Induction of specific brain oscillations may restore neural circuits and be used for the treatment of Alzheimer's disease.

Brain oscillations underlie the function of our brains, dictating how we both think and react to the world around us. The synchronous activity of neurons generates these rhythms, which allow different parts of the brain to communicate and orchestrate responses to internal and external stimuli. Perturbations of cognitive rhythms and the underlying oscillator neurons that synchronize different parts of the brain contribute to the pathophysiology of diseases including Alzheimer's disease, (AD), Parkinson's disease (PD), epilepsy and other diseases of rhythm that have been studied extensively by Gyorgy Buzsaki. In this review, we discuss how neurologists manipulate brain oscillations with neuromodulation to treat diseases and how this can be leveraged to improve cognition and pathology underlying AD. While multiple modalities of neuromodulation are currently clinically indicated for some disorders, nothing is yet approved for improving memory in AD. Recent investigations into novel methods of neuromodulation show potential for improving cognition in memory disorders. Here, we demonstrate that neuronal stimulation using audiovisual sensory stimulation that generated 40-HZ gamma waves reduced AD-specific pathology and improved performance in behavioural tests in mouse models of AD, making this new mode of neuromodulation a promising new avenue for developing a new therapeutic intervention for the treatment of dementia.

Improving outcomes for teenagers and young adults (TYA) with cancer.

The management of TYA with cancer is characterized by biological features in comparison to children. Therefore specialized treatment units have been established within professional structures of care for this group, and a European multidisciplinary framework for the treatment of TYA with cancer was founded.Objectives are to promote interdisciplinary collaboration and provide strategic concepts to improve patient care centered to the special needs of this age group. Access to clinical trials for all TYA in the EU will be improved and research initiated, examining biology, epidemiology and health services.Special goals of the interprofessional cooperation are:Different measurements are discussed improving outcomes for TYA is proceeding at different speeds in different parts of the world. In some there are established teams, bringing together paediatric and adult specialists from many healthcare professions, reviewing and contributing to the optimal care of all TYA with cancer as part of national health policy.

New advances in the in-vitro culture of Dientamoeba fragilis.

SUMMARYDientamoeba fragilis is an intestinal protozoan in humans that is commonly associated with diarrhoea and other gastrointestinal complaints. Studies conducted to investigate the biology of this parasite are limited by methods for in vitro cultivation. The objective of this study was to improve a biphasic culture medium, based on the Loeffler's slope, by further supplementation in order to increase the yield of trophozoites in culture. The current in vitro culture of D. fragilis is a xenic culture with a mix of bacteria. Three different liquid overlays were evaluated including Earle's balanced salt solution (EBSS), PBS and Dulbecco's modified PBS (DPBS), for their ability to support the in vitro growth of D. fragilis trophozoites. Out of these 3 overlays EBSS gave the highest increase in the trophozoite numbers. The effect of supplementation was analysed by supplementing EBSS with ascorbic acid, ferric ammonium citrate, L-cysteine, cholesterol and alpha-lipoic acid and quantification of in vitro growth by cell counts. A new liquid overlay is here described based upon EBSS supplemented with cholesterol and ferric ammonium citrate that, in conjunction with the Loeffler's slope, supports the growth of D. fragilis trophozoites in vitro. This modified overlay supported a 2-fold increase in the numbers of trophozoite in culture from all 4 D. fragilis isolates tested, when compared to a PBS overlay. These advances enable the harvest of a larger number of trophozoites needed for further studies on this parasite.

Rhizopus microsporus var. rhizopodiformis sinus-orbital zygomycosis in an immunosuppressed patient: successful treatment with posaconazole after a complicated clinical course.

A case of sinus-orbital Rhizopus microsporus var. rhizopodiformis infection in a patient with graft versus host disease following allogeneic blood stem cell transplantation is reported. Commercially available pea straw compost used for gardening was suspected to be the source of the infection. After an initial relapse, treatment with surgical debridement, liposomal amphotericin B and posaconazole was successful.

