Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Aβ levels

Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPP_wt) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but β-amyloid peptide (Aβ₄₂) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Aβ₄₂ were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Aβ-independent pathogenic pathways in Alzheimer's disease.     

Alpha 1-antichymotrypsin contributes to stem cell characteristics and enhances tumorigenicity of glioblastoma

BackgroundGlioblastomas (GBMs) are the main primary brain tumors in adults with almost 100% recurrence rate. Patients with lateral ventricle proximal GBMs (LV-GBMs) exhibit worse survival compared to distal locations for unknown reasons. One hypothesis is the proximity of these tumors to the cerebrospinal fluid (CSF) and its chemical cues that can regulate cellular phenotype. We therefore investigated the role of CSF on GBM gene expression and the role of a CSF-induced gene, SERPINA3, in GBM malignancy in vitro and in vivo.MethodsWe utilized human CSF and GBM brain tumor-initiating cells (BTICs). We determined the impact of SERPINA3 expression in glioma patients using The Cancer Genome Atlas (TCGA) database. SERPINA3 expression changes were evaluated at mRNA and protein levels. The effects of knockdown (KD) and overexpression (OE) of SERPINA3 on cell migration, viability and cell proliferation were evaluated. Stem cell characteristics on KD cells were evaluated by differentiation and colony formation experiments. Tumor growth was studied by intracranial and flank injections.ResultsGBM-CSF increased BTIC migration accompanied by upregulation of the SERPINA3 gene. In patient samples and TCGA data, we observed SERPINA3 to correlate directly with brain tumor grade and indirectly with GBM patient survival. SERPINA3 KD induced a decrease in cell proliferation, migration, invasion, and stem cell characteristics, while SERPINA3 OE increased cell migration. In vivo, SERPINA3 KD BTICs showed increased survival in a murine model.Conclusions SERPINA3 plays a key role in GBM malignancy and its inhibition results in a better outcome using GBM preclinical models.     

The Genovese grading scale is not reliable for MR assessment of collagen meniscus implants

Background

The purpose of the study was to evaluate the intra- and inter-observer reliabilities of the Genovese grading on MRI in patients after collagen meniscus substitution.

Migraine and stroke: the role of oral contraceptives

The use of oral contraceptives (OCs) confers an increased risk for ischaemic stroke (IS). This risk slightly decreases, but remains significant, if low-dose formulations are used, particularly if other risk factors, such as hypertension or smoking, are associated. Some inherited prothrombotic conditions (e.g., Factor V Leiden, G20210A prothrombin or methylenetetrahydrofolate reductase C677T polymorphism) could also greatly increase the IS risk if present in OC users. Migraine, particularly with aura, is an independent risk factor for IS, and the patient’s IS risk is probably affected by other individual risk factors (e.g., age, genetic predisposition to thrombosis, presence of patent foramen ovale or enhanced platelet aggregation) which seem to be over-represented in migraine patients. IS risk among migraineurs is further increased when OCs are currently used and can become very high if associated with smoking. Consequently, in 2004 the WHO stated in its ‘Medical Eligibility Criteria for Contraceptive Use’ that women suffering from migraine with aura at any age should never use OCs. Moreover, since the exposure to the effects of OCs may greatly increase the IS risk in some migraine subpopulations with specific personal characteristic, testing for these risk factors may allow for more accurate stratification of the population at risk before long-term use of OCs is prescribed.     

Opposing effects of AMPA and 5-HT1A receptor blockade on passive avoidance and object recognition performance: correlation with AMPA receptor subunit expression in rat hippocampus

It has been suggested that antagonists at serotonin 5-HT1A receptors may exert a procognitive effect by facilitating glutamatergic neurotransmission. Here we further explored this issue by looking for the ability of a 5-HT1A antagonist to prevent the learning deficit induced by AMPA receptor blockade in two behavioural procedures in rats, and for concomitant molecular changes presumably involved in memory formation in the hippocampus. Pretraining administration of the competitive AMPA receptor antagonist, NBQX, produced a dose-related retention impairment in a passive avoidance task 24h later, and also impaired retention in a novel object recognition test when an intertrial interval of 3h was selected. Pretreatment with the selective 5-HT1A receptor antagonist, WAY-100635, prevented the learning deficit induced by NBQX in the two behavioural procedures. In biochemical studies performed on rat hippocampus after the retention tests, we found that learning increased the membrane levels of AMPA receptor GluR1 and GluR2/3 subunits, as well as the phosphorylated forms of GluR1, effects that were abolished by NBQX administration before the training session. Pretreatment with WAY-100635 counteracted the NBQX effects and restored the initial learning-specific increase in Ca2+/calmodulin-dependent protein kinase II (CaMKII) function and the later increase in GluR2/3 and phosphorylated GluR1 surface expression. Moreover, administration of WAY-100635 before object recognition training improved recognition memory 24h later and potentiated the learning-associated increase in AMPA receptor subunits. The results support the proposed utility of 5-HT1A antagonists in the treatment of cognitive disorders.     

