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Following publication of the original article [1], the authors reported that one of the authors' names was processed incorrectly.

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BACKGROUND: Automated treatment planning and/or optimization systems (ATPS) are in the process of broad clinical implementation aiming at reducing inter-planner variability, reducing the planning time allocated for the optimization process and improving plan quality. Five different ATPS used clinically were evaluated for advanced head and neck cancer (HNC). METHODS: Three radiation oncology departments compared 5 different ATPS: 1) Automatic Interactive Optimizer (AIO) in combination with RapidArc (in-house developed and Varian Medical Systems); 2) Auto-Planning (AP) (Philips Radiation Oncology Systems); 3) RapidPlan version 13.6 (RP1) with HNC model from University Hospital A (Varian Medical Systems, Palo Alto, USA); 4) RapidPlan version 13.7 (RP2) combined with scripting for automated setup of fields with HNC model from University Hospital B; 5) Raystation multicriteria optimization algorithm version 5 (RS) (Laboratories AB, Stockholm, Sweden). Eight randomly selected HNC cases from institution A and 8 from institution B were used. PTV coverage, mean and maximum dose to the organs at risk and effective planning time were compared. Ranking was done based on 3 Gy increments for the parallel organs. RESULTS: All planning systems achieved the hard dose constraints for the PTVs and serial organs for all patients. Overall, AP achieved the best ranking for the parallel organs followed by RS, AIO, RP2 and RP1. The oral cavity mean dose was the lowest for RS (31.3 ± 17.6 Gy), followed by AP (33.8 ± 17.8 Gy), RP1 (34.1 ± 16.7 Gy), AIO (36.1 ± 16.8 Gy) and RP2 (36.3 ± 16.2 Gy). The submandibular glands mean dose was 33.6 ± 10.8 Gy (AP), 35.2 ± 8.4 Gy (AIO), 35.5 ± 9.3 Gy (RP2), 36.9 ± 7.6 Gy (RS) and 38.2 ± 7.0 Gy (RP1). The average effective planning working time was substantially different between the five ATPS (in minutes): < 2 ± 1 for AIO and RP2, 5 ± 1 for AP, 15 ± 2 for RP1 and 340 ± 48 for RS, respectively. CONCLUSIONS: All ATPS were able to achieve all planning DVH constraints and the effective working time was kept bellow 20 min for each ATPS except for RS. For the parallel organs, AP performed the best, although the differences were small.

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In the Middle East and North Africa (MENA), a vitamin D dose ≥2000 IU/day may be needed to allow to the majority of the population to reach the target 25-hydroxyvitamin D (25(OH)D) level ≥20 ng/ml. Data in the region on the effect of vitamin D supplementation on various skeletal and extra-skeletal effects are scarce. INTRODUCTION: Hypovitaminosis D is prevalent worldwide, more so in the Middle East and North Africa (MENA). This study aims to determine the effects of vitamin D replacement on the mean difference in 25-hydroxyvitamin D [25(OH)D] level reached and other outcomes, in the MENA. METHODS: This is a meta-analysis of randomized trials from the MENA, administering vitamin D supplementation for at least 3 months, without language or time restriction. We conducted a comprehensive search in seven databases until July 2015. We abstracted data from published reports, independently and in duplicate. We calculated the mean difference (MD) and 95 % CI of 25(OH)D level reached for eligible comparisons, and pooled data using RevMan version 5.3. RESULTS: We identified 2 studies in elderly and 17 in adults; for the latter, 11 were included in the meta-analysis. Comparing a high vitamin D dose (>2000 IU/day) to placebo (nine studies), the MD in 25(OH)D level achieved was 18.3 (CI 14.1; 22.5) ng/ml; p value < 0.001; I 2 = 92 %. Comparing an intermediate dose (800-2000 IU/day) to placebo (two studies), the MD in 25(OH)D level achieved was 14.7 (CI 4.6; 24.9) ng/ml; p value 0.004; I 2 = 91 %. Accordingly, 89 and 71 % of participants, in the high and intermediate dose groups, respectively, reached the desirable level of 20 ng/ml. The risk of bias in the included studies was unclear to high, except for three studies. CONCLUSION: In the MENA region, vitamin D doses ≥2000 IU/day may be needed to reach the target 25(OH)D level ≥20 ng/ml. The long-term safety and the efficacy of such doses on various outcomes are unknown.