Fungal pathogen protection in potato by expression of a plant defensin peptide.

Defensins are small cysteine-rich peptides with antimicrobial activity. We demonstrate that the alfalfa antifungal peptide (alfAFP) defensin isolated from seeds of Medicago sativa displays strong activity against the agronomically important fungal pathogen Verticillium dahliae. Expression of the alfAFP peptide in transgenic potato plants provides robust resistance in the greenhouse. Importantly, this resistance is maintained under field conditions. There have been no previous demonstrations of a single transgene imparting a disease resistance phenotype that is at least equivalent to those achieved through current practices using fumigants.

Hedgehog family member is expressed throughout regenerating and developing limbs.

Members of the hedgehog family have been shown to play a key role in many developmental processes, including limb patterning and chondrogenesis. We have therefore investigated whether members of this family are also expressed during regeneration of the adult urodele limb and are regulated by retinoic acid (RA), since this derivative induces proximodistal duplications in regenerating limbs, and has been shown to regulate sonic hedgehog (shh) in the developing limbs of birds and mammals. We report here that a newt homologue of Xenopus banded hedgehog, called N-bhh, is uniformly expressed by mesenchymal blastemal cells from the initial stages of regeneration and is up-regulated by RA. In addition, we show that N-bhh is uniformly expressed in the early limb bud of the newt embryo. Since bhh has not been detected in developing limbs of higher vertebrates, its expression in developing and regenerating newt limbs may be related to the regenerative capability of urodeles.

Contrast-enhanced MR imaging of the liver.

Postcontrast images with a 0.1 mmol/kg dose of a gadolinium chelate with extracellular distribution, when acquired dynamically during breath holding, can improve both differential diagnosis and lesion recognition in liver MR imaging. Initial results at 0.3 mmol/kg, compared with 0.1 mmol/kg, suggest a substantial improvement in lesion identification at the high dose, as assessed by using signal intensity difference divided by noise. Of the gadolinium chelates with predominantly renal excretion, only gadoteridol is presently approved in the United States at the high dose, with limited clinical evaluation for liver imaging performed to date. For linear chelates, such as gadopentetate dimeglumine and gadodiamide injection, the degree to which release of free gadolinium ion occurs is a possible issue because of lower in vivo stability (42,43). Preliminary results with hepatobiliary gadolinium chelates and iron particulate agents are favorable with regard to efficacy, although these agents remain in clinical trials.

Preclinical evaluation of MnDPDP: new paramagnetic hepatobiliary contrast agent for MR imaging.

Manganese(II)-N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis (phosphate) (MnDPDP) is a paramagnetic complex designed for use as a hepatobiliary agent. The T1 relaxivity of MnDPDP (2.8 [mmol/L]-1.sec-1 in aqueous solution) was similar to that of gadolinium diethylenetriaminepentaacetic acid (DTPA) (4.5 [mmol/L]-1.sec-1) and gadolinium tetraazocyclodecanetetraacetic acid (DOTA) (3.8 [mmol/L]-1.sec-1). However, in liver tissue the T1 relaxivity of MnDPDP (21.7 [mmol/L]-1.sec-1) was threefold higher than that reported for Gd-DOTA (6.7 [mmol/L]-1.sec-1). Maximum liver T1 relaxation enhancement occurred 30 minutes after injection of MnDPDP, at which time 54MnDPDP biodistribution studies indicated that 13% of total body activity was in the liver. Enhanced (MnDPDP, 50 mumol/kg) MR images showed a fivefold increase in tumor-liver contrast-to-noise ratio over baseline unenhanced images. Results of the authors' acute and subchronic toxicity studies suggest that MnDPDP will be safe at the doses necessary for clinical imaging; at 10 mumol/kg, the safety factor (LD50/effective dose) for MnDPDP is 540, significantly greater than the safety factor of Gd-DTPA (ie, 60-100).

Localization of P-31 MR signal with use of superparamagnetic iron oxide particles.

