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Asthma, a chronic inflammatory disorder of the airways, is coordinated by Th2 cells in both human asthmatics and animal models of allergic asthma. It has been shown that helminth infections including Schistosoma mansoni may modulate atopic diseases including asthma. In the present study, BALB/c mice were infected with bisexual and unisexual (male) S. japonicum, respectively, prior to ovalbumin (OVA) sensitization and challenge. Compared to mice with OVA sensitization/challenge alone, S. japonicum infection led to a significant decrease of eosinophil accumulation in bronchoalveolar lavage fluid (BALF) collected 48 h postchallenge, as well as to a marked reduction in inflammatory cell infiltration around the airways and pulmonary blood vessels. Compared to OVA-immunized uninfected mice, the level of OVA-specific serum IgE as well as interleukin (IL)-4 and IL-5 in BALF were reduced, but IL-10 was strongly elevated in mice with preexisting S. japonicum infection prior to OVA immunization. These results suggest that both bisexual and male S. japonicum infections may modulate the development of allergic asthma.	Can parasite infections by Schistosoma japonicum prevent or improve asthma?	It has been shown that helminth infections including Schistosoma mansoni may modulate atopic diseases including asthma.
T-cell acute lymphoblastic leukemia (T-ALL) is characterized as a high-risk stratified disease associated with frequent relapse, chemotherapy resistance, and a poorer prognostic outlook than B-precursor ALL. Many of the challenges in treating T-ALL reflect the lack of prognostic cytogenetic or molecular abnormalities on which to base therapy, including targeted therapy. Notch1 activating mutations were identified in more than 50% of T-ALL cases and can be therapeutically targeted with γ-secretase inhibitors (GSIs). Mutant Notch1 can activate cMyc and PI3K-AKT-mTOR1 signaling in T-ALL. In T-ALLs with wild-type phosphatase and tensin homolog deleted on chromosome ten (PTEN), Notch1 transcriptionally represses PTEN, an effect reversible by GSIs. Notch1 also promotes growth factor receptor (IGF1R and IL7Rα) signaling to PI3K-AKT. Loss of PTEN is common in primary T-ALLs due to mutation or posttranslational inactivation and results in chronic activation of PI3K-AKT-mTOR1 signaling, GSI-resistance, and repression of p53-mediated apoptosis. Notch1 itself might regulate posttranslational inactivation of PTEN. PP2A is activated by Notch1 in PTEN-null T-ALL cells, and GSIs reduce PP2A activity and increase phosphorylation of AKT, AMPK, and p70S6K. This review focuses on the central role of the PI3K-AKT-mTOR1 signaling in T-ALL, including its regulation by Notch1 and potential therapeutic interventions, with emphasis on GSI-resistant T-ALL.	Are Notch mutations related to T-cell Acute Lymphoblastic Leukemia (T-ALL)?	T-cell acute lymphoblastic leukemia (T-ALL) is characterized as a high-risk stratified disease associated with frequent relapse, chemotherapy resistance, and a poorer prognostic outlook than B-precursor ALL. Many of the challenges in treating T-ALL reflect the lack of prognostic cytogenetic or molecular abnormalities on which to base therapy, including targeted therapy. Notch1 activating mutations were identified in more than 50% of T-ALL cases and can be therapeutically targeted with γ-secretase inhibitors (GSIs).
Adaptive (stationary phase) mutagenesis is a phenomenon by which nondividing cells acquire beneficial mutations as a response to stress. Although the generation of adaptive mutations is essentially stochastic, genetic factors are involved in this phenomenon. We examined how defects in a transcriptional factor, previously reported to alter the acquisition of adaptive mutations, affected mutation levels in a gene under selection. The acquisition of mutations was directly correlated to the level of transcription of a defective leuC allele placed under selection. To further examine the correlation between transcription and adaptive mutation, we placed a point-mutated allele, leuC427, under the control of an inducible promoter and assayed the level of reversion to leucine prototrophy under conditions of leucine starvation. Our results demonstrate that the level of Leu(+) reversions increased significantly in parallel with the induced increase in transcription levels. This mutagenic response was not observed under conditions of exponential growth. Since transcription is a ubiquitous biological process, transcription-associated mutagenesis may influence evolutionary processes in all organisms.	Is transcription-associated mutagenesis (TAM) related to gene expression levels?	The acquisition of mutations was directly correlated to the level of transcription
Atlanto-axial rotatory fixation (AARF) is a rare cause of childhood torticollis that may occur spontaneously or in association with trauma and upper respiratory infections. We describe the clinical findings, as well as the effectiveness of imaging in the diagnosis and the treatment of 4 children with AARF, in whom acute fixed non-dystonic torticollis was the presenting symptom. Onset of torticollis was spontaneous in Case 1, after general anesthesia for cholesteatoma surgery in Case 2, after a trauma in Case 3, and during hypersomnia in Case 4. Duration of torticollis prior to diagnosis was 3 months in the first two patients and 20 days in the other two. All the patients underwent cervical X-rays examinations, which were not contributory to the diagnosis, followed by CT, which demonstrated C1-C2 rotatory fixation. One patient had a spontaneous resolution; treatment with Gardner's tongs and soft collar permitted restoration of the normal alignment in the other 3 patients. AARF must be considered in all the patients with persistent painful torticollis.	Atlanto-axial rotary instability (Fielding type 1) is common to what diseases?	Atlanto-axial rotatory fixation (AARF) is a rare cause of childhood torticollis that may occur spontaneously or in association with trauma and upper respiratory infections.
Patau syndrome is a chromosomal disorder associated with multiple malformations caused by inheritance of an extra chromosome (trisomy 13). Some skin defects have been reported in patients with Patau syndrome, such as scalp defects, glabellar stains, deep palmar creases, rocker-bottom feet, convex soles, hyperconvextity of the nails, and multiple hemangiomas. To our knowledge, widespread comedonal and cystic acne have not been previously reported in Patau syndrome.	Which is the main cause of the Patau syndrome?	Patau syndrome is a chromosomal disorder associated with multiple malformations caused by inheritance of an extra chromosome (trisomy 13).
In 2 large, randomized, double-masked trials reported here, once-daily dosing of netarsudil 0.02% was found to be effective and well tolerated for the treatment of patients with ocular hypertension and open-angle glaucoma. The novel pharmacology and aqueous humor dynamic effects of this molecule suggest it may be a useful addition to the armamentarium of ocular hypotensive medications.	Which diseases are treated with netarsudil?	In 2 large, randomized, double-masked trials reported here, once-daily dosing of netarsudil 0.02% was found to be effective and well tolerated for the treatment of patients with ocular hypertension and open-angle glaucoma.
