The ALMANACH Project: Preliminary results and potentiality from Afghanistan.

INTRODUCTION: ALMANACH (ALgorithms for the MANagement of Acute CHildhood illnesses) is an electronic version of IMCI (Integrated Management of Childhood Illness) running on tablets. ALMANACH enhances its concept, it integrates well into health staff's daily consultation work and facilitates diagnosis and treatment. ALMANACH informs when to refer a child or to perform a rapid diagnostic test (RDT), recommends the right treatment dosage and synchronizes collected data real time with a Health Management Information System (DHIS2) for epidemiological evaluation and decision making. OBJECTIVES: Since May 2016, ALMANACH is under investigational deployment in three primary health care facilities in Afghanistan with the goal to improve the quality of care provided to children between 2 months and 5 years old. METHODS: IMCI's algorithms were updated in considering latest scientific publications, national guidelines, innovations in RDTs, the target population's epidemiological profile and the local resources available. Before the implementation of the project, a direct observation of 599 consultations was carried out to assess the daily performance at three selected health facilities in Kabul. RESULTS: The baseline survey showed that nutritional screening, vitamin A supplementation and deworming were not systematically performed: few patients were diagnosed for malnutrition (1.8%), received vitamin A (2.7%) or deworming (7.5%). Physical examination was appropriate only for 23.8% of the diagnoses of respiratory or gastrointestinal diseases, ear infection and sore throat. Respiratory rate was checked only in 33.5% of the children with fever and cough, dehydration status was assessed in only 16.5% of the diarrhoea cases. Forty-seven percent of patients received incorrect treatment. Sixty-four percent of the children, before the introduction of ALMANACH, received at least one antibiotic, although for 87.1% antibiotic therapy was unnecessary. The review of 8'047 paediatric consultations between May 2016 and September 2017 showed that with ALMANACH, malnutrition detection, deworming and Vitamin A supplementation increased respectively to 4.4%, 50.2% and 27.5%. Antibiotic prescription decreased to 21.83% and all children were examined and treated in compliance with the protocols. CONCLUSION: A survey will be conducted one year after the implementation to validate these initial promising results. If the efficacy of the approach is confirmed, ALMANACH could establish as a powerful innovation for primary health care.

Self vs. other: neural correlates underlying agent identification based on unimodal auditory information as revealed by electrotomography (sLORETA).

Recent neuroscientific studies have identified activity changes in an extensive cerebral network consisting of medial prefrontal cortex, precuneus, temporo-parietal junction, and temporal pole during the perception and identification of self- and other-generated stimuli. Because this network is supposed to be engaged in tasks which require agent identification, it has been labeled the evaluation network (e-network). The present study used self- versus other-generated movement sounds (long jumps) and electroencephalography (EEG) in order to unravel the neural dynamics of agent identification for complex auditory information. Participants (N=14) performed an auditory self-other identification task with EEG. Data was then subjected to a subsequent standardized low-resolution brain electromagnetic tomography (sLORETA) analysis (source localization analysis). Differences between conditions were assessed using t-statistics (corrected for multiple testing) on the normalized and log-transformed current density values of the sLORETA images. Three-dimensional sLORETA source localization analysis revealed cortical activations in brain regions mostly associated with the e-network, especially in the medial prefrontal cortex (bilaterally in the alpha-1-band and right-lateralized in the gamma-band) and the temporo-parietal junction (right hemisphere in the alpha-1-band). Taken together, the findings are partly consistent with previous functional neuroimaging studies investigating unimodal visual or multimodal agent identification tasks (cf. e-network) and extent them to the auditory domain. Cortical activations in brain regions of the e-network seem to have functional relevance, especially the significantly higher cortical activation in the right medial prefrontal cortex.

Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma.

Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in >50% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclin-dependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspase-dependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.

Endothelial cell compatibility of azithromycin and erythromycin.

Phlebitis is a severe local adverse event related to the use of parenteral macrolides. In order to evaluate the effect of azithromycin and erythromycin on human venous endothelial cells, we set up an in vitro model. The intracellular levels of purine nucleotides, as adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP) and guanosine 5'-triphosphate (GTP), were measured by means of high-performance liquid chromatography. Incubation of cells with 2 mg/mL azithromycin and erythromycin resulted in a rapid decline of intracellular ATP from 12.5 +/- 0.9 nmol/million cells to 4.1 +/- 0.3 and 2.6 +/- 0.4 nmol/million cells, respectively, after 60 min. In addition, ADP was extensively depleted from 2.1 +/- 0.17 nmol/million cells to 0.8 +/- 0.09 and 0.8 +/- 0.13 nmol/million cells after 60 min. After exposure of 0.5 mg/mL azithromycin and erythromycin, no significant decline of intracellular high-energy phosphate levels occurred after 20 and 60 min. Based on these results, solutions of azithromycin and erythromycin may not be well tolerated and may cause local adverse reactions even if diluted according to the manufacturer's recommendation.