Volume localization of magnetic resonance signals was achieved by using the regional susceptibility differences produced by superparamagnetic iron oxide particles. In vitro experiments demonstrated a direct linear relationship between the concentration of particulate iron and phosphorus-31 chemical shift or line broadening. In vivo experiments indicated that an intravenous dose of 5-10 mg of iron per kilogram of body weight suppressed P-31 signal from normal liver in healthy rats. In rats with hepatic implants of mammary adenocarcinoma, superparamagnetic iron oxide particles suppressed detectable P-31 or hydrogen-1 signal arising from healthy liver tissue, but not that from tumor. Signal due to surface tissues, which affect surface-coil spectra, could be selectively suppressed with a film-based application of particles to the abdominal wall. Thus, P-31 spectra from simulated or actual lesions could be selectively detected after chemically suppressing signals from neighboring or surrounding tissue.

Ferrite particles for bowel contrast in MR imaging: design issues and feasibility studies.

Diverse materials with varying physical and magnetic properties have been evaluated as gastrointestinal contrast agents for magnetic resonance (MR) imaging. Uniform marking of the small bowel remains the greatest challenge. Ferrites are magnetically active iron oxide particles that are miscible with water and cause loss of signal on MR images. The decrease in MR signal intensity produced by ferrites occurs with a wide range of iron concentrations (0.1-10 mM) and with both T1- and T2-weighted pulse sequences. These effects of ferrites are explained by predominant T2 shortening with negligible T1 effects. The ferrite preparation used in this study was stable in vitro, with little iron solubilized by acid. Intragastric administration of ferrite (5 mg of iron per kg in 6 ml) routinely marked the small bowel of rats. The authors conclude that ferrites represent a promising new class of contrast agents for gastrointestinal MR imaging.

Value of high resolution real-time ultrasonography in secondary hyperparathyroidism.

Thirty-two patients were treated surgically for symptomatic secondary or tertiary hyperparathyroidism, and 27 of these patients had high resolution (10 mHz) real-time ultrasonography before parathyroidectomy. This preoperative localization study identified one or more enlarged hyperplastic parathyroid glands in all but one patient who had not had a previous parathyroid operation, and in five of six patients who did have previous parathyroid operations. In both of the patients in whom no parathyroid glands were identified by ultrasonography the only abnormal enlarged parathyroid glands were those situated within the superior mediastinum. When large glands are not observed by ultrasonography in patients with severe secondary hyperparathyroidism, the glands are usually situated in the superior mediastinum, behind the trachea or esophagus, or deeply within the neck. The size of the parathyroid glands correlated positively with the serum parathyroid hormone level and with the severity of the secondary hyperparathyroidism. Thus, the preoperative identification of parathyroid glands by ultrasonography not only localizes the site of most hyperplastic parathyroid glands (70 percent of patients), but also detects those patients who have enlarged parathyroid glands, elevated serum parathyroid hormone levels, and severe secondary hyperparathyroidism. These are the patients who are thus unlikely to respond to further medical therapy.

A note on the ADP-ribose-protein linkages in rat-liver nuclei: a possible approach to assessing megavitamin therapy with niacin.

Nuclei isolated from rat liver were incubated with NAD whose two ribose moieties were respectively labeled with 3H or 14C. By enzymatic (phosphodiesterase) and/or chemical (hydroxylamine) attack on doubly labeled ADP-ribosylated nuclear residues, AMP was found after hydroxylaminolysis as well as iso-ADP-ribose after phosphodiesterase plus hydroxylamine, in the absence of detectable amounts of ribose-5-phosphate. This is taken to indicate the existence of additional ribose-protein binding sites in in vitro ADP-ribosylated nuclear proteins: Besides C-1" (Hayaishi et al., Stocken et al.) C-2' and/or C-3' (purine-near) as well as C-2" and/or C-3" (pyrimidine-near), not only at the end but also within the chain of oligo-ADPR.