Non-alcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide, reflecting the epidemic of global obesity. Those with the progressive variant of NAFLD, non-alcoholic steatohepatitis (NASH), are at significantly increased risk of multisystem morbidity and mortality. However, there are currently no approved pharmacologic therapies for NASH. Given the disease burden, there is an important unmet need for pharmacologic treatment options for this patient population. The underlying pathophysiologic mechanisms that contribute to the development and progression of NAFLD and NASH are complex and reflected by the myriad of therapies, with different targets, currently under investigation. In broad strokes, drug development has focused on modulation of metabolic pathways, inflammatory cascades, and/or mechanisms impacting fibrosis. Although much progress has been made in enhancing our understanding of NAFLD pathogenesis, development of pharmacologic treatments has been hindered by challenges in clinical trial enrollment and complexities in clinical trial design. The compounds in phase IIa have provided promising results in terms of potential benefits on various aspects of histopathology. Agents in later stages of development have shown fairly modest results in terms of reduction of hepatic steatosis, necroinflammation and fibrosis. If longer term safety and efficacy are established among heterogeneous cohorts, these medications may help mitigate potential morbidity and mortality for this burgeoning patient population.	Is there any approved treatment for NAFLD?	Non-alcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide, reflecting the epidemic of global obesity. Those with the progressive variant of NAFLD, non-alcoholic steatohepatitis (NASH), are at significantly increased risk of multisystem morbidity and mortality. However, there are currently no approved pharmacologic therapies for NASH.
Thirty-two children with refractory partial epilepsy received open-label gabapentin as an additional medication to their antiepileptic drug regimen. Gabapentin was given in a dose ranging from 10 to 50 mg/kg per day (mean dose, 26.7 mg/kg daily). All patients had partial seizures with or without secondary generalization. Compared with baseline, 11 patients (34.4%) had a greater than 50% decrease in seizure frequency, and 4 (12.5%) had a 25% to 50% decrease in seizure frequency. Of the seven children who received the medication for 6 months or longer, two were seizure free and four were almost seizure free (having one seizure every few months). Mean gabapentin concentration was 4.8 micrograms/ml, and mean apparent clearance was 372 ml/kg per hour. The major reported side effects were behavioral. These consisted of hyperactivity, irritability, and agitation that occurred in patients with baseline mental retardation with attention deficit. We conclude that gabapentin can be a useful adjunctive medication in the treatment of refractory partial epilepsy in children.	What are the reported adverse effects of gabapentin used in children?	The major reported side effects were behavioral. These consisted of hyperactivity, irritability, and agitation that occurred in patients with baseline mental retardation with attention deficit.
A Chinese family affected with autosomal dominant disorder-neurofibromatosis type I was identified in this study. Linkage analysis was performed, and DNA sequencing for whole coding region of NF1 was carried out to identify the disease-causing mutation. The disease gene of the Chinese NF1 family was linked to NF1 locus, and a nonsense mutation, G1336X in the NF1 gene was identified. This mutation truncates the NF1 protein by 1 483 amino acid residues at the C-terminus, and is co-segregate with all the patients, but not present in unaffected individuals in the family. The present study demonstrated that G1336X mutation in the NF1 gene cause Neurofibromatosis type I in the family. To our knowledge, this mutation is firstly reported in Chinese population.	Mutation of which gene and which chromosome cause Neurofibromatosis type I?	The present study demonstrated that G1336X mutation in the NF1 gene cause Neurofibromatosis type I in the family.
Aberrant expression of microRNAs (miRNAs) plays important roles in carcinogenesis and tumor progression. However, the expression and biological role of miR-301b in triple-negative breast cancer (TNBC) remains unclear. Here we aimed to evaluate the roles and mechanisms of miR-301b in TNBC cells. miR-301b expression was assessed in TNBC specimens and cell lines by quantitative Real-Time PCR (qRT-PCR). TNBC cells were transfected with miR-301b mimics, inhibitors or Cylindromatosis (CYLD) small interfering RNA (siRNA) using Lipofectamine 2000. The functional roles of miR-301b were determined by cell proliferation, colony formation, and apoptosis assays. Western blots and qRT-PCR were used to measure the expression of mRNAs and proteins in the cells. We found that miR-301b was upregulated in TNBC specimens and cell lines. Overexpression of miR-301b promoted cell proliferation in TNBC cells, while inhibited the apoptosis induced by 5-FU. CYLD was downregulated by miR-301b at both mRNA and protein levels in TNBC cells. Dual-luciferase report assay confirmed that miR-301b downregulated CYLD by direct interaction with the 3'-untranslated region(3'-UTR) of CYLD mRNA. NF-κB activation was mechanistically associated with miR-301b-mediated downregulation of CYLD. However, inhibition of miR-301b reversed all the effects of miR-301b. In conclusion, miR-301b plays an oncogenic role in TNBC possibly by downregulating CYLD and subsequently activating NF-κB p65, and this may provide a novel therapeutic approach for TNBC. [BMB Reports 2018; 51(11): 602-607].	Which microRNAs are involved in targeting CYLD in triple negative breast cancer?	Aberrant expression of microRNAs (miRNAs) plays important roles in carcinogenesis and tumor progression. However, the expression and biological role of miR-301b in triple-negative breast cancer (TNBC) remains unclear. Here we aimed to evaluate the roles and mechanisms of miR-301b in TNBC cells. miR-301b expression was assessed in TNBC specimens and cell lines by quantitative Real-Time PCR (qRT-PCR). TNBC cells were transfected with miR-301b mimics, inhibitors or Cylindromatosis (CYLD) small interfering RNA (siRNA) using Lipofectamine 2000. The functional roles of miR-301b were determined by cell proliferation, colony formation, and apoptosis assays. Western blots and qRT-PCR were used to measure the expression of mRNAs and proteins in the cells. We found that miR-301b was upregulated in TNBC specimens and cell lines. Overexpression of miR-301b promoted cell proliferation in TNBC cells, while inhibited the apoptosis induced by 5-FU. CYLD was downregulated by miR-301b at both mRNA and protein levels in TNBC cells. Dual-luciferase report assay confirmed that miR-301b downregulated CYLD by direct interaction with the 3'-untranslated region(3'-UTR) of CYLD mRNA. NF-κB activation was mechanistically associated with miR-301b-mediated downregulation of CYLD. However, inhibition of miR-301b reversed all the effects of miR-301b. In conclusion, miR-301b plays an oncogenic role in TNBC possibly by downregulating CYLD and subsequently activating NF-κB p65, and this may provide a novel therapeutic approach for TNBC.
