A network-based cognitive training induces cognitive improvements and neuroplastic changes in patients with relapsing-remitting multiple sclerosis: an exploratory case-control study

Cognitive impairments are commonly observed in patients with multiple sclerosis and are associated with lower levels of quality of life. No consensus has been reached on how to tackle effectively cognitive decline in this clinical population non-pharmacologically. This exploratory case-control study aims to investigate the effectiveness of a hypothesis-based cognitive training designed to target multiple domains by promoting the synchronous co-activation of different brain areas and thereby improve cognition and induce changes in functional connectivity in patients with relapsing-remitting multiple sclerosis. Forty-five patients(36 females and 9 males, mean age 44.62 ± 8.80 years) with clinically stable relapsing-remitting multiple sclerosis were assigned to either a standard cognitive training or to control groups(sham training and nonactive control). The standard training included twenty sessions of computerized exercises involving various cognitive functions supported by distinct brain networks. The sham training was a modified version of the standard training that comprised the same exercises and number of sessions but with increased processing speed load. The non-active control group received no cognitive training. All patients underwent comprehensive neuropsychological and magnetic resonance imaging assessments at baseline and after 5 weeks. Cognitive and resting-state magnetic resonance imaging data were analyzed using repeated measures models. At reassessment, the standard training group showed significant cognitive improvements compared to both control groups in memory tasks not specifically targeted by the training: the Buschke Selective Reminding Test and the Semantic Fluency test. The standard training group showed reductions in functional connectivity of the salience network, in the anterior cingulate cortex, associated with improvements on the Buschke Selective Reminding Test. No changes were observed in the sham training group. These findings suggest that multi-domain training that stimulates multiple brain areas synchronously may improve cognition in people with relapsing-remitting multiple sclerosis if sufficient time to process training material is allowed. The associated reduction in functional connectivity of the salience network suggests that training-induced neuroplastic functional reorganization may be the mechanism supporting performance gains. This study was approved by the Regional Ethics Committee of Yorkshire and Humber(approval No. 12/YH/0474) on November 20, 2013.     

Blood glucose response after oral lactulose intake in type 2 diabetic individuals

BACKGROUNDLactulose is approved for the symptomatic treatment of constipation, a gastrointestinal (GI) complication common in individuals with diabetes. Lactulose products contain carbohydrate impurities (e.g., lactose, fructose, galactose), which occur during the lactulose manufacturing process. These impurities may affect the blood glucose levels of individuals with type 2 diabetes mellitus (T2DM) using lactulose for the treatment of mild constipation. A previous study in healthy subjects revealed no increase in blood glucose levels after oral lactulose intake. However, it is still unclear whether the intake of lactulose increases blood glucose levels in individuals with diabetes.AIMTo evaluate the blood glucose profile after oral lactulose intake in mildly constipated, non-insulin-dependent subjects with T2DM in an outpatient setting.METHODSThis prospective, double-blind, randomized, controlled, single-center trial was conducted at the Clinical Research Center at the Medical University of Graz, Austria, in 24 adult Caucasian mildly constipated, non-insulin-dependent subjects with T2DM. Eligible subjects were randomized and assigned to one of six treatment sequences, each consisting of four treatments stratified by sex using an incomplete block design. Subjects received a single dose of 20 g or 30 g lactulose (crystal and liquid formulation), water as negative control or 30 g glucose as positive control. Capillary blood glucose concentrations were measured over a period of 180 min post dose. The primary endpoint was the baseline-corrected area under the curve of blood glucose concentrations over the complete assessment period [AUC_{baseline_c (0-180 min)}]. Quantitative comparisons were performed for both lactulose doses and formulations vs water for the equal lactulose dose vs glucose, as well as for liquid lactulose vs crystal lactulose. Safety parameters included GI tolerability, which was assessed at 180 min and 24 h post dose, and adverse events occurring up to 24 h post dose.RESULTSIn 24 randomized and analyzed subjects blood glucose concentration-time curves after intake of 20 g and 30 g lactulose were almost identical to those after water intake for both lactulose formulations despite the different amounts of carbohydrate impurities (≤ 3.0% for crystals and approx. 30% for liquid). The primary endpoint [AUC_{baseline_c (0-180 min)}] was not significantly different between lactulose and water regardless of lactulose dose and formulation. Also with regard to all secondary endpoints lactulose formulations showed comparable results to water with one exception concerning maximum glucose level. A minor increase in maximum blood glucose was observed after the 30 g dose, liquid lactulose, in comparison to water with a mean treatment difference of 0.63 mmol/L (95% confidence intervals: 0.19, 1.07). Intake of 30 g glucose significantly increased all blood glucose endpoints vs 30 g liquid and crystal lactulose, respectively (all P < 0.0001). No differences in blood glucose response were observed between the different lactulose formulations. As expected, lactulose increased the number of bowel movements and was generally well tolerated. Subjects experienced only mild to moderate GI symptoms due to the laxative action of lactulose.CONCLUSIONBlood glucose AUC_{baseline_c (0-180 min)} levels in mildly constipated, non-insulin dependent subjects with T2DM are not affected by the carbohydrate impurities contained in 20 g and 30 g crystal or liquid lactulose formulations.     

