉质人工龋,以同一牙齿样本的显微数码摄影和偏光显微镜检测作为对照．比较和检验OCT有效检出早期龋变的敏感性和可行性。结果全光纤口腔OCT装置可早期准确检测到脱矿12h以内牙釉质表面组织学水平的微观改变,早于裸眼和临床显微摄影的观察结果：开窗区釉质表面完整度随脱矿作用时间出现递减变化;而釉质脱矿深度随脱矿作用时间而出现递增性变化,不同时段脱矿深度的OCT量化数据与偏光显微镜检出结果相吻合．统计学分析结果表明2者间无显著性差异（P〉0．05）,证实OCT可早期、敏感、精确地检出组织学水平的早期牙釉质人工龋。结论全光纤口腔OCT系统可无创准确检出早期牙釉质表面和表层下人工龋变．获得的龋变深度量化测量数据与偏光显微镜下组织学水平的测量结果高度相关。系统进一步完善后有望作为一种新型光学手段用于口腔临床龋病的早期诊断、量化监控以及干预效果的有效评估。     

Efficacy of bisphosphonates in detection of early enamel caries using NIR fluorescence imaging and inhibition of caries progression

NIR fluorescence imaging using bisphosphonate-Indocyanine green has been indicated for early interproximal caries detection. This study assessed diagnostic accuracy of caries detection by NIR fluorescence imaging with OsteoSense 750^® (OS750) in vitro and ex vivo, and to analyze the therapeutic efficacy of a bisphosphonate (Etidronate) in inhibiting enamel caries progression in vitro.Methods: Four experiments were conducted using extracted human teeth; 1) to calculate the infiltration rate of OS750 into interproximal white spot lesions using fluorescence microscope, 2) to assess diagnostic accuracy of interproximal natural white spot lesions using desktop NIR fluorescence imaging device in vitro setting, 3) to assess diagnostic accuracy of artificially created deeper enamel carious lesion (0.5 mm~1.0 mm) using NIR fluorescence image through the head-mount display in ex vivo setting, 4) to compare the progression on the enamel caries lesions treated by Etidronate, NaF and distilled-water. Diagnostic accuracy was analyzed using sensitivity, specificity and receiver operating curves (ROC). The caries progression was calculated with micro-CT and was statistically analyzed using a two-way ANOVA and the Tukey HDS post-hoc test.Results: 1) The infiltration rate of OS750 was 101.83% ± 8.66 (Min: 90.10%, Max: 133.94%). 2) The average of sensitivity and specificity in vitro setting experiments were 86.7% ± 4.4% and 70% ± 11%, respectively. The average of area under the ROC curves (AUC) was 0.883 ± 0.059 indicating excellent performance. 3) The mean sensitivity and specificity in ex vivo setting was 82.97% ± 15% and 76.78% ± 13.27% respectively. 4) The carious lesion volume treated by Etidronate was significantly smaller at post treatment-1 (p<0.05) and treatment-2 (p<0.01) than the control. There was no significant difference in lesion volume in the Etidronate and NaF group at the time point of post treatment-1.Conclusion: This study suggests that bisphosphonates contribute to both early diagnosis of enamel caries and inhibition of caries progression.     

Hormone replacement therapy and Alzheimer’s disease

There is ample evidence to show the beneficial effect of estrogen on the risk and course of Alzheimer’s disease (AD). Estrogen may play a role in the pathophysiology of AD through improvement of cerebral blood flow, stimulation of the neuron or gliacyte and interaction with genetic factors. Most etiological studies of estrogen replacement therapy and AD have been retrospective studies. In these studies, the history of estrogen use was obtained from an informant, limiting the validity of the findings. Of the three follow-up studies conducted to date, one has failed to show a protective effect. There is some evidence for a synergistic effect between estrogen and the genetic factors involved in AD. However, up until now, studies of estrogen replacement therapy have generally been too small and of low validity. Large scale, long-term population studies may clarify the role of estrogen replacement therapy in the prevention and therapy of AD.     

The molecular etiology of Alzheimer’s disease

Alzheimer’s disease (AD) is a growing global healthcare epidemic. Owing to advances in technology, genome‐scale studies of various layers of molecular information have been undertaken in recent years and robust variation in key loci have now been published and reproduced by others. This mini‐symposium highlights four key areas of current research in the field of molecular biology in AD, including articles focused on large‐scale genomic profiling, epigenetic research, integrative multi‐omic approaches and how these can be appropriately modeled to address reverse causality. This mini‐symposium provides a timely update on research focused on elucidating the molecular etiology of AD to date and highlights new methodological advances that could enable neuroscientists to identify novel therapeutic targets.     