REPAIRtoire is the first comprehensive database resource for systems biology of DNA damage and repair. The database collects and organizes the following types of information: (i) DNA damage linked to environmental mutagenic and cytotoxic agents, (ii) pathways comprising individual processes and enzymatic reactions involved in the removal of damage, (iii) proteins participating in DNA repair and (iv) diseases correlated with mutations in genes encoding DNA repair proteins. REPAIRtoire provides also links to publications and external databases. REPAIRtoire contains information about eight main DNA damage checkpoint, repair and tolerance pathways: DNA damage signaling, direct reversal repair, base excision repair, nucleotide excision repair, mismatch repair, homologous recombination repair, nonhomologous end-joining and translesion synthesis. The pathway/protein dataset is currently limited to three model organisms: Escherichia coli, Saccharomyces cerevisiae and Homo sapiens. The DNA repair and tolerance pathways are represented as graphs and in tabular form with descriptions of each repair step and corresponding proteins, and individual entries are cross-referenced to supporting literature and primary databases. REPAIRtoire can be queried by the name of pathway, protein, enzymatic complex, damage and disease. In addition, a tool for drawing custom DNA-protein complexes is available online. REPAIRtoire is freely available and can be accessed at http://repairtoire.genesilico.pl/.	What is the content of the REPAIRtoire database?	The database collects and organizes the following types of information: (i) DNA damage linked to environmental mutagenic and cytotoxic agents, (ii) pathways comprising individual processes and enzymatic reactions involved in the removal of damage, (iii) proteins participating in DNA repair and (iv) diseases correlated with mutations in genes encoding DNA repair proteins. REPAIRtoire provides also links to publications and external databases.
An overexpression of the transmembrane ATP-binding cassette transporter G2 (ABCG2, BCRP) in cancer tissues is supposed to play a role in the multidrug resistance (MDR) of tumors resulting in an inefficient chemotherapy. Therefore, co-administration of selective and non-toxic ABCG2 inhibitors is a promising strategy for improving the efficacy of chemotherapy by blocking ABCG2-mediated export of the cytostatic drugs. In the present study, we designed a small library of 38 novel compounds containing a heteroaryl-phenyl scaffold possessing several (bioisosteric) moieties, and twelve new precursors. We investigated the library for ABCG2 inhibition, for the selectivity against MDR-involved efflux pump ABCB1 (P-gp) and for toxicity. Structure activity relationship (SAR) studies revealed that, at least a phenylheteroaryl-phenylamide scaffold is necessary for observing an ABCG2 inhibition. 4-Methoxy-N-(2-(2-(6-methoxypyridin-3-yl)-2H-tetrazol-5-yl)phenyl)benzamide (43) exhibited a high potency (IC = 61 nM)), selectivity, low intrinsic toxicity and reversed the ABCG2-mediated drug resistance in presence of only 0.1 μM.	Is the protein ABCG2 transmembrane?	the transmembrane ATP-binding cassette transporter G2
The authors present a 21-year-old woman who has been receiving rapamycin for 5 months for bilateral subependymal giant cell astrocytomas. The patient was started at a dose of 0.2 mg/kg/day. Levels were maintained between 11 and 13 ng/mL. Magnetic resonance imaging of the brain 2(1/2) months after initiating rapamycin demonstrated a decrease in size of both astrocytomas (11 to 7.5 mm on the right and 8 to 5 mm on the left). Further studies are needed with prolonged observation to confirm these findings, determine the length of necessary treatment, and evaluate recurrence risk after discontinuation of rapamycin.	List two chemotherapeutic agents that are used for treatment of Subependymal Giant Cell Astrocytoma	The authors present a 21-year-old woman who has been receiving rapamycin for 5 months for bilateral subependymal giant cell astrocytomas.
Cystic fibrosis (CF) was considered to be non-existent in Indian subcontinent. Reports in last one decade have suggested that cystic fibrosis occurs in India but its precise magnitude is not known. Studies on migrant Indian population in United States and United Kingdom estimate frequency of CF as 1:10,000 to 1:40,000. The clinical features are similar to that reported in Caucasian population. CF in Indian children is usually diagnosed late and in advanced stage. Children are more malnourished and may have clinically evident deficiency of fat soluble vitamins. The frequency of clubbing, colonization with Pseudomonas, and laboratory evidence of pseudo-Bartter syndrome is relatively more at the time of diagnosis. Diagnostic facilities in form of sweat chloride estimation and genetic studies are not available readily. Mutation profile is different. The frequency of common mutation F508del in Indian children is between 19% and 34%. Other mutations are heterogeneous. Management of CF in India is difficult due to less number of trained manpower, limited availability, and high cost of pharmacologic agents. The determinants of early death include: severe malnutrition and colonization with Pseudomonas at the time of diagnosis, more than four episodes of lower respiratory infection per year and age of onset of symptoms before 2 months of age. To conclude, CF does occur in India; however, precise magnitude of problem is not known. There is need to create awareness amongst pediatricians, developing diagnostic facilities, and management protocols based on locally available resources.	What is the incidence of cystic fibrosis in the caucasian population?	Studies on migrant Indian population in United States and United Kingdom estimate frequency of CF as 1:10,000 to 1:40,000
Arrhythmias can develop in various cardiac diseases, such as ischemic heart disease, cardiomyopathy and congenital heart disease. It can also contribute to the aggravation of heart failure and sudden cardiac death. Redox stress and Ca(2+) overload are thought to be the important triggering factors in the generation of arrhythmias in failing myocardium. From recent studies, it appears evident that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a central role in the arrhythmogenic processes in heart failure by sensing intracellular Ca(2+) and redox stress, affecting individual ion channels and thereby leading to electrical instability in the heart. CaMKII, a multifunctional serine/threonine kinase, is an abundant molecule in the neuron and the heart. It has a specific property as "a memory molecule" such that the binding of calcified calmodulin (Ca(2+)/CaM) to the regulatory domain on CaMKII initially activates this enzyme. Further, it allows autophosphorylation of T287 or oxidation of M281/282 in the regulatory domain, resulting in sustained activation of CaMKII even after the dissociation of Ca(2+)/CaM. This review provides the understanding of both the structural and functional properties of CaMKII, the experimental findings of the interactions between CaMKII, redox stress and individual ion channels, and the evidences proving the potential participation of CaMKII and oxidative stress in the diverse arrhythmogenic processes in a diseased heart.	Is Calcium/Calmodulin dependent protein kinase II (CaMKII) involved in cardiac arrhythmias and heart failure?	From recent studies, it appears evident that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a central role in the arrhythmogenic processes in heart failure by sensing intracellular Ca(2+) and redox stress, affecting individual ion channels and thereby leading to electrical instability in the heart.