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Current experimental evidence concerning the potential activity of corticotropin releasing factor (CRF) in inflammatory processes still remains controversial. To determine whether CRF has protective effects on three remote organs (liver, lung and stomach) affected by cold injury and to characterize the role of neutrophils in cold-induced inflammation, dorsums of anesthetized rats were exposed for 5 min to a 22% NaCl solution maintained at -20+/-0.5 degrees C and the rats were sacrificed at 24 h after the cold injury. The results indicate that cold-exposure-induced edema in the liver, lung and stomach was blocked by subcutaneous (s.c.; 1.2 and 12 nmol/kg; 30 min before cold trauma) CRF pretreatment, while the central administration of CRF (intracisternally (i.c.); 0.30 and 1.5 nmol/rat; 15 min before cold) had the similar effect at the higher dose. Histological assessment and the tissue myeloperoxidase activities also revealed that CRF given peripherally has a protective role in damage generation. Moreover, CRF had a facilitatory effect in the recovery of the body temperature following cold exposure. In conclusion, CRF is likely to act on its peripheral receptors in the inflamed remote organs, suppressing the edematogenic effects of inflammatory mediators, some of which are neutrophil-derived.

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Both experimental and clinical studies suggest that lymphotoxin (LT) plays an important role in multiple sclerosis (MS) by inducing oligodendrocyte (OL) depletion. However, the mechanism of LT cytotoxicity is unknown. Because of the role of ceramide as a cell death mediator for a large variety of cytotoxic molecules, we have investigated the possible role of this second messenger in LT-induced cytotoxicity on SV40 immortalized new-born mice OL. Human recombinant LT exposure (50 ng/ml) resulted in intracellular ceramide accumulation which peaked at 48 h (approximately 170% increase) and paralleled LT-induced cytotoxicity. Moreover, fumonisin B1, a potent and specific ceramide synthase inhibitor, not only inhibited ceramide accumulation but also protected OL from LT cytotoxicity. These results suggest that LT-induced ceramide synthase stimulation and subsequent increased intracellular ceramide concentration are implicated in oligodendrocyte death.

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We report neuropathological, biochemical and molecular studies on two patients with childhood ataxia with diffuse central nervous system hypomyelination (CACH) syndrome, a leukodystrophy recently defined according to clinical and radiological criteria. Both had severe cavitating orthochromatic leukodystrophy without atrophy, predominating in hemispheric white matter, whereas U-fibers, internal capsule, corpus callosum, anterior commissure and cerebellar white matter were relatively spared. The severity of white matter lesions contrasted with the rarity of myelin breakdown products and astroglial and microglial reactions. In the white matter, there was an increase in a homogeneous cell population with the morphological features of oligodendrocytes, in many instances presenting an abundant cytoplasm like myelination glia. These cells were negative for glial fibrillary acidic protein and antibodies PGM1 and MIB1. Some were positive for myelin basic protein, proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein, but the majority were positive for human 2'-3' cyclic nucleotide 3' phosphodiesterase and all were positive for carbonic anhydrase II, confirming that they are oligodendrocytes. Myelin protein and lipid content were reduced. The PLP gene, analyzed in one case, was not mutated or duplicated. The increased number of oligodendrocytes without mitotic activity suggests an intrinsic oligodendroglial defect or an abnormal interaction with axons or other glial cells. This neuropathological study supports the notion that CACH syndrome constitutes a specific entity.

