The Effect of the Association between Donepezil and Choline Alphoscerate on Behavioral Disturbances in Alzheimer's Disease: Interim Results of the ASCOMALVA Trial

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are a group of psychological reactions, psychiatric symptoms, and behaviors commonly found in Alzheimer's disease (AD). Four clusters of BPSD have been described: mood disorders (depression, anxiety, and apathy), psychotic symptoms (delusions and hallucinations), aberrant motor behaviors (pacing, wandering, and other purposeless behaviors), and inappropriate behaviors (agitation, disinhibition, and euphoria). Most of them are attributed to acetylcholine deficiency. OBJECTIVE: To evaluate if a higher amount of acetylcholine obtained by associating donepezil and choline alphoscerate might have a favorable effect on BPSD. METHODS: BPSD were measured at baseline and after 24 months in 113 mild/moderate AD patients, included in the double-blind randomized trial ASCOMALVA, by the Neuropsychiatric Inventory (NPI). Two matched groups were compared: group A treated with donepezil (10 mg/day) plus choline alphoscerate (1200 mg/day), and group B treated with donepezil (10 mg/day) plus placebo. RESULTS: Data of NPI revealed a significant decrease of BPSD severity and distress of the caregiver in patients of group A compared with group B. Mood disorders (depression, anxiety and apathy) were significantly decreased in subjects treated with donepezil and choline alphoscerate, while their severity and frequency was increased in the other group. CONCLUSIONS: Patients treated with donepezil plus choline alphoscerate showed a lower level of behavioral disturbances than subjects treated with donepezil only, suggesting that the association can have beneficial effect

Thoracic Unilateral Spinal Cord Injury After Spinal Anaesthesia for Total Hip Replacement: Fate or Mistake?

Spinal anaesthesia is the most preferred anesthesia technique for total hip replacement, and its complications range from low entity (insignificant) to life threatening. The incidence of neurologic complications after neuraxial anaesthesia is not perfectly clear, although there are several described cases of spinal cord ischaemia. We present a case of unilateral T8–T11 spinal cord ischaemia following L2–L3 spinal anaesthesia for total hip replacement. Magnetic resonance imaging showed a hyperintense T8–T11 signal alteration on the leftside of paramedian spinal cord. A temporal epidemiologic linkage between the damage and the surgery seems to be present. The injury occurred without anatomical proximity between the injury site and the spinal needle entry site. This may be due to multiple contributing factors, each of them is probably not enough to determine the damage by itself; however, acting simultaneously, they could have been responsible for the complication. The result was unpredictable and unavoidable and was caused by unforeseeable circumstances and not by inadequate medical practice

Physical and chemical stability of expired fixed dose combination artemether-lumefantrine in uncontrolled tropical conditions

<p>Abstract</p> <p>Background</p> <p>New artemisinin combination therapies pose difficulties of implementation in developing and tropical settings because they have a short shelf-life (two years) relative to the medicines they replace. This limits the reliability and cost of treatment, and the acceptability of this treatment to health care workers. A multi-pronged investigation was made into the chemical and physical stability of fixed dose combination artemether-lumefantrine (FDC-ALU) stored under heterogeneous, uncontrolled African conditions, to probe if a shelf-life extension might be possible.</p> <p>Methods</p> <p>Seventy samples of expired FDC-ALU were collected from private pharmacies and malaria researchers in seven African countries. The samples were subjected to thin-layer chromatography (TLC), disintegration testing, and near infrared Raman spectrometry for ascertainment of active ingredients, tablet integrity, and chemical degradation of the tablet formulation including both active ingredients and excipients.</p> <p>Results</p> <p>Seventy samples of FDC-ALU were tested in July 2008, between one and 58 months post-expiry. 68 of 70 (97%) samples passed TLC, disintegration and Raman spectrometry testing, including eight samples that were post-expiry by 20 months or longer. A weak linear association (R²= 0.33) was observed between the age of samples and their state of degradation relative to brand-identical samples on Raman spectrometry. Sixty-eight samples were retested in February 2009 using Raman spectrometry, between eight and 65 months post-expiry. 66 of 68 (97%) samples passed Raman spectrometry retesting. An unexpected observation about African drug logistics was made in three batches of FDC-ALU, which had been sold into the public sector at concessional pricing in accordance with a World Health Organization (WHO) agreement, and which were illegally diverted to the private sector where they were sold for profit.</p> <p>Conclusion</p> <p>The data indicate that FDC-ALU is chemically and physically stable well beyond its stated shelf-life in uncontrolled, tropical conditions. While these data are not themselves sufficient, it is strongly suggested that a re-evaluation of the two-year shelf-life by drug regulatory authorities is warranted.</p