Genital herpes is the most prevalent sexually transmitted infection in the USA. While sometimes mild in severity, it can be a distressing and painful chronic condition. Likewise, herpes labialis and herpes zoster can be both physically and psychologically painful. While there is no cure for these conditions, treatment to alleviate symptoms, suppress recurrences and reduce transmission has been drastically improved over the past 20 years with the use of guanine nucleoside antivirals, such as valacyclovir hydrochloride (Valtrex), GlaxoSmithKline) the highly bioavailable prodrug of acyclovir (Zovirax((R)), GlaxoSmithKline), and famciclovir (Famvir, Novartis), a highly bioavailable prodrug of penciclovir (Denavir, Novartis). Clinical trials involving approximately 10,000 patients (including patients from nongenital herpes studies, such as herpes zoster) have assessed the safety and efficacy of valacyclovir in the treatment of initial genital herpes outbreaks, episodic treatment of recurrent episodes and daily suppressive therapy. It was shown that valacyclovir has similar efficacy to acyclovir in the episodic and suppressive treatment of genital herpes. Valacyclovir is the only antiviral drug approved for a once-daily dose of suppressive therapy for genital herpes, as well as the only antiviral drug US FDA approved for a 3-day regimen of episodic treatment of recurrent genital herpes. In addition, valacyclovir is also indicated in the reduction of the sexual transmission of herpes simplex virus infection and for the treatment of herpes labialis. In herpes zoster, valacyclovir is more effective than acyclovir or placebo (and as equally effective as famciclovir) in shortening the length and severity of herpes zoster-associated pain and postherpetic neuralgia. Valacyclovir has an acceptable safety profile in patients with herpes simplex and herpes zoster. The less frequent dosing regimen makes it an attractive option in the treatment of genital herpes and other viral infections, and may contribute to increased patient adherence to therapy.	Please list 3 diseases treated with Valtrex(valacyclovir)	n herpes zoster, valacyclovir is more effective than acyclovir or placebo (and as equally effective as famciclovir) in shortening the length and severity of herpes zoster-associated pain and postherpetic neuralgia.
Calcification, fibrosis, and chronic inflammation are the predominant features of calcific aortic valve disease, a life-threatening condition. Drugs that induce serotonin (5-hydroxytryptamine [5-HT]) are known to damage valves, and activated platelets, which carry peripheral serotonin, are known to promote calcific aortic valve stenosis. However, the role of 5-HT in valve leaflet pathology is not known. We tested whether serotonin mediates inflammation-induced matrix mineralization in valve cells. Real-time reverse transcription-polymerase chain reaction analysis showed that murine aortic valve interstitial cells (VICs) expressed both serotonin receptor types 2A and 2B (Htr2a and Htr2b). Although Htr2a expression was greater at baseline, Htr2b expression was induced several-fold more than Htr2a in response to the pro-calcific tumor necrosis factor-α (TNF-α) treatment. 5-HT also augmented TNF-α-induced osteoblastic differentiation and matrix mineralization of VIC, but 5-HT alone had no effects. Inhibition of serotonin receptor type 2B, using specific inhibitors or lentiviral knockdown in VIC, attenuated 5-HT effects on TNF-α-induced osteoblastic differentiation and mineralization. 5-HT treatment also augmented TNF-α-induced matrix metalloproteinase-3 expression, which was also attenuated by Htr2b knockdown. Htr2b expression in aortic roots and serum levels of peripheral 5-HT were also greater in the hyperlipidemic Apoe mice than in control normolipemic mice. These findings suggest a new role for serotonin signaling in inflammation-induced calcific valvulopathy.	Is serotonin transported by platelets?	activated platelets, which carry peripheral serotonin,
We present a simple, time- and cost-efficient approach to tackle the proteome of prokaryotic organisms. To obtain large data sets of complex biological experiments high-throughput and time- and cost-efficient methods still have to be developed and refined. In this study, we combined well-approved techniques, namely elevated chromatographic temperatures, long RP columns and the multidimensional protein identification technology MudPIT to achieve high proteome coverage. The advanced MudPIT approach has been evaluated and delivered very comprehensive results for Gram-positive as well as Gram-negative bacteria (53% proteome coverage for Corynebacterium glutamicum and 46% proteome coverage for Escherichia coli). Also, a high identification rate for the challenging integral membrane proteins was achieved. The competitiveness of the advanced MudPIT technology is strengthened by the fact that in this approach only two fractions were analyzed with both, simple and time-efficient sample preparation, and a moderate data acquisition time.	What is the advantage of using long nano columns in proteomics?	Also, a high identification rate for the challenging integral membrane proteins was achieved.
Inherited and acquired changes in DNA can influence the coding for gene products (proteins). When the function of a protein is disturbed, this may lead to disease. DNA in chromatin can be condensed or be arranged in an open structure. The activity of genes is significantly affected by the accessibility to DNA by transcription factors and other proteins involved in the transcription of genes. The accessibility of DNA is regulated by epigenetic processes, including methylation of cytosine. In these circumstances the nucleic sequence of the DNA does not change. Nevertheless, disturbances of these processes can also culminate in disease. Epigenetic changes to DNA are reversible. This offers opportunities for treatment and recovery in conditions that are a result of disturbed epigenetic processes.	Do epigenetic changes change the DNA sequence?	The accessibility of DNA is regulated by epigenetic processes, including methylation of cytosine. In these circumstances the nucleic sequence of the DNA does not change.
During 'emergency' situations such as infections, host defense requires rapid mobilization of bone marrow granulocyte progenitors. 'Steady-state' granulopoiesis is absolutely dependent on the C/EBPalpha transcription factor, but the transcriptional mechanisms underlying emergency granulopoiesis remain unclear. Here we show that large numbers of granulocytes were generated from C/EBPalpha-deficient progenitors after cytokine stimulation in vivo. Cytokine treatment or fungal infection induced upregulation of C/EBPbeta but not C/EBPalpha or C/EBPepsilon transcripts in granulocyte progenitors, and C/EBPbeta-deficient progenitors showed decreased emergency-induced granulopoiesis in vitro and in vivo. C/EBPbeta inhibited proliferation less severely than did C/EBPalpha. These data suggest a critical function for C/EBPbeta in emergency granulopoiesis, which demands both differentiation and proliferation of granulocyte precursors.	Which transcription factor regulates emergency granulopoiesis?	Cytokine treatment or fungal infection induced upregulation of C/EBPbeta but not C/EBPalpha or C/EBPepsilon transcripts in granulocyte progenitors, and C/EBPbeta-deficient progenitors showed decreased emergency-induced granulopoiesis in vitro and in vivo.