Human herpesvirus‐6 in patients with Crohn’s disease

Sura R, Gavrilov B, Flamand L, Ablashi D, Cartun R, Colombel J‐F, Van Kruiningen HJ. Human herpesvirus‐6 in patients with Crohn’s disease. APMIS 2010; 118: 394–400. Human herpesvirus‐6 (HHV‐6) infections are usually asymptomatic reactivations in immunocompetent persons, but may be severe in immunocompromised individuals. Although primary HHV‐6 infection is mainly associated with roseola infantum, it has also been associated with gastroenteritis, diarrhea, and nausea in children. In this study, we investigated the potential role of HHV‐6 in Crohn’s disease (CD). Evidence of HHV‐6 infection in CD patients and controls was determined by immunohistochemistry (IHC), polymerase chain reaction (PCR), and quantitative real‐time PCR (qPCR). Fifty‐one tissue blocks from 23 CD patients and 20 tissue blocks from 20 controls were examined. Quantitativereal‐time PCR was used to assess HHV‐6 viral loads. IHC, PCR and qPCR indicated the presence of HHV‐6 in both CD patients and controls. Immunohistochemistry of tissues revealed an almost equal frequency and distribution of positive cells; however, non‐specific immunostaining confounded interpretation. HHV‐6 DNA was detected in 52% (12/23) of CD and 55% (11/20) of control patients by PCR and in 69.5% (16/23) of CD cases and 65% (13/20) of controls by qPCR. Mean viral load in intestinal tissues was similar in CD and controls (33.4 and 57.9 copies μg^?1 DNA, respectively). Finding equal evidence of HHV‐6 in patients and controls by multiple methods suggests that this virus is ubiquitous and probably not a cause of CD.     

Sleep’s role in the processing of unwanted memories

The concept of ‘repression’ dates back to Freud, assuming that undesirable memories can become suppressed and that dreams ease repression by permitting these memories to be reinstated. Here, we followed this idea adopting the ‘directed forgetting’ approach of experimental psychology. The voluntary suppression of unwanted memories results in impaired later retrieval. Because sleep is known to benefit consolidation of newly learned materials, including cognitive skills, we hypothesized that memory suppression would be enhanced by sleep, and perhaps particularly by rapid eye movement (REM) sleep, which is associated more often with dream reports. Subjects (n = 42) learned a list of word‐pairs and, subsequently, the first (cue) words of the pairs were presented again; for half these words subjects had to recall respective second words (response pairs) and for the other half they had to keep respective second words out of mind (suppression pairs). Retrieval of both response and suppression pairs was tested after 8 h of sleep or wakefulness (main experiment) or after 3‐h periods of early slow wave sleep (SWS)‐rich or late REM‐rich sleep (supplementary experiment). Response pairs were generally recalled better after sleep than wakefulness (P < 0.05). Recall of suppression pairs was, as expected, worse than of response pairs. Contrary to our hypothesis, memory for suppression pairs was not affected differentially by sleep. In the supplementary experiment, compared to SWS‐rich sleep, REM‐rich sleep even improved recall of suppression pairs (P < 0.05). Thus, sleep does not benefit the forgetting of unwanted memories but, on the contrary, REM sleep might even counteract the voluntary suppression of memories making them more accessible for retrieval.     

自研全光纤光学相干计算机断层摄影术灵敏检测早期牙釉质龋

目的探索新型生物组织高分辨率成像技术——光学相干计算机断层摄影术（OCT）用于龋病早期诊断。方法选用化学酸蚀法在离体人恒牙釉质光滑面制备0、12、24、48、72、96、120h不同时间的早期脱矿人工龋模型,采用自行研发的口腔全光纤OCT（AF-OCT）进行离体人恒牙早期牙釉质人工龋的体外检测．并与同一牙齿样本的显微数码摄影、扫描电子显微镜和偏振光显微镜的检测结果进行比较．检验AF—OCT体外检测早期龋变的效能。结果AF—OCT可早期准确检测到脱矿12h以内的牙釉质表面组织学水平的改变．开窗区釉质表面脱矿深度与脱矿时间成正比。与3种常用体内外检测手段相比．AF—OCT可早于显微数码摄影观察到牙釉质表面的形貌改变．与扫描电子显微镜和偏振光显微镜检测结果高度相关。结论自研AF—OCT可早期、精确、无创地检测出脱矿12h以内的早期牙釉质表面人工龋变,并可实现量化测定和分析．获得的龋变深度量化测量数据与偏振光显微镜下组织学测量结果高度相关。     

Comparing virtual with conventional microscopy for the consensus diagnosis of Barrett’s neoplasia in the AspECT Barrett’s chemoprevention trial pathology audit

Sanders D S A, Grabsch H, Harrison R, Bateman A, Going J, Goldin R, Mapstone N, Novelli M, Walker M M & Jankowski J
(2012) Histopathology  61, 795–800 Comparing virtual with conventional microscopy for the consensus diagnosis of Barrett’s neoplasia in the AspECT Barrett’s chemoprevention trial pathology audit Aims: To compare the diagnostic accuracy of conventional versus virtual microscopy for the diagnosis of Barrett’s neoplasia. Methods and results: Sixty‐one biopsies from 35 ASPirin Esomeprazole ChemopreventionTrial (AspECT) trial patients were given a Barrett’s neoplasia score (1–5) by a panel of five pathologists using conventional microscopy. Thirty‐three biopsies positive for neoplasia were digitized and rescored blindly by virtual microscopy. Diagnostic reliability was compared between conventional and virtual microscopy using Fleiss’ kappa. There was substantial reliability of diagnostic agreement (κ = 0.712) scoring the 61 biopsies and moderate agreement scoring the subgroup of 33 ‘positive’ biopsies with both conventional microscopy (κ = 0.598) and virtual microscopy (κ = 0.436). Inter‐observer diagnostic agreement between two pathologists by virtual microscopy was substantial (κ = 0.76). Comparison of panel consensus neoplasia scores between conventional and virtual microscopy was almost perfect (κ = 0.8769). However, with virtual microscopy there was lowering of the consensus neoplasia score in nine biopsies. Conclusions: Diagnostic agreement with virtual microscopy compares favourably with conventional microscopy in what is recognized to be a challenging area of diagnostic practice. However, this study highlights possible limitations for this method in the primary diagnostic setting.