Physostigmine Restores Impaired Autophagy in the Rat Hippocampus after Surgery Stress and LPS Treatment

Tissue damage and pathogen invasion during surgical trauma have been identified as contributing factors leading to neuroinflammation in the hippocampus, which can be protected by stimulation of the cholinergic anti-inflammatory pathway using the acetylcholinesterase inhibitor physostigmine. Macroautophagy, an intracellular degradation pathway used to recycle and eliminate damaged proteins and organelles by lysosomal digestion, seems to be important for cell survival under stress conditions. This study aimed to examine the role of autophagy in physostigmine-mediated hippocampal cell protection in a rat model of surgery stress. In the presence or absence of physostigmine, adult Wistar rats underwent surgery in combination with lipopolysaccharide (LPS). Activated microglia, apoptosis-, autophagy-, and anti-inflammatory-related genes and -proteins in the hippocampus were determined by Real-Time PCR, Western blot and fluorescence microscopy after 1 h, 24 h and 3 d. Surgery combined with LPS-treatment led to microglia activation after 1 h and 24 h which was accompanied by apoptotic cell death after 24 h in the hippocampus. Furthermore, it led to a decreased expression of ATG-3 after 24 h and an increased expression of p62/ SQSTM1 after 1 h and 24 h. Administration of physostigmine significantly increased autophagy related markers and restored the autophagic flux after surgery stress, detected by increased degradation of p62/ SQSTM1 in the hippocampus after 1 h and 24 h. Furthermore, physostigmine reduced activated microglia and apoptosis relevant proteins and elevated the increased expression of TGF-beta1 and MFG-E8 after surgery stress. In conclusion, activation of autophagy may be essential in physostigmine-induced neuroprotection against surgery stress.     

Epidemiologic study of idiopathic enamel hypomineralization in permanent teeth of Swedish children

In the late seventies an increasing number of children showing extensive and severe idiopathic hypomineralization of the enamel of incisors and permanent first molars was reported within the Public Dental Services in Sweden. An epidemiologic study was initiated to analyze the prevalence, extension and severity in Swedish children born in 1970 and in the years before and after. 2252 children born in 1966-74 were examined according to well defined criteria on enamel hypomineralization. It was found that 15.4% of the children born in 1970 showed such changes. The corresponding figures for children born in 1966, 1969, 1971, 1972 and 1974 were 6.3, 7.3, 7.1, 5.2 and 4.4, respectively.     

Leishmania disease development depends on the presence of apoptotic promastigotes in the virulent inoculum

The obligate intracellular pathogen Leishmania major survives and multiplies in professional phagocytes. The evasion strategy to circumvent killing by host phagocytes and establish a productive infection is poorly understood. Here we report that the virulent inoculum of Leishmania promastigotes contains a high ratio of annexin A5-binding apoptotic parasites. This subpopulation of parasites is characterized by a round body shape, a swollen kinetoplast, nuclear condensation, and a lack of multiplication and represents dying or already dead parasites. After depleting the apoptotic parasites from a virulent population, Leishmania do not survive in phagocytes in vitro and lose their disease-inducing ability in vivo. TGF-beta induced by apoptotic parasites is likely to mediate the silencing of phagocytes and lead to survival of infectious Leishmania populations. The data demonstrate that apoptotic promastigotes, in an altruistic way, enable the intracellular survival of the viable parasites.     

Direct ratings of acceptance of dental treatment in Swedish children

The aim of the present study was to bring forward data of acceptance of dental treatment for 3-16-yr-old children in a population with good dental health and annual dental care, and to evaluate the influence on acceptance of age, sex, residential area, and previous experience and present need of dental treatment. The material consisted of 2773 children. Direct ratings of behavior were made at each of 10 different treatment steps passed during dental appointments. The majority of children needed no more than one dental visit and 79% showed positive acceptance at all steps of treatment passed during dental visits. Eight percent of all children sometimes reacted in such a way that treatment could not be carried out without restraint or undue delay. Dental fear was diagnosed in 3% of all children.     

Changes in caries experience among 6-year-olds in Blekinge, Sweden between 1994 and 2000

For 6-year-old children in the County of Blekinge, the goal was that > 65 percent should have dmft = 0 in the year 2000. To formulate this goal a study on prevalence and distribution of caries in 6-year-old children was performed in 1994. The aim of the present study was to evaluate whether the dental health goal for the year 2000 was achieved and compare clinical data regarding oral status in children in 1994 and in 2000. The material comprised a random sample of 225 children.The studyfrom year 1994, which included 213 children, was repeated. A clinical investigation was performed and completed with bite-wing radiographs on individual indication, whenever the proximal surfaces could not be inspected clinically due to close and broad contact. In addition, the parents were asked questions about toothbrushing and use of fluoride tablets. 53 percent of the children showed healthy teeth with no initial caries lesions or restorations compared to 35 percent in 1994. The pattern of dental health was still very skewed among the children.The children with nine or more decayed surfaces increased from 2 percent in 1994 to almost 4 percent in 2000. The number of fissure sealings performed had increased between 1994 and 2000 by almost 50 percent in both primary molars and first permanent molars. However,the use of fluoride tablets had decreased from 20 percent in 1994 to 7 percent of the children in 2000. The data showed a decline in prevalence of dmf teeth and an increase in the percent of caries-free children but the difference was not significant on the 5% level. However, as 47% of the children were in need of restorative treatment, our dental health goal was not achieved.We also recommend that our preventive program with focus on primary prevention and individual risk assessment should also be targeted at the whole population of pre-school children and their parents.