Relatively little is known about programmed cell death (PCD) in plants. It is nonetheless suggested here that tonoplast rupture and the subsequent rapid destruction of the cytoplasm can distinguish two large PCD classes. One class, which is here called 'autolytic', shows this feature, whilst the second class (called 'non-autolytic') can include tonoplast rupture but does not show the rapid cytoplasm clearance. Examples of the 'autolytic' PCD class mainly occur during normal plant development and after mild abiotic stress. The 'non-autolytic' PCD class is mainly found during PCD that is due to plant-pathogen interactions. Three categories of PCD are currently recognized in animals: apoptosis, autophagy, and necrosis. An attempt is made to reconcile the recognized plant PCD classes with these groups. Apoptosis is apparently absent in plants. Autophagic PCD in animals is defined as being accompanied by an increase in the number of autophagosomes, autolysosomes, and small lytic vacuoles produced by autolysosomes. When very strictly adhering to this definition, there is no (proof for) autophagic PCD in plants. Upon a slightly more lenient definition, however, the 'autolytic' class of plant PCD can be merged with the autophagic PCD type in animal cells. The 'non-autolytic' class of plant PCD, as defined here, can be merged with necrotic PCD in animals.	What is the definition of autophagy?	Autophagic PCD in animals is defined as being accompanied by an increase in the number of autophagosomes, autolysosomes, and small lytic vacuoles produced by autolysosomes
Devic's neuromyelitis optica is a rare syndrome characterised by the combination of acute or subacute optic neuritis and transverse myelitis, in some cases considered to be a variant of multiple sclerosis. Mutations of mitochondrial DNA (mtDNA) associated with Leber hereditary optic neuropathy (LHON) have been identified in some patients with multiple sclerosis in whom optic neuritis is a prominent early feature. Using restriction enzyme digestion of mtDNA products amplified by the polymerase chain reaction, the primary LHON mtDNA mutations at positions 3460 bp, 11,778 bp, and 14,484 bp have been excluded in four women with Devic's neuromyelitis optica. A mutation at 4160 bp associated in some LHON families with more widespread neurological disease was also not detected. It is concluded that the primary mtDNA mutations currently associated with LHON are not responsible for the prominence of optic nerve disease in Devic's neuromyelitis optica.	What is LHON, also known as Lebers syndrome?	Leber hereditary optic neuropathy (LHON)
Ingestion of soapberry fruit toxins hypoglycin A and methylenecyclopropylglycine has been linked to public health challenges worldwide. In 1976, over 100 years after Jamaican vomiting sickness (JVS) was first reported, the cause of JVS was linked to the ingestion of the toxin hypoglycin A produced by ackee fruit. A structural analogue of hypoglycin A, methylenecyclopropylglycine (MCPG), was implicated as the cause of an acute encephalitis syndrome (AES). Much of the evidence linking hypoglycin A and MCPG to these diseases has been largely circumstantial due to the lack of an analytical method for specific metabolites. This study presents an analytical approach to identify and quantify specific urine metabolites for exposure to hypoglycin A and MCPG. The metabolites are excreted in urine as glycine adducts methylenecyclopropylacetyl-glycine (MCPA-Gly) and methylenecyclopropylformyl-glycine (MCPF-Gly). These metabolites were processed by isotope dilution, separated by reverse-phase liquid chromatography, and monitored by electrospray ionization tandem mass spectrometry. The analytical response ratio was linearly proportional to the concentration of MCPF-Gly and MCPA-Gly in urine from 0.10 to 20 μg/mL with a correlation coefficient of r > 0.99. The assay demonstrated accuracy ≥80% and precision ≤20% RSD across the calibration range. This method has been applied to assess exposure to hypoglycin A and MCPG as part of a larger public health initiative and was used to provide the first reported identification of MCPF-Gly and MCPA-Gly in human urine.	What fruit causes Jamaican vomiting sickness?	In 1976, over 100 years after Jamaican vomiting sickness (JVS) was first reported, the cause of JVS was linked to the ingestion of the toxin hypoglycin A produced by ackee fruit.
Guanidino compounds (GCs), such as creatine, phosphocreatine, guanidinoacetic acid, creatinine, methylguanidine, guanidinosuccinic acid, γ-guanidinobutyric acid, β-guanidinopropionic acid, guanidinoethane sulfonic acid and α-guanidinoglutaric acid, are present in the mammalian brain. Although creatine and phosphocreatine play important roles in energy homeostasis in the brain, accumulation of GCs may induce epileptic discharges and convulsions. This review focuses on how physiologically important and/or neurotoxic GCs are distributed in the brain under physiological and pathological conditions. Transporters for GCs at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB) have emerged as substantial contributors to GCs distribution in the brain. Creatine transporter (CRT/solute carrier (SLC) 6A8) expressed at the BBB regulates creatine concentration in the brain, and represents a major pathway for supply of creatine from the circulating blood to the brain. CRT may be a key factor facilitating blood-to-brain guanidinoacetate transport in patients deficient in S-adenosylmethionine:guanidinoacetate N-methyltransferase, the creatine biosynthetic enzyme, resulting in cerebral accumulation of guanidinoacetate. CRT, taurine transporter (TauT/SLC6A6) and organic cation transporter (OCT3/SLC22A3) expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF. Interestingly, BBB efflux transport of GCs, including guanidinoacetate and creatinine, is negligible, though the BBB has a variety of efflux transport systems for synthetic precursors of GCs, such as amino acids and neurotransmitters. Instead, the BCSFB functions as a major cerebral clearance system for GCs. In conclusion, transport of GCs at the BBB and BCSFB appears to be the key determinant of the cerebral levels of GCs, and changes in the transport characteristics may cause the abnormal distribution of GCs in the brain seen in patients with certain neurological disorders.	Is SLC22A3 expressed in the brain?	CRT, taurine transporter (TauT/SLC6A6) and organic cation transporter (OCT3/SLC22A3) expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF.
X-Linked Emery-Dreifuss muscular dystrophy is caused by mutations in the gene encoding emerin. Emerin is an inner nuclear membrane protein important for repressive chromatin organization at the nuclear periphery. Myogenic differentiation is a tightly regulated process characterized by genomic reorganization leading to coordinated temporal expression of key transcription factors, including MyoD, Pax7, and Myf5. Emerin was shown to interact with repressive histone modification machinery, including HDAC3 and EZH2. Using emerin-null myogenic progenitor cells we established several EDMD-causing emerin mutant lines in the effort to understand how the functional interaction of emerin with HDAC3 regulates histone methyltransferase localization or function to organize repressive chromatin at the nuclear periphery. We found that, in addition to its interaction with HDAC3, emerin interacts with the histone methyltransferases EZH2 and G9a in myogenic progenitor cells. Further, we show enhanced binding of emerin HDAC3-binding mutants S54F and Q133H to EZH2 and G9a. Treatment with small molecule inhibitors of EZH2 and G9a reduced H3K9me2 or H3K27me3 throughout differentiation. EZH2 and G9a inhibitors impaired cell cycle withdrawal, differentiation commitment, and myotube formation in wildtype progenitors, while they had no effect on emerin-null progenitors. Interestingly, these inhibitors exacerbated the impaired differentiation of emerin S54F and Q133H mutant progenitors. Collectively, these results suggest the functional interaction between emerin and HDAC3, EZH2, and G9a are important for myogenic differentiation.	What is Emery-Dreifuss Muscular Dystrophy (EDMD)?	X-Linked Emery-Dreifuss muscular dystrophy is caused by mutations in the gene encoding emerin.