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The pathogenesis of multiple sclerosis (MS) is unknown. Searching for possible toxic factors, it was found that 3-day exposure to heat-treated cerebrospinal fluid (CSF) from MS patients caused apoptotic death of astrocytes and oligodendrocytes, but not fibroblasts, myoblasts, Schwann cells, endothelial cells and neurons, in vitro. CSFs from other inflammatory or non-inflammatory neurological diseases showed no toxicity. Exposure of these glial cells to partially purified MS CSF produced DNA fragmentation, apoptotic bodies, chromatin condensation, cell shrinkage, and changes in the levels of known cytokines. A cytotoxic factor, called gliotoxin, was characterized chromatographically as a stable 17-kDa glycoprotein. Since this protein is highly cytotoxic for astrocytes and oligodendrocytes, it may represent an initial pathogenic factor, leading to the neuropathological features of MS, such as blood-brain barrier involvement and demyelination.

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The regionalization of oligodendrocyte potentialities and the cellular interactions leading to the expression of the oligodendrocyte phenotype have been analyzed in the embryonic chick spinal cord. Dorsal and ventral regions of the spinal cord of 4-day-old embryos (E4) were cultivated separately. Oligodendrocyte differentiation was monitored at various times after explantation, using specific oligodendrocyte markers. After 2 weeks, several hundreds of differentiated oligodendrocytes were invariably observed in ventral cultures whereas significant numbers of oligodendrocytes failed to develop in dorsal spinal cord cultures. However, the E7 dorsal spinal cord was found to produce large numbers of oligodendrocytes, indicating that the ventral restriction of oligodendrocyte potentialities is transient. To test whether ventrally derived signals might influence oligodendrocyte differentiation, E4 dorsal spinal cord microexplants were cocultivated with notochord segments or with floor plate tissue. Numerous oligodendrocytes were found in dorsal explants associated with either tissue, notochord or floor plate, but not in dorsal explants cultivated alone, indicating that cells competent to be induced along the oligodendrocyte phenotype exist in the dorsal spinal cord. These results show that oligodendrocyte differentiation potentialities are initially restricted to the ventral spinal cord and suggest that ventrally derived signals from notochord and floor plate influence oligodendrocyte differentiation in the embryonic spinal cord.

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Caretaker recognition of clinical utility of respiratory signs and symptoms in the prediction of pneumonia was examined in a prospective study of infants and children in four cities in Egypt. In all 688 children aged 2 months-5 years presenting with a history and/or physical examination findings of cough and difficult or fast breathing were recruited from out-patient health facilities. The validity of caretaker terms was determined using paediatrician observation of standard respiratory signs and symptoms, x-ray diagnosis and pulse oximetry as standards. The sensitivity of 'nahagan' (Egyptian Arabic for fast breathing) for identifying elevated respiratory rate was 78% +/- 4, and was slightly higher for < 12 month olds (85% +/- 5) versus children aged 1-5 years (74% +/- 5). 'Sedro tale nazel', which describes the chest as moving up and down, was a sensitive (86% +/- 3) and specific (60% +/- 4) indicator of chest indrawing. 'Tazyeek' (wheeze) had a sensitivity of 75% +/- 3 and specificity of 66% +/- 4 when compared to paediatrician assessment of wheezing during physical examination. Although not specific, the caretaker terms, 'nahagan' or 'nafas seria' (fast breathing) and 'sedro tale nazel' (chest indrawing), either spontaneously or after asking, were sensitive (> 71%) indicators of radiologic pneumonia and oxygen desaturation, and therefore can be used to prompt timely health seeking behaviour in these settings.

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Neoangiogenesis of transplants implanted into the brains of newborn rodent hosts was evaluated by immunohistochemistry for 2 weeks after the operation. The use of species-specific antibodies directed against mouse endothelial cells demonstrated the respective participation of the host and the donor in the formation of new vessels in the graft after crossed rabbit into mouse and mouse into rat transplantation experiments. We show that blood vessels made by host endothelial cells begin to penetrate the transplant 24 h after grafting, and cross it completely by 72 h. Simultaneously, host astrocytes invade the transplant.

