This guideline represents an evidence-based approach to FN specific to children with cancer. Although some recommendations are similar to adult-based guidelines, there are key distinctions in multiple areas. Implementation will require adaptation to the local context.

Two recent reports have highlighted ANK3 as a susceptibility gene for bipolar disorder (BD). We first reported association between BD and the ANK3 marker rs9804190 in a genome-wide association study (GWAS) of two independent samples (Baum et al 2008). Subsequently, a meta-analysis of GWAS data based on samples from the US and the UK reported association with a different ANK3 marker, rs10994336 (Ferreira et al 2008). The markers lie about 340 kb apart in the gene. Here we test both markers in additional samples and characterize the contribution of each marker to BD risk. Our previously reported findings at rs9804190, which had been based on DNA pooling, were confirmed by individual genotyping in the NIMH Waves 1-4 (p=0.050; OR=1.24) and German (p=0.0006; OR=1.34) samples. This association was replicated in an independent US sample known as NIMH Wave 5 (466 cases, 212 controls; p=0.017; OR=1.38). A random-effects meta-analysis of all three samples was significant (p = 3 × 10−6; OR=1.32), with no heterogeneity. Individual genotyping of rs10994336 revealed a significant association in the German sample (p=0.0001; OR=1.70), and similar ORs in the NIMH 1–4 and NIMH 5 samples that were not significant at the p<0.05 level. Meta-analysis of all three samples supported an association with rs10994336 (p=1.7 × 10−5; OR=1.54), again with no heterogeneity. There was little linkage disequilibrium between the two markers. Further analysis suggested that each marker contributed independently to BD, with no significant marker × marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.

Summary CRISPR /Cas9 has been widely used for genome editing in many organisms, including important crops like wheat. Despite the tractability in designing CRISPR /Cas9, efficacy in the application of this powerful genome editing tool also depends on DNA delivery methods. In wheat, the biolistics based transformation is the most used method for delivery of the CRISPR /Cas9 complex. Due to the high frequency of gene silencing associated with co‐transferred plasmid backbone and low edit rate in wheat, a large T 0 transgenic plant population are required for recovery of desired mutations, which poses a bottleneck for many genome editing projects. Here, we report an Agrobacterium ‐delivered CRISPR /Cas9 system in wheat, which includes a wheat codon optimized Cas9 driven by a maize ubiquitin gene promoter and a guide RNA cassette driven by wheat U6 promoters in a single binary vector. Using this CRISPR /Cas9 system, we have developed 68 edit mutants for four grain‐regulatory genes, Ta CKX 2‐1 , Ta GLW 7 , Ta GW 2, and Ta GW 8 , in T 0 , T 1 , and T 2 generation plants at an average edit rate of 10% without detecting off‐target mutations in the most Cas9‐active plants. Homozygous mutations can be recovered from a large population in a single generation. Different from most plant species, deletions over 10 bp are the dominant mutation types in wheat. Plants homozygous of 1160‐bp deletion in Ta CKX 2‐D1 significantly increased grain number per spikelet. In conclusion, our Agrobacterium ‐delivered CRISPR /Cas9 system provides an alternative option for wheat genome editing, which requires a small number of transformation events because CRISPR /Cas9 remains active for novel mutations through generations.

Neutropenic fever is an important cause of morbidity and mortality during therapy of acute myeloid leukemia (AML). We retrospectively analyzed 382 febrile episodes encountered during induction and consolidation chemotherapy to determine the potential etiology, microbiologic spectrum, response/resistance to antibiotics and outcome. Between May, 2001 and December, 2006, 95 patients with de novo non-M3 AML received remission induction chemotherapy followed by consolidation in those who achieved complete remission. Patients median age was 28 years, ranging from 2 to 61 years, 26 patients were ≤15 years of age. There were 57 males and 38 females. Febrile neutropenia was defined as per international guidelines. A total of 382 febrile episodes were recorded; neutropenic 347 (induction phase 172, consolidation phase 175) and non-neutropenic 35 (induction 16, consolidation 19). Clinical, microbiological and radiological evidence of infection could be identified in 64% of the febrile episodes (74% during induction, 52% during consolidation). Pulmonary infections were most common, both during induction and consolidation phase. Microbiologically gram-negative infections predominated. There were 60 possible/probable/definite episodes of fungal infection. Six cases of tuberculosis (pulmonary 5 and spine 1) and 3 cases of malaria (including one case of cerebral malaria) were also identified. Nineteen patients died (17 during induction, 2 during consolidation); 17 deaths were infection related, 12/17 possibly due to fungal infections. We suggest that evaluation of antibacterial resistance patterns in an institution must be done routinely in order to choose empiric antibiotics therapy. Careful selection of antibiotics and early institution of antifungal therapy besides considering alternative diagnosis peculiar to the region (e.g. tuberculosis, malaria) may help in reducing morbidity and mortality during AML therapy.

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Tropical spastic paraparesis (TSP) and other chronic-progressive myelopathies have been clearly associated with increased serum and cerebrospinal fluid antibody titers to human T-lymphotropic virus type I (HTLV-I). However, little is known about the cellular immune function in TSP. In the present study, activated T lymphocytes were found in the peripheral blood of patients with TSP. Specifically, there were increased numbers of large CD3+ cells that also expressed HLA-DR and interleukin-2-receptor molecules. A significantly elevated spontaneous lymphoproliferative response was demonstrated in all patients tested. Generation of measles virus-specific cytotoxic T-cell response was reduced in 4 of 4 patients. This was similar to previous findings in patients with multiple sclerosis. However, unlike multiple sclerosis, reduced generation of cytotoxic T-cell response to influenza and mumps viruses was observed in 2 of 4 patients. These observations confirm further the strong association between TSP and an HTLV-I-like virus and suggest that the observed abnormalities of the cellular immune response in TSP are related to infection of lymphocytes by the retrovirus.

We prospectively studied 19 children with severe hypertension to evaluate the spectrum of radiological changes, severity and reversibility of this entity. All of them were subjected to clinical and biochemical evaluation, followed by magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Headache was seen in 17 children, 13 had confusion and drowsiness, 12 had nausea and vomiting, 10 patients had visual disturbances, seizure and dyspnoea. Only two had focal neurological deficit (one with right facial palsy and another with right lateral rectus palsy). Of these 19 children, 15 patients had hypertensive retinopathy and four had normal fundi. The positive MRI findings in 17/19 patients were: bilateral leukoencephalopathic changes in occipitoparietal region (9/17), diffuse white/grey matter lesion (3/17) patients, brain stem hyperintensity (2/17) and haemorrhagic lesions (3/17). On MRA, 12/19 patients had attenuation of cerebral arteries of different degree. On follow up, MRI findings resolved in all except three patients. All patients had normal MRA on follow up, except one with persistent minimal attenuation of middle cerebral artery and another had spasm in anterior, middle and posterior cerebral arteries. The intracranial abnormalities in these patients with severe hypertension were reversible in many of the cases after control of blood pressure was achieved. We therefore conclude that severe hypertension may lead to leuoencephalopathy, which had a wide radiological spectrum. A better understanding of this complex syndrome may obviate unnecessary investigations and allow management of associated problems in prompt and appropriate ways.

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