mRNA?	With this step, a pre-messenger RNA is processed and polyadenylated, giving rise to a mature mRNA bearing the characteristic poly(A) tract.	null
Hirschsprung disease (HSCR, OMIM 142623) is a developmental disorder characterized by the absence of ganglion cells along variable lengths of the distal gastrointestinal tract, which results in tonic contraction of the aganglionic gut segment and functional intestinal obstruction. The RET proto-oncogene is the major gene for HSCR with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. Many other genes have been described to be associated with the pathology, as NRG1 gene (8p12), encoding neuregulin 1, which is implicated in the development of the enteric nervous system (ENS), and seems to contribute by both common and rare variants. Here we present the results of a comprehensive analysis of the NRG1 gene in the context of the disease in a series of 207 Spanish HSCR patients, by both mutational screening of its coding sequence and evaluation of 3 common tag SNPs as low penetrance susceptibility factors, finding some potentially damaging variants which we have functionally characterized. All of them were found to be associated with a significant reduction of the normal NRG1 protein levels. The fact that those mutations analyzed alter NRG1 protein would suggest that they would be related with HSCR disease not only in Chinese but also in a Caucasian population, which reinforces the implication of NRG1 gene in this pathology.	Is RET the major gene involved in Hirschsprung disease?	The RET proto-oncogene is the major gene for HSCR with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology
We now recognize that not all breast cancers are the same. Different characteristics in gene expression profiles result in differential clinical behavior. With the use of gene microarrays, different subtypes of breast cancer have been characterized. These subtypes include the basal, the ERBB2+, and the luminal A, B and C subtypes. The importance of these different subtypes lies in the fact that they differ in clinical outcome, with the basal and ERBB2+ subtypes having the worst prognosis and the luminal A group having the best prognosis. However, identification of these subtypes is still not clinically used. Other strategies for evaluating tumors in a clinical setting have been developed using smaller sets of genes. One such strategy is the 21-gene assay (Oncotype DX), which is currently in commercial use in the USA. One advantage of this test is the use of paraffin-embedded blocks instead of previous methods, which required fresh frozen tissue. Oncotype DX has been shown to predict 10-year distant recurrence in patients with estrogen receptor-positive, axillary lymph node-negative breast cancer. This genomic assay has also been shown to predict chemotherapy and endocrine therapy response. Large, prospective, randomized clinical trials are currently underway using this genomic test. Other similar tests are also finding their way in clinical practice. A 70-gene assay, which has been developed by a group in The Netherlands, is currently being used as a tool to assign treatment in women with early stage breast cancer. In the near future, clinical decisions will most likely be dictated by the genetic characteristics of the tumor, with the clinical characteristics becoming less important. Tailoring our treatment based on individual tumor characteristics will help us develop better therapeutic strategies and save many of our patients from receiving unnecessary toxic therapy.	Does the Oncotype DX test work with paraffin embedded tissues?	One such strategy is the 21-gene assay (Oncotype DX), which is currently in commercial use in the USA. One advantage of this test is the use of paraffin-embedded blocks instead of previous methods, which required fresh frozen tissue.
Although it is debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients undergo endovascular treatment (ET) of CCSVI. A study is ongoing in Italy to evaluate the clinical outcome of ET. Severe adverse events (AEs) occurred in 15/462 subjects at a variable interval after ET: jugular thrombosis in seven patients, tetraventricular hydrocephalus, stroke, paroxysmal atrial fibrillation, status epilepticus, aspiration pneumonia, hypertension with tachicardia, or bleeding of bedsore in the remaining seven cases. One patient died because of myocardial infarction 10 weeks after ET. The risk of severe AEs related to ET for CCSVI must be carefully considered.	What is the lay name of the treatment for CCSVI (chronic cerebro-spinal venous insufficiency) in multiple sclerosis.	Although it is debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients undergo endovascular treatment (ET) of CCSVI
Regulatory sequences recognized by the unique pair of paralogous factors, CTCF and BORIS, have been implicated in epigenetic regulation of imprinting and X chromosome inactivation. Lung cancers exhibit genome-wide demethylation associated with derepression of a specific class of genes encoding cancer-testis (CT) antigens such as NY-ESO-1. CT genes are normally expressed in BORIS-positive male germ cells deficient in CTCF and meCpG contents, but are strictly silenced in somatic cells. The present study was undertaken to ascertain if aberrant activation of BORIS contributes to derepression of NY-ESO-1 during pulmonary carcinogenesis. Preliminary experiments indicated that NY-ESO-1 expression coincided with derepression of BORIS in cultured lung cancer cells. Quantitative reverse transcription-PCR analysis revealed robust, coincident induction of BORIS and NY-ESO-1 expression in lung cancer cells, but not normal human bronchial epithelial cells following 5-aza-2'-deoxycytidine (5-azadC), Depsipeptide FK228 (DP), or sequential 5-azadC/DP exposure under clinically relevant conditions. Bisulfite sequencing, methylation-specific PCR, and chromatin immunoprecipitation (ChIP) experiments showed that induction of BORIS coincided with direct modulation of chromatin structure within a CpG island in the 5'-flanking noncoding region of this gene. Cotransfection experiments using promoter-reporter constructs confirmed that BORIS modulates NY-ESO-1 expression in lung cancer cells. Gel shift and ChIP experiments revealed a novel CTCF/BORIS-binding site in the NY-ESO-1 promoter, which unlike such sites in the H19-imprinting control region and X chromosome, is insensitive to CpG methylation in vitro. In vivo occupancy of this site by CTCF was associated with silencing of the NY-ESO-1 promoter, whereas switching from CTCF to BORIS occupancy coincided with derepression of NY-ESO-1. Collectively, these data indicate that reciprocal binding of CTCF and BORIS to the NY-ESO-1 promoter mediates epigenetic regulation of this CT gene in lung cancer cells, and suggest that induction of BORIS may be a novel strategy to augment immunogenicity of pulmonary carcinomas.	Are CTCF and BORIS involved in genome regulation and cancer?	Collectively, these data indicate that reciprocal binding of CTCF and BORIS to the NY-ESO-1 promoter mediates epigenetic regulation of this CT gene in lung cancer cells, and suggest that induction of BORIS may be a novel strategy to augment immunogenicity of pulmonary carcinomas.
