Neuroprotective and symptomatological action of memantine relevant for alzheimer’s disease — a unified glutamatergic hypothesis on the mechanism of action

The involvement of glutamate mediated neurotoxicity in the pathogenesis of Alzheimer's disease is finding increasingly more acceptance in the scientific community. Central to this hypothesis is the assumption that in particular glutamate receptors of the N-methyl-D-aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner. Such continuous mild activation leads under chronic conditions to neuronal damage. Moreover, one should consider that impairment of plasticity (learning) may result not only from neuronal damage per se but also from continuous activation of NMDA receptors. To investigate this possibility we tested whether overactivation of NMDA receptors using either non-toxic doses/concentrations of a direct NMDA agonist or through an indirect approach--decrease in magnesium concentration--produces deficits in plasticity. In fact NMDA both in vivo (passive avoidance test) and in vitro (LTP in CA1 region) impaired learning and synaptic plasticity. Under these conditions memantine which is an uncompetitive NMDA receptor antagonist with features of "improved magnesium" (voltage dependence, affinity) attenuated the deficit. The more direct proof that memantine can act as a surrogate for magnesium was obtained in LTP experiments under low magnesium conditions. In this case as well, impaired LTP was restored in the presence of therapeutically relevant concentrations of memantine (1 microM). In vivo, doses leading to similar brain/serum levels produce neuroprotection in animal models relevant for neurodegeneration in Alzheimer's disease such as neurotoxicity produced by inflammation in the NBM or beta-amyloid injection to the hippocampus. Hence, we postulate that if in Alzheimer's disease overactivation of NMDA receptors occurs indeed, memantine would be expected to improve both symptoms (cognition) and slow down disease progression because it takes over the physiological function of magnesium.     

Treatment of human tumor xenografts with monoclonal antibody 806 in combination with a prototypical epidermal growth factor receptor-specific antibody generates enhanced antitumor activity.

Monoclonal antibody (mAb) 806 is a novel epidermal growth factor receptor (EGFR) antibody with significant antitumor activity that recognizes a mutant EGFR commonly expressed in glioma known as delta2-7 EGFR (de2-7 EGFR or EGFRvIII) and a subset of the wild-type (wt) EGFR found in cells that overexpress the receptor. We have used two human xenograft mouse models to examine the efficacy of mAb 806 in combination with mAb 528, a prototypical anti-EGFR antibody with similar specificity to cetuximab. Treatment of nude mice, bearing s.c. or i.c. tumor human xenografts expressing the wt or de2-7 EGFR, with mAbs 806 and 528 in combination resulted in additive and in some cases synergistic, antitumor activity. Interestingly, mAb 528 was also effective against xenografts expressing the ligand independent de2-7 EGFR when used as a single agent, showing that its antitumor activity is not merely mediated through inhibition of ligand binding. When used as single agents, neither mAbs 806 or 528 induced down-regulation of the de2-7 EGFR either in vitro or in vivo. In contrast, the combination of antibodies produced a rapid and dramatic decrease in the total cell surface de2-7 EGFR both in vitro and in xenografts. Consistent with this decrease in total cell surface de2-7 EGFR, we observed up-regulation of the cell cycle inhibitor p27(KIP1) and a decrease in tumor cell proliferation as measured by Ki-67 immunostaining when the antibodies were used in combination in vivo. Thus, mAb 806 can synergize with other EGFR-specific antibodies thereby providing a rationale for its translation into the clinic.     

Radionuclide imaging in patients with amputations of the lower leg: typical imaging patterns in five cases

Amputation of the lower leg is not uncommon in elderly patients with chronic infections or vascular problems of the leg and foot, and most often it is performed below the knee or on the distal part of the lower leg (i.e., Syme's amputation). After operation, healing disorders with or without infection can occur, and usually structural imaging methods are performed for diagnosis. Radionuclide imaging using a combination of bone scans and infection scintigraphy can help to identify bone and soft tissue infection. Interpreting radionuclide scans is difficult, because imaging findings after amputation may depend not only on the level of resection and the disease investigated but also on the time that has elapsed since surgery. Typical imaging patterns of bone or infection scintigraphy of five patients are described     

Impact of Food Intake on Liver Stiffness Determined by 2-D Shear Wave Elastography: Prospective Interventional Study in 100 Healthy Patients

The aim was to evaluate the influence of food intake on liver stiffness measurement (LSM), performed with 2-D shear wave elastography (Logiq E9, GE Medical Systems, Wauwatosa, WI, USA). One hundred healthy volunteers were prospectively enrolled. Mean age was 25.8 (19–55) y, and mean body mass index was 22.43 (17.3–30.8) kg/m². Patients fasted for at least 3 h and subsequently ingested a liquid meal of 800 kcal. Liver stiffness and portal vein velocity were measured before and after food intake. Food intake resulted in significantly higher LSM values compared with baseline LSM (5.74 ± 0.94 kPa vs. 4.80 ± 0.94 kPa, p < 0.001). On multiple linear regression analysis, body mass index was significantly positively correlated with the LSM increase after food intake (p?=?0.01). No correlation between the increase in LSM and the increase in post-prandial portal vein velocity was observed (r?=?0.09). In summary, food intake has a significant influence on LSM. There is an 11% risk of misclassifying non-fasting, healthy patients as having significant fibrosis.     

Influenza and pneumococcal vaccination in patients with rheumatoid arthritis in comparison with age- and sex-matched controls: results of a claims data analysis

The aim of this study was to assess the vaccination status for influenza and pneumonia and the prevalence of hospitalised pneumonia in rheumatoid arthritis (RA) patients and population controls in Germany. Members of a large statutory health insurance fund in Germany who were continuously insured between 2009 and 2013 and had a diagnosis of RA in 2013 were age and sex matched 1:5 to members without RA. Pneumococcal and influenza vaccinations were evaluated with regard to age, sex and region of residence. Logistic regression models were used to determine predictors for influenza vaccination in RA patients. Prevalences of pneumonia that required hospitalisation were compared to regional vaccination rates. The data of 111,482 RA patients and 557,410 matched controls were available for analysis. Compared to controls, RA patients were vaccinated more frequently against influenza (40.8 vs. 32.2 %) and pneumonia (15.0 vs. 10.0 %). Vaccination rates increased with older age and differed between the federal states (highest in East Germany, lowest in South Germany). The region of residence, comorbidities, rheumatologic care and biologic treatment was associated with a higher probability of an influenza vaccination. Prevalences of pneumonia that required hospitalisation were 2–3 times higher in patients compared to controls and tended to be higher in regions with low vaccination rates. The increased pneumonia prevalence in RA patients confirms their status as a risk group. RA patients are vaccinated more frequently than controls, but vaccination rates are still low. The lower pneumonia prevalence in East Germany indicates that vaccination may help to reduce pneumonia in RA.