[Direct-current treatment of chemically induced mammary carcinoma in an animal model: MR volumetric assessment of the effect of the therapy]. / Gleichstrombehandlung des chemisch induzierten Mammakarzinoms im Tiermodell: MR-volumetrische Erfassung des Therapieeinflusses.

PURPOSE: To investigate the effect of direct current treatment (DCT) on the growth of mammary carcinomas in rats by MR-volumetry. METHODS: Chemically induced mammary adenocarcinomas in a control group (n = 17) were compared with treated tumours (18 C/cm3 in group A: n = 7 or 36 C/cm3 in group B: n = 12). 31 untreated tumours were situated near a treated tumour (group C). Experiments were carried out using one positive electrode in the tumour centre and three negative electrodes in the periphery. The tumour volume was measured by MRI before, and 1, 3, 6, 9 and 12 weeks after treatment. RESULTS: 12 weeks after DCT, the mean tumour volume in group A (164% +/- 158%, p < 0.05) and group B (13% +/- 24%, p < 0.001) was significantly reduced compared to the control group (434% +/- 230, Mann-Whitney U-Test). Complete tumour regression occurred in 42% of tumours in group B and was not achieved in group A, C and control group. Tumour growth in group C was decreased compared to the control group. CONCLUSIONS: The effectiveness of DCT was found to depend on the applied dosage -36 C/cm3 was more effective than 18 C/cm3. The effect of DCT is not limited to the area between the electrodes.

p56Lck and p59Fyn regulate CD28 binding to phosphatidylinositol 3-kinase, growth factor receptor-bound protein GRB-2, and T cell-specific protein-tyrosine kinase ITK: implications for T-cell costimulation.

T-cell activation requires cooperative signals generated by the T-cell antigen receptor zeta-chain complex (TCR zeta-CD3) and the costimulatory antigen CD28. CD28 interacts with three intracellular proteins-phosphatidylinositol 3-kinase (PI 3-kinase), T cell-specific protein-tyrosine kinase ITK (formerly TSK or EMT), and the complex between growth factor receptor-bound protein 2 and son of sevenless guanine nucleotide exchange protein (GRB-2-SOS). PI 3-kinase and GRB-2 bind to the CD28 phosphotyrosine-based Tyr-Met-Asn-Met motif by means of intrinsic Src-homology 2 (SH2) domains. The requirement for tyrosine phosphorylation of the Tyr-Met-Asn-Met motif for SH2 domain binding implicates an intervening protein-tyrosine kinase in the recruitment of PI 3-kinase and GRB-2 by CD28. Candidate kinases include p56Lck, p59Fyn, zeta-chain-associated 70-kDa protein (ZAP-70), and ITK. In this study, we demonstrate in coexpression studies that p56Lck and p59Fyn phosphorylate CD28 primarily at Tyr-191 of the Tyr-Met-Asn-Met motif, inducing a 3- to 8-fold increase in p85 (subunit of PI 3-kinase) and GRB-2 SH2 binding to CD28. Phosphatase digestion of CD28 eliminated binding. In contrast to Src kinases, ZAP-70 and ITK failed to induce these events. Further, ITK binding to CD28 was dependent on the presence of p56Lck and is thus likely to act downstream of p56Lck/p59Fyn in a signaling cascade. p56Lck is therefore likely to be a central switch in T-cell activation, with the dual function of regulating CD28-mediated costimulation as well as TCR-CD3-CD4 signaling.

[Electrostimulation test for intraoperative vagotomy control. Results of a prospective randomized study]. / Der Elektrostimulationstest zur intraoperativen Vagotomiekontrolle. Ergebnisse einer prospektiven randomiserten Studie.

In a prospective random trial the intraoperative electro-stimulation test of Burge and Vane was conducted with 100 patients, in whom selective proximal vagotomy was performed for a duodenal ulcer. In 6 out of 50 patients histologically proved nerve fibres were found by the applying of the test. The postoperative acid values did not differ significantly between those patients who underwent the electrostimulation test and those who did not. The rate of recurrence was 8% in both groups 2-4 years after the operation. Obviously, the application of the test did not have any effect on the results.