Mutation of EMD can underlie X-linked familial AF. Lys37del is associated with epithelial cell emerin deficiency, as in EDMD, yet it causes electrical atriomyopathy in the absence of skeletal muscle disease. Targeted genetic testing of EMD should be considered in patients with SND-associated AF and/or family history suggesting X-linked inheritance.	What is the inheritance pattern of Emery-Dreifuss muscular dystrophy?	Mutation of EMD can underlie X-linked familial AF. Lys37del is associated with epithelial cell emerin deficiency, as in EDMD, yet it causes electrical atriomyopathy in the absence of skeletal muscle disease. Targeted genetic testing of EMD should be considered in patients with SND-associated AF and/or family history suggesting X-linked inheritance.
Multiple loss-of-function (LOF) alleles at the same gene may influence a phenotype not only in the homozygote state when alleles are considered individually, but also in the compound heterozygote (CH) state. Such LOF alleles typically have low frequencies and moderate to large effects. Detecting such variants is of interest to the genetics community, and relevant statistical methods for detecting and quantifying their effects are sorely needed. We present a collapsed double heterozygosity (CDH) test to detect the presence of multiple LOF alleles at a gene. When causal SNPs are available, which may be the case in next generation genome sequencing studies, this CDH test has overwhelmingly higher power than single SNP analysis. When causal SNPs are not directly available such as in current GWA settings, we show the CDH test has higher power than standard single SNP analysis if tagging SNPs are in linkage disequilibrium with the underlying causal SNPs to at least a moderate degree (r²>0.1). The test is implemented for genome-wide analysis in the publically available software package GenABEL which is based on a sliding window approach. We provide the proof of principle by conducting a genome-wide CDH analysis of red hair color, a trait known to be influenced by multiple loss-of-function alleles, in a total of 7,732 Dutch individuals with hair color ascertained. The association signals at the MC1R gene locus from CDH were uniformly more significant than traditional GWA analyses (the most significant P for CDH = 3.11×10⁻¹⁴² vs. P for rs258322 = 1.33×10⁻⁶⁶). The CDH test will contribute towards finding rare LOF variants in GWAS and sequencing studies.	Which gene is responsible for red hair?	The association signals at the MC1R gene locus from CDH were uniformly more significant than traditional GWA analyses (the most significant P for CDH = 3.11×10⁻¹⁴² vs. P for rs258322 = 1.33×10⁻⁶⁶). The CDH test will contribute towards finding rare LOF variants in GWAS and sequencing studies.
Intracranial complications of paranasal sinusitis have become rare due to the use of antibiotics nowadays. However, several cases have been reported due the ability of paranasal sinusitis to cause serious complications. Once the infection spreads over the cranial structure, it could infect the orbits, underlying bones, meninges, adjacent veins, and brain. Subdural empyema is a rare but potentially life-threatening complication following paranasal sinusitis and should be considered as a neurological emergency. The location where subdural empyema may appear is a challenge in diagnosis and treatment. We report the case of a 17-year-old boy who presented in a state of somnolence due to interhemispheric and infratentorial subdural empyema with preseptal cellulitis secondary to pansinusitis. Early diagnosis and aggressive antibiotic treatment combined with neurosurgical operation were mandatorily implemented. The case was managed using a multidisciplinary approach including the ENT, eye, and nutrition departments. The boy achieved clinical improvement, with impairment of eye movement as the only persistent symptom before discharge. Daily supervision at the primary health care center with continuous antibiotic treatment was recommended to the patient. Pertinent literature with controversies in the management of subdural empyema will be briefly discussed in this case report.	Is subdural empyema a complication of sinusitis?	Subdural empyema is a rare but potentially life-threatening complication following paranasal sinusitis and should be considered as a neurological emergency.
Transcription factor binding sites (TFBSs) are most commonly characterized by the nucleotide preferences at each position of the DNA target. Whereas these sequence motifs are quite accurate descriptions of DNA binding specificities of transcription factors (TFs), proteins recognize DNA as a three-dimensional object. DNA structural features refine the description of TF binding specificities and provide mechanistic insights into protein-DNA recognition. Existing motif databases contain extensive nucleotide sequences identified in binding experiments based on their selection by a TF. To utilize DNA shape information when analysing the DNA binding specificities of TFs, we developed a new tool, the TFBSshape database (available at http://rohslab.cmb.usc.edu/TFBSshape/), for calculating DNA structural features from nucleotide sequences provided by motif databases. The TFBSshape database can be used to generate heat maps and quantitative data for DNA structural features (i.e., minor groove width, roll, propeller twist and helix twist) for 739 TF datasets from 23 different species derived from the motif databases JASPAR and UniPROBE. As demonstrated for the basic helix-loop-helix and homeodomain TF families, our TFBSshape database can be used to compare, qualitatively and quantitatively, the DNA binding specificities of closely related TFs and, thus, uncover differential DNA binding specificities that are not apparent from nucleotide sequence alone.	What is TFBSshape?	To utilize DNA shape information when analysing the DNA binding specificities of TFs, we developed a new tool, the TFBSshape database (available at http://rohslab.cmb.usc.edu/TFBSshape/), for calculating DNA structural features from nucleotide sequences provided by motif databases. The TFBSshape database can be used to generate heat maps and quantitative data for DNA structural features (i.e., minor groove width, roll, propeller twist and helix twist) for 739 TF datasets from 23 different species derived from the motif databases JASPAR and UniPROBE. As demonstrated for the basic helix-loop-helix and homeodomain TF families, our TFBSshape database can be used to compare, qualitatively and quantitatively, the DNA binding specificities of closely related TFs and, thus, uncover differential DNA binding specificities that are not apparent from nucleotide sequence alone.