Energy-Spin Trajectories in AdS_5 x S^5 from Semiclassical Vertex Operators

We study the relation between vertex operators in AdS_5 x S^5 and classical spinning string solutions. In the limit of large quantum numbers the treatment of vertex operators becomes semiclassical. In this regime, a given vertex operator carrying a certain set of quantum numbers defines a singular solution. We show in a number of examples that this solution coincides with the classical string solution with the same quantum numbers but written in a different two-dimensional coordinate system. The marginality condition imposed on an operator yields a relation between the energy and the other quantum numbers which is shown to coincide with that of the corresponding classical string solution. We also argue that in some cases vertex operators in AdS_5 x S^5 cannot be given by expressions similar to the ones in flat space and a more involved consideration is required.Comment: 23 pages, 1 Figur

Proapoptotic activity of new glutathione S-transferase inhibitors

Selected 7-nitro-2,1,3-benzoxadiazole derivatives have been recently found very efficient inhibitors of glutathione S-transferase (GST) PI-1,(5) an enzyme which displays antiapoptotic activity and is also involved in the cellular resistance to anticancer drugs. These new inhibitors are not tripeptide glutathione-peptidomimetic molecules and display lipophylic properties suitable for crossing the plasma membrane. In the present work, we show the strong cytotoxic activity of these compounds in the following four different cell lines: K562 (human myeloid leukemia), HepG2 (human hepatic carcinoma), CCRF-CEM (human T-lymphoblastic leukemia), and GLC-4 (human small cell lung carcinoma). The LC50 values are in the micromolar/submicromolar range and are close to the ICs values obtained with GSTPI-1, suggesting that the target of these molecules inside the cell is indeed this enzyme. The cytotoxic mechanism of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol, the most effective GSTPI-1 inhibitor, has been carefully investigated in leukemic CCRF-CEM and K562 cell lines. Western blot and immunoprecipitation analyzes have shown that 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanoI promotes in both cell lines the dissociation of the GSTPI-1 in a complex with c-jun NH2-terminal kinase (JNK). This process triggers a reactive oxygen species (ROS) -independent activation of the JNK-mediated pathway that results in a typical process of apoptosis. Besides this main pathway, in K562 cells, a ROS-mediated apoptosis partially occurs (about 30%) which involves the p38(MAPK) signal transduction pathway. The low concentration of this new compound needed to trigger cytotoxic effects on tumor cells and the low toxicity on mice indicate that the new 7-nitro-2,1,3-benzoxadiazole derivatives are promising anticancer agents

A gap in the planetesimal disc around HD 107146 and asymmetric warm dust emission revealed by ALMA

While detecting low mass exoplanets at tens of au is beyond current instrumentation, debris discs provide a unique opportunity to study the outer regions of planetary systems. Here we report new ALMA observations of the 80-200 Myr old Solar analogue HD 107146 that reveal the radial structure of its exo-Kuiper belt at wavelengths of 1.1 and 0.86 mm. We find that the planetesimal disc is broad, extending from 40 to 140 au, and it is characterised by a circular gap extending from 60 to 100 au in which the continuum emission drops by about 50%. We also report the non-detection of the CO J=3-2 emission line, confirming that there is not enough gas to affect the dust distribution. To date, HD 107146 is the only gas-poor system showing multiple rings in the distribution of millimeter sized particles. These rings suggest a similar distribution of the planetesimals producing small dust grains that could be explained invoking the presence of one or more perturbing planets. Because the disk appears axisymmetric, such planets should be on circular orbits. By comparing N-body simulations with the observed visibilities we find that to explain the radial extent and depth of the gap, it would be required the presence of multiple low mass planets or a single planet that migrated through the disc. Interior to HD 107146's exo-Kuiper belt we find extended emission with a peak at ~20 au and consistent with the inner warm belt that was previously predicted based on 22$\mu$m excess as in many other systems. This warm belt is the first to be imaged, although unexpectedly suggesting that it is asymmetric. This could be due to a large belt eccentricity or due to clumpy structure produced by resonant trapping with an additional inner planet