Acupuncture versus pharmacological approach to reduce Hyperemesis gravidarum discomfort

AIM: Several reports have suggested the use of acupuncture as a useful treatment for hyperemesis gravidarum (HG), in particular the effects on nausea intensity was underlined. The aim of this study was to compare the efficacy of acupuncture sessions plus acupressure with a metoclopramide/vitamin B12 treatment. METHODS: In this study we randomized 88 pregnant patients suffering from HG to receive either acupuncture sessions plus acupressure (acupuncture group) or metoclopramide infusion (metoclopramide group) supplemented by vitamin B12 complex. Somatic symptoms and the ability to achieve the daily routine activity (functioning) were evaluated. Acupuncture sessions were performed at the hospital twice a week for 2 weeks according to the traditional Chinese medicine criteria. Acupression was applied for 6-8 h/day. In the metoclopramide group, patients received at hospital metoclopramide infusion (20 mg/500 mL saline for 60 min) twice a week for 2 weeks. An oral supplementation with vitamin B12 complex (30 mg/day) was also prescribed. RESULTS: Both treatments reduced vomiting episodes and then nausea intensity with a consequent improvement in the rate of food intake. The effect of acupuncture seems to be progressive, increasing at the end of treatment whereas pharmacological approach has a prompt effect in responders remaining stable thereafter. Moreover, acupuncture was significantly more effective than drugs in improving functioning. CONCLUSIONS: In our study for the first time acupuncture, applied accordingly to Chinese formula, was compared to drugs demonstrating the same effect of both treatments on HG symptoms. Interestingly, functioning was significantly improved just by acupuncture. Even if the effect of acupuncture on HG discomfort remains to be confirmed, the reports on the effect of acupuncture on psychosocial variables could represent a further advantage of acupuncture application and provide an incentive to widen the base of the research.     

Acupressure in the control of migraine-associated nausea

Migraine is a disabling neurological disorder, aggravated by accompanying symptomatology, such as nausea. One of the most interesting approaches to nausea adopted by traditional Chinese medicine is the stimulation of the acupoint PC6 Neiguan. Actually there are no studies in medical literature as to the efficacy of treating PC6 acupoint for gastrointestinal symptoms in migraine attacks. Our study aimed at verifying if pressure applied to the acupoint PC6 was effective on nausea during migraine. Forty female patients suffering from migraine without aura were enrolled, if nausea was always present as accompanying symptomatology of their migraine. The patients were treated randomly for a total of six migraine attacks: three with the application of a device, the Sea-Band(?) wristband, which applies continual pressure to the PC6 acupoint (phase SB), and three without it (phase C). The intensities of nausea at the onset, at 30, 60, 120 and 240 min were evaluated on a scale from 0 to 10. The values were always significantly lower in phase SB than in phase C. Also the number of patients who reported at least a 50 % reduction in the nausea score was significantly higher in phase SB than in phase C at 30, 60 and 120 min. Moreover, the consistency of the treatment (response in at least two out of three treated attacks) was reached in 28 % patients at 60 min; in 40 % at 120 min and 59 % at 240 min. Our results encourage the application of PC6 acupressure for the treatment of migraine-associated nausea.     

Acupuncture in labor management

Acupuncture is being increasingly used in Western medical practice. The various applications of acupuncture during labor are reviewed in this paper. This ancient therapeutic technique can be employed with a significant percentage of positive results to induce labor in post-term pregnancies, to strengthen uterine contractility and to favour cervical maturation. The acupoints LI 4 Hegu e SP 6 Sanyinjiao electrostimulated are those more frequently used in labor induction and in increasing the frequency and duration of uterine contractions. Moreover, our experience indicates that the acupoint BL 67 Zhiyin can be helpful in accelerating the dilation of the cervix: the treatment is effective in about 75% of patients. The studies on the use of acupuncture to achieve pain relief and analgesia during labor show more controversial results, mainly due to the great heterogeneity of applied treatments and some methodological biases. Nevertheless, the general evidence seems to be positive also for this application.