Somatic mutations of calreticulin (CALR) have been identified as a main disease driver of myeloproliferative neoplasms, suggesting that development of drugs targeting mutant CALR is of great significance. Site-directed mutagenesis in the N-glycan binding domain (GBD) abolishes the ability of mutant CALR to oncogenically activate the thrombopoietin receptor (MPL). We therefore hypothesized that a small molecule targeting the GBD might inhibit the oncogenicity of the mutant CALR. Using an in silico molecular docking study, we identified candidate binders to the GBD of CALR. Further experimental validation of the hits identified a group of catechols inducing a selective growth inhibitory effect on cells that depend on oncogenic CALR for survival and proliferation. Apoptosis-inducing effects by the compound were significantly higher in the CALR-mutated cells than in CALR wild-type cells. Additionally, knockout or C-terminal truncation of CALR eliminated drug hypersensitivity in CALR-mutated cells. We experimentally confirmed the direct binding of the selected compound to CALR, disruption of the mutant CALR-MPL interaction, inhibition of the JAK2-STAT5 pathway, and reduction at the intracellular level of mutant CALR upon drug treatment. Our data indicate that small molecules targeting the GBD of CALR can selectively kill CALR-mutated cells by disrupting the CALR-MPL interaction and inhibiting oncogenic signaling.	Which disease is caused by mutations in the gene CALR?	Somatic mutations of calreticulin (CALR) have been identified as a main disease driver of myeloproliferative neoplasms,
On the histone H3 tail, Lys 9 and Lys 27 are both methylation sites associated with epigenetic repression, and reside within a highly related sequence motif ARKS. Here we show that the chromodomain proteins Polycomb (Pc) and HP1 (heterochromatin protein 1) are highly discriminatory for binding to these sites in vivo and in vitro. In Drosophila S2 cells, and on polytene chromosomes, methyl-Lys 27 and Pc are both excluded from areas that are enriched in methyl-Lys 9 and HP1. Swapping of the chromodomain regions of Pc and HP1 is sufficient for switching the nuclear localization patterns of these factors, indicating a role for their chromodomains in both target site binding and discrimination. To better understand the molecular basis for the selection of methyl-lysine binding sites, we solved the 1.8 A structure of the Pc chromodomain in complex with a H3 peptide bearing trimethyl-Lys 27, and compared it with our previously determined structure of the HP1 chromodomain in complex with a H3 peptide bearing trimethyl-Lys 9. The Pc chromodomain distinguishes its methylation target on the H3 tail via an extended recognition groove that binds five additional residues preceding the ARKS motif.	Which histone mark is recognized by HP1?	To better understand the molecular basis for the selection of methyl-lysine binding sites, we solved the 1.8 A structure of the Pc chromodomain in complex with a H3 peptide bearing trimethyl-Lys 27, and compared it with our previously determined structure of the HP1 chromodomain in complex with a H3 peptide bearing trimethyl-Lys 9.
Inflammatory bowel diseases (IBD) are known as chronic inflammatory disorders of the digestive tract, represented mainly by Crohn's disease (CD) and ulcerative colitis (UC). Among the main oral manifestations of IBD are cobblestoning of the oral mucosa, labial swellings with vertical fissures, pyostomatitis vegetans, angular cheilitis, perioral erythema, and glossitis. In this sense, understanding these nosological entities by dentists would help reach early and differential diagnosis. Thus, two case reports are presented and discussed based on theoretical references obtained by a literature review. The first case report refers to an adult patient whose IBD diagnosis was established after stomatological assessment. The second case was a patient with CD diagnosed in childhood with characteristic oral lesions.	Is there an association between pyostomatitis vegetans and Crohn's disease?	Among the main oral manifestations of IBD are cobblestoning of the oral mucosa, labial swellings with vertical fissures, pyostomatitis vegetans, angular cheilitis, perioral erythema, and glossitis.
Oral amitriptyline has been used as an analgesic in a wide range of pain settings. Despite long-term availability of a parenteral form, the few reports about this formulation have been limited to pharmacokinetic studies in normal volunteers, trials in depressed patients, and analyses of electroencephalogram (EEG) activation. We retrospectively reviewed our experience using intravenous (IV) amitriptyline at Children's Hospital, Boston and at Children's Hospital at Stanford. Eight children (aged 5-16.6 years), who were unable to tolerate medications by the oral route, received IV amitriptyline for a variety of indications, including neuropathic pain, depression, sleep disturbance, and as an adjuvant agent for opioid analgesia. One patient experienced an extrapyramidal reaction temporally related to the administration of IV amitriptyline, which was successfully managed with diphenhydramine. Further prospective, controlled studies are needed to further assess the safety, efficacy and tolerability of this novel use of amitriptyline.	What is the treatment of neuropathic pain in children?	Oral amitriptyline has been used as an analgesic in a wide range of pain settings. Despite long-term availability of a parenteral form, the few reports about this formulation have been limited to pharmacokinetic studies in normal volunteers, trials in depressed patients, and analyses of electroencephalogram (EEG) activation. We retrospectively reviewed our experience using intravenous (IV) amitriptyline at Children's Hospital, Boston and at Children's Hospital at Stanford. Eight children (aged 5-16.6 years), who were unable to tolerate medications by the oral route, received IV amitriptyline for a variety of indications, including neuropathic pain, depression, sleep disturbance, and as an adjuvant agent for opioid analgesia.
Genomic aberrations and gene expression-defined subtypes in the large METABRIC patient cohort have been used to stratify and predict survival. The present study used normalized gene expression signatures of paclitaxel drug response to predict outcome for different survival times in METABRIC patients receiving hormone (HT) and, in some cases, chemotherapy (CT) agents. This machine learning method, which distinguishes sensitivity vs. resistance in breast cancer cell lines and validates predictions in patients; was also used to derive gene signatures of other HT (tamoxifen) and CT agents (methotrexate, epirubicin, doxorubicin, and 5-fluorouracil) used in METABRIC. Paclitaxel gene signatures exhibited the best performance, however the other agents also predicted survival with acceptable accuracies. A support vector machine (SVM) model of paclitaxel response containing genes and was 78.6% accurate in predicting survival of 84 patients treated with both HT and CT (median survival ≥ 4.4 yr). Accuracy was lower (73.4%) in 304 untreated patients. The performance of other machine learning approaches was also evaluated at different survival thresholds. Minimum redundancy maximum relevance feature selection of a paclitaxel-based SVM classifier based on expression of genes and was 81.1% accurate in 53 CT patients. In addition, a random forest (RF) classifier using a gene signature ( and ) predicted >3-year survival with 85.5% accuracy in 420 HT patients. A similar RF gene signature showed 82.7% accuracy in 504 patients treated with CT and/or HT. These results suggest that tumor gene expression signatures refined by machine learning techniques can be useful for predicting survival after drug therapies.	What is the aim of the METABRIC project?	The present study used normalized gene expression signatures of paclitaxel drug response to predict outcome for different survival times in METABRIC patients receiving hormone (HT) and, in some cases, chemotherapy (CT) agents.
Williams syndrome (WS) is a neurodevelopmental genetic disorder associated with high rates of anxiety and social issues. We examined diurnal cortisol, a biomarker of the stress response, in adults with WS in novel and familiar settings, and compared these profiles to typically developing (TD) adults. WS and TD participants had similar profiles in a familiar setting, while participants with WS had elevated cortisol late in the day in the novel setting when social demands were higher. The cortisol awakening response in WS was associated with parent-reported levels of somatic complaints and social difficulties. Results suggest that adults with WS have a typical diurnal cortisol profile that may be sensitive to social and activity transitions throughout the day.	Which hormone abnormalities are common in Williams syndrome	Results suggest that adults with WS have a typical diurnal cortisol profile