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Newborn mouse neocortical tissue was transplanted into the third ventricle of rat brain and the reconstruction and the origin of the blood vessels were investigated by using a monoclonal antibody against mouse endothelial surface antigen-1 (MESA-1). It was clearly demonstrated that some of the blood vessels in the graft originated in the donor mouse neocortical tissue. An India ink perfusion experiment revealed that the blood was supplied to the MESA-1-positive blood vessels. Furthermore, electron microscopic immunohistochemical studies demonstrated the existence of a mosaic reconstruction of blood vessels which consisted of mouse- and rat-derived vascular endothelial cells. It was concluded that the blood vessels originating in the donor tissue and those originating in the host tissue inoculate with each other in the grafted tissue.

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To overcome the deficiencies of previous findings, the activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AchE) were studied at very short age intervals to allow a more precise definition of the shape and timing of their developmental curves in normal, hypothyroid and underfed rats. In addition, AchE expression in developing cerebellum was studied histochemically in these three neurological models. When compared with structural findings in the literature, the results provide the following information on the normal and abnormal developing cholinergic system, related or not to cerebellar neurotransmission (1) AchE activity, unlike ChAT, can be considered as a good marker of the developing cholinergic archicerebellum. (2) ChAT and AchE are transiently expressed together in functionally noncholinergic Purkinje cells. In contrast with most regions of the central nervous system, the high ratio of ChAT to AchE activities in the early stage of cerebellar development suggests an enhanced synthesis of acetylcholine (Ach). The level of ChAT activity correlates with Purkinje cell size, supporting the concept of a neurotrophic role of Ach in early maturing macroneurons. (3) The archicerebellar cholinergic network appears to be relatively well preserved from undernutrition and, to an even greater extent, from hypothyroidism, compared to other systems of neurotransmission formed later and more widely distributed throughout the cerebellum. The presynaptic compartment seems to be more affected than the postsynaptic compartment. (4) In disagreement with some data in the literature, the abnormalities induced by both abnormal thyroidal and nutritional states were found to be irreversible.

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Modifications of the morphology, the proliferation and the synthesis of carbonic anhydrase of glial cells in primary cultures maintained in defined medium have been investigated under the action of basic fibroblast growth factor. Cultures contained essentially three cell types: astrocytes which expressed glial fibrillary acidic protein, oligodendrocytes which were characterized by the presence of carbonic anhydrase and precursor cells in which these two proteins were detected by immunocytochemistry. In the presence of basic fibroblast growth factor astrocytes and oligodendrocytes underwent morphological changes, characterized by a fibrous aspect; astroglial cells acquired essentially several long processes and oligodendroglial cells formed generally two long processes. The factor increased the proliferation of these two cell types. The quantity of carbonic anhydrase per oligodendrocyte was enhanced in treated cultures. The double-stained precursor cells were present between days 7 and 11 of culture in defined medium, while in the presence of fibroblast growth factor these cells were more numerous and were still present after 14 days. The basic fibroblast growth factor stimulated the proliferation of these young glial cells and modified their morphology. But the differentiation of precursor cells towards one glial cell type appeared to be delayed.

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Spleen cells from a rat immunized with mouse cerebellar cells were fused with mouse myeloma cells. One of the hybridomas secreted a monoclonal antibody that reacts with a surface antigen on vascular endothelial cells. The antibody stained endothelial cells lining blood vessels in brain, heart, lung, kidney, and liver. It did not, however, stain endothelial cells lining hepatic sinusoids. Parenchymal cells were always negative. So far, an antigen of similar tissue distribution has not been described in the mouse and we have called it mouse endothelial surface antigen-1 (MESA-1). The antibody could be used as a highly specific usefulness for identifying endothelium-derived cells in culture has been demonstrated on cultures of dissociated mouse cerebellum, where it stained a subclass of fibronectin-expressing cells.

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