Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders.

Excitation/inhibition (E/I) balance plays important roles in mental disorders. Bioactive phospholipids like lysophosphatidic acid (LPA) are synthesized by the enzyme autotaxin (ATX) at cortical synapses and modulate glutamatergic transmission, and eventually alter E/I balance of cortical networks. Here, we analyzed functional consequences of altered E/I balance in 25 human subjects induced by genetic disruption of the synaptic lipid signaling modifier PRG-1, which were compared to 25 age and sex matched control subjects. Furthermore, we tested therapeutic options targeting ATX in a related mouse line. Using EEG combined with TMS in an instructed fear paradigm, neuropsychological analysis and an fMRI based episodic memory task, we found intermediate phenotypes of mental disorders in human carriers of a loss-of-function single nucleotide polymorphism of PRG-1 (PRG-1R345T/WT). Prg-1R346T/WT animals phenocopied human carriers showing increased anxiety, a depressive phenotype and lower stress resilience. Network analysis revealed that coherence and phase-amplitude coupling were altered by PRG-1 deficiency in memory related circuits in humans and mice alike. Brain oscillation phenotypes were restored by inhibtion of ATX in Prg-1 deficient mice indicating an interventional potential for mental disorders.

Temporal and Spatial Gene Expression Profile of Stroke Recovery Genes in Mice.

Stroke patients show some degree of spontaneous functional recovery, but this is not sufficient to prevent long-term disability. One promising approach is to characterize the dynamics of stroke recovery genes in the lesion and distant areas. We induced sensorimotor cortex lesions in adult C57BL/6J mice using photothrombosis and performed qPCR on selected brain areas at 14, 28, and 56 days post-stroke (P14-56). Based on the grid walk and rotating beam test, the mice were classified into two groups. The expression of cAMP pathway genes Adora2a, Pde10a, and Drd2, was higher in poor- compared to well-recovered mice in contralesional primary motor cortex (cl-MOp) at P14&56 and cl-thalamus (cl-TH), but lower in cl-striatum (cl-Str) at P14 and cl-primary somatosensory cortex (cl-SSp) at P28. Plasticity and axonal sprouting genes, Lingo1 and BDNF, were decreased in cl-MOp at P14 and cl-Str at P28 and increased in cl-SSp at P28 and cl-Str at P14, respectively. In the cl-TH, Lingo1 was increased, and BDNF decreased at P14. Atrx, also involved in axonal sprouting, was only increased in poor-recovered mice in cl-MOp at P28. The results underline the gene expression dynamics and spatial variability and challenge existing theories of restricted neural plasticity.

Permeability of porous materials determined from the Euler characteristic.

We study the permeability of quasi-two-dimensional porous structures of randomly placed overlapping monodisperse circular and elliptical grains. Measurements in microfluidic devices and lattice Boltzmann simulations demonstrate that the permeability is determined by the Euler characteristic of the conducting phase. We obtain an expression for the permeability that is independent of the percolation threshold and shows agreement with experimental and simulated data over a wide range of porosities. Our approach suggests that the permeability explicitly depends on the overlapping probability of grains rather than their shape.

Approach to treatment of dyspepsia in primary care: a randomized trial comparing "test-and-treat" with prompt endoscopy.

BACKGROUND: The value of the "test-and-treat" strategy in the approach to dyspepsia has been evaluated only in a few secondary care studies. Most patients with dyspepsia, however, are treated by their primary care physician. This study evaluated the test-and-treat strategy in primary care. METHODS: Patients consulting their general practitioners for dyspepsia were randomized to either direct open-access endoscopy with Helicobacter pylori testing or a test-and-treat strategy by H pylori serology. In the 12-month follow-up period, any additional treatment or referral for investigations was left at the discretion of the general practitioner. At the end of the study, data were collected concerning the number of endoscopies, changes in symptom severity and quality of life, patient satisfaction, and the use of medical resources. RESULTS: Two hundred seventy patients were enrolled (129 who received endoscopy and 141 in the test-and-treat group). The prevalence of H pylori infection was 38.3% and 37.2% in the test-and-treat and endoscopy groups, respectively. In the test-and-treat group, 46 patients (33%) were referred for endoscopy during follow-up. Improvement in symptom severity, quality of life, and patient satisfaction was comparable in both groups. Patients in the test-and-treat group paid more dyspepsia-related visits to their general practitioner (P =.005). Patients in the endoscopy group were more often prescribed proton pump inhibitors (P =.007), whereas patients in the test-and-treat group were more often prescribed prokinetic drugs (P =.005). CONCLUSIONS: The test-and-treat strategy proved to be as effective and safe as prompt endoscopy. Only a minority of patients were referred for endoscopy after the test-and-treat approach.

High-grade dysplasia in sporadic fundic gland polyps: a case report and review of the literature.

We present a case of fundic gland polyps (FGPs) containing high-grade dysplasia in a 68-year-old man. High-grade dysplasia, and even gastric adenocarcinoma, associated with FGPs have been described in patients with familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP) but never in non-FAP patients. Two colonoscopies in the past six years virtually rule out FAP and AFAP in our patient. Dysplasia in FGPs from non-FAP patients is extremely rare, and until now only cases of low-grade dysplasia have been described. The literature on dysplasia in FGPs is reviewed briefly. Additional immunohistochemical investigations in this case showed nuclear staining of beta-catenin, increased proliferation and apoptosis in the dysplastic areas of the FGPs. Our case suggests that the malignant potential of FGPs is not limited to FAP-associated FGPs.