Prophylactic activity of increasing doses of intravenous histamine in refractory migraine: Retrospective observations of a series of patients with migraine without aura

Background: Histamine is thought to play a pivotal role in the modulation of peripheral and central pain. The administration of increasing doses of histamine may lead to desensitization of receptors of histamine types 1 and 2, causing meningeal vasodilation, and to depletion of neuropeptides in the trigeminal ganglion, thus inhibiting the initiation of migraine. Objective: In this study, the efficacy and tolerability of increasing doses of IV histamine in migraine prophylaxis were investigated. Methods: This single-center, open-label, retrospective, controlled study was conducted at the Headache Center (Department of Internal Medicine, University of Florence, Villa Monna Tessa, Italy). Patients included in the study had 3 to 6 migraines without aura per month that were refractory to common symptomatic and prophylactic agents in the 6 months preceding the study. Patients were treated with IV histamine hydrochloride for 21 days starting with a dosage of 0.5 mg/d and increasing to 4.0 mg/d. To assess the efficacy of the treatment, these patients were matched for age; sex; and frequency, duration, and severity of attacks with untreated migraineurs. Clinical benefit was defined as ⩽ 1 migraine of mild intensity per month. Tolerability was assessed during the hospitalization period, and patients were instructed to contact the Headache Center to report any adverse effects after hospital discharge. Results: The histamine group comprised 47 patients (40 women, 7 men; mean [SD] age, 42.0 [8.6] years) and the control group comprised 23 patients (20 women, 3 men; mean [SD] age, 38.8 [8.4] years). The histamine-treated patients showed a clinical benefit lasting for a mean of 10.4 (4.2) months, while the patients in the control group showed a clinical benefit of 3.8 (1.9) months. The difference in the duration of the clinical benefit between the 2 groups was 6.6 months (95% CI, 5.15-7.99). Adverse effects consisted of flushing, heat sensation during infusion, headache, and palpitations. Conclusions: In this study, histamine showed lasting prophylactic efficacy in migraineurs. If further research confirms this preliminary finding, histamine could be considered when established prophylactic drugs, such as betablockers, calcium antagonists, antidepressants, and antiepileptics, have not been effective

A statistical approach to detect protein complexes at X-ray free electron laser facilities

The Flash X-ray Imaging (FXI) technique, under development at X-ray free electron lasers (XFEL), aims to achieve structure determination based on diffraction from individual macromolecular complexes. We report an FXI study on the first protein complex-RNA polymerase II-ever injected at an XFEL. A successful 3D reconstruction requires a high number of observations of the sample in various orientations. The measured diffraction signal for many shots can be comparable to background. Here we present a robust and highly sensitive hit-identification method based on automated modeling of beamline background through photon statistics. It can operate at controlled false positive hit-rate of 3 x10(-5). We demonstrate its power in determining particle hits and validate our findings against an independent hit-identification approach based on ion time-of-flight spectra. We also validate the advantages of our method over simpler hit-identification schemes via tests on other samples and using computer simulations, showing a doubled hit-identification power

Frontotemporal dementia and its subtypes: a genome-wide association study

SummaryBackground Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with {FTD} and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with {FTD} and 4308 controls), we did separate association analyses for each {FTD} subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and {FTD} overlapping with motor neuron disease FTD-MND), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, \{HLA\} locus (immune system), for rs9268877 (p=1·05 × 10−8; odds ratio=1·204 95% \{CI\} 1·11–1·30), rs9268856 (p=5·51 × 10−9; 0·809 0·76–0·86) and rs1980493 (p value=1·57 × 10−8, 0·775 0·69–0·86) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural \{FTD\} subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10−7; 0·814 0·71–0·92). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center

Intergenerational impacts of maternal mortality: Qualitative findings from rural Malawi

Background: Maternal mortality, although largely preventable, remains unacceptably high in developing countries such as Malawi and creates a number of intergenerational impacts. Few studies have investigated the far-reaching impacts of maternal death beyond infant survival. This study demonstrates the short- and long-term impacts of maternal death on children, families, and the community in order to raise awareness of the true costs of maternal mortality and poor maternal health care in Neno, a rural and remote district in Malawi. Methods: Qualitative in-depth interviews were conducted to assess the impact of maternal mortality on child, family, and community well-being. We conducted 20 key informant interviews, 20 stakeholder interviews, and six sex-stratified focus group discussions in the seven health centers that cover the district. Transcripts were translated, coded, and analyzed in NVivo 10. Results: Participants noted a number of far-reaching impacts on orphaned children, their new caretakers, and extended families following a maternal death. Female relatives typically took on caregiving responsibilities for orphaned children, regardless of the accompanying financial hardship and frequent lack of familial or governmental support. Maternal death exacerbated children’s vulnerabilities to long-term health and social impacts related to nutrition, education, employment, early partnership, pregnancy, and caretaking. Impacts were particularly salient for female children who were often forced to take on the majority of the household responsibilities. Participants cited a number of barriers to accessing quality child health care or support services, and many were unaware of programming available to assist them in raising orphaned children or how to access these services. Conclusions: In order to both reduce preventable maternal mortality and diminish the impacts on children, extended families, and communities, our findings highlight the importance of financing and implementing universal access to emergency obstetric and neonatal care, and contraception, as well as social protection programs, including among remote populations

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Funder: QingLan Research Project of Jiangsu for Outstanding Young TeachersFunder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical UniversityFunder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical UniversityAbstract: We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population

Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA\xe2\x80\x99s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Statistical processing of Flash X-ray Imaging of protein complexes

Flash X-ray Imaging (FXI) at X-ray Free Electron Lasers (XFELs) is a promising technique that permits the investigation of the 3D structure of molecules without the need for crystallization, by diffracting on single individual sample particles. In the past few years, some success has been achieved by using FXI on quite large biological complexes (40 nm-1 μm in diameter size). Still, the desired dream-goal of imaging a single individual of a molecule or a protein complex (<15 nm in diameter size) has not been reached yet. The main issue that prevented us from a complete success has been the low signal strength, almost comparable to background noise. That is particularly true for experiments performed at the Coherent X-ray Imaging (CXI) instrument at the Linac Coherent Light Source (LCLS). In this thesis, we provide a brief review of the CXI instrument (focusing on experiments there performed) and present a statistical method to deal with low signal-to-noise ratios. We take into account a variety of biological particles, showing the benefits of estimating a background model from sample data and using that for processing said data. Moreover, we present the results of some computer simulations in order to explore the limits and potentials of the proposed approach. Last, we show another method (named COACS) that, being fed with the previous findings from the background model, helps obtaining clearer results in the phase retrieval problem

Statistical processing of Flash X-ray Imaging of protein complexes

Flash X-ray Imaging (FXI) at X-ray Free Electron Lasers (XFELs) is a promising technique that permits the investigation of the 3D structure of molecules without the need for crystallization, by diffracting on single individual sample particles. In the past few years, some success has been achieved by using FXI on quite large biological complexes (40 nm-1 μm in diameter size). Still, the desired dream-goal of imaging a single individual of a molecule or a protein complex (<15 nm in diameter size) has not been reached yet. The main issue that prevented us from a complete success has been the low signal strength, almost comparable to background noise. That is particularly true for experiments performed at the Coherent X-ray Imaging (CXI) instrument at the Linac Coherent Light Source (LCLS). In this thesis, we provide a brief review of the CXI instrument (focusing on experiments there performed) and present a statistical method to deal with low signal-to-noise ratios. We take into account a variety of biological particles, showing the benefits of estimating a background model from sample data and using that for processing said data. Moreover, we present the results of some computer simulations in order to explore the limits and potentials of the proposed approach. Last, we show another method (named COACS) that, being fed with the previous findings from the background model, helps obtaining clearer results in the phase retrieval problem