A novel human pain insensitivity disorder caused by a point mutation in ZFHX2

Chronic pain is a major global public health issue causing a severe impact on both the quality of life for sufferers and the wider economy. Despite the significant clinical burden, little progress has been made in terms of therapeutic development. A unique approach to identifying new human-validated analgesic drug targets is to study rare families with inherited pain insensitivity. Here we have analysed an otherwise normal family where six affected individuals display a pain insensitive phenotype that is characterized by hyposensitivity to noxious heat and painless bone fractures. This autosomal dominant disorder is found in three generations and is not associated with a peripheral neuropathy. A novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons, was identified by whole exome sequencing that segregates with the pain insensitivity. The mutation is predicted to change an evolutionarily highly conserved arginine residue 1913 to a lysine within a homeodomain. Bacterial artificial chromosome (BAC) transgenic mice bearing the orthologous murine p.R1907K mutation, as well as Zfhx2 null mutant mice, have significant deficits in pain sensitivity. Gene expression analyses in dorsal root ganglia from mutant and wild-Type mice show altered expression of genes implicated in peripheral pain mechanisms. The ZFHX2 variant and downstream regulated genes associated with a human pain-insensitive phenotype are therefore potential novel targets for the development of new analgesic drugs. awx326media1 5680039660001 The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.We thank the Medical Research Council (J.J.C., Career Development Award, G1100340), Wellcome Trust (200183/ Z/15/Z and 101054/Z/13/Z) and Arthritis Research UK (20200) for generous support and Shionogi for an academic research grant (165302). Thanks to the University of Siena for partially funding this research. J.T.B. is supported by a Research Fellowship from the Alzheimer�s Society. J.D.R. received funding from the Wellcome Trust through the London Pain Consortium and from Colciencias through a Francisco Jose de Caldas Scholarship (LASPAU, Harvard University). D.L.H.B. is a Wellcome senior clinical scientist (ref. no. 095698z/11/z and 202747/Z/16/Z) and member of the Wellcome Pain Consortium.Scopu

Investigating the Chemical Homogeneity of Low-Metallicity Blue Compact Dwarf Galaxies Using Integral Field Spectroscopy

It has been claimed in the past that in low-metallicity Blue Compact Dwarf (BCDs) galaxies, the N/O value is independent of metallicity (O/H ratio), implying the need to invoke a primary production of nitrogen in intermediate-mass stars, in addition to the secondary nitrogen produced from the CNO cycle in high-mass stars. In order to better understand this controversial issue we undertook an integral field spectroscopic study of the nebular gas within a sample of BCDs previously thought to have anomalously high N/O values. Here we present the results of this study for 3 BCDs: two with anomalous N/O values (Mrk 996 and UM 420) and one with more normal N/O values (UM 462). We describe in detail how we derived the physical conditions (Te, Ne) as a function of position within the galaxy, and as a consequence, how this revealed both revised metallicities and normal N/O ratios and uncovered one of the first clear evidences of nitrogen self-enrichment of an H i

The relationship of depressive symptoms, neurocognitive impairment and HAART adherence among HIV-infected persons

The association of depressive symptoms, neurocognitive impairment, and adherence to highly active antiretroviral therapy (HAART) was evaluated in 135 HIV-infected persons. Thirty percent reported nonadherence to HAART. Depressive symptoms (assessed with the Montgomery-Asberg Depression Rating Scale) and neurocognitive impairment (assessed with a neuropsychological test battery) were documented in 24% and 12%, respectively, of the study participants. Nonadherence to HAART was independently associated with worse depression rating scale scores (odds ratio = 1.05, 95% confidence interval [CI] = 1.00-1.10), acquisition of HIV through injection of drugs (odds ratio = 2.59, 95% CI = 1.05-6.39), and complaints about impairment of sexual activity (odds ratio = 6.62, 95% CI = 1.16-37.6). The presence of depressive symptoms, but not neurocognitive impairment, was associated with nonadherence

Delayed presentation and late testing for HIV : demographic and behavioural risk factors in a multicenter study in Italy

Ensuring timely access to care for persons with HIV is an important public health goal. To identify factors associated with delayed presentation to medical care after testing HIV-positive or with late HIV testing, we studied 968 patients at their first HIV care visit, enrolled in a multicenter study in Italy from 1997-2000. Patients completed a questionnaire on HIV-testing history, sexual behavior, and drug use behavior. Delayed presenters were patients with >6 months between their first HIV-positive test and presentation for HIV care; late testers were patients with CD4 count < 200 /mm or clinically defined AIDS at their first HIV-positive test. Among the study patients, 255 (26.3%) were delayed presenters, and 280 (28.9%) were late testers. In multinomial logistic regression analysis, injection drug use significantly increased (odds ratio [OR]= 5.04) the probability of delayed presentation but reduced (OR = 0.55) the chance of late testing. A previous HIV-negative test was associated with a reduced risk of both delayed presentation (OR = 0.39) and late testing (OR = 0.36). Unemployment was positively associated with delayed presentation and increasing age with late testing, whereas HIV counseling at the time of first positive HIV test strongly (OR = 0.42) reduced the odds of delayed presentation. Interventions aimed at promoting timely access to care of HIV-infected persons should consider differentiated programs for delayed presentation and late testing

Sexual behaviour of women living with HIV/AIDS naive for antiretroviral therapy: the ICONA-BEHEPI Study.

Abstract This study describes the sexual behaviours of women living with HIV, and assesses differences by history of drug use. Its general aim is to contribute in the design of programmes to help people with HIV/AIDS (PWH/A) adopt and maintain safe sexual behaviours. A self-administered questionnaire on sexual and drug use behaviours was distributed to study participants. Between 1997 and 1999, 573 women with HIV infection naive to antiretroviral therapies completed the questionnaire (of whom 234 reported a history of injection drug use (IDU) and were enrolled in the study. Non-IDU women reported fewer sexual partners, both in their lifetime and in the preceding month, than IDU women: 19% of IDU and 4% of non-IDU women reported more than 25 lifetime sexual partners (p < 0.001). Interestingly, 83% of non-IDU women were infected by their regular partners: these women reported the lowest number of sexual partners. No difference emerged between IDU and non-IDU women in terms of number of sexual intercourse in the two weeks preceding the interview or in terms of condom use in the last intercourse (reported, overall, by 54% of these 573 women). Among women who had sex partners at the time of interview, more non-IDU (65%) than IDU (43%) women reported HIV-positive partners (p < 0.001). Overall, these findings stress a marked heterogeneity in the levels of past and recent sexual promiscuity according to history of drug use. It suggests the need to differentiate and individualize messages about self-protection and behaviours that may prevent further spread of HIV infection

Cognitive and affective disorders associated to HIV infection in the HAART era. Findings from the NeuroICONA Study.

Objective: To assess the natural story of HIV-associated affective and cognitive disorders and the relationship with clinical, pharmacological, immunological and behavioural factors. Method: A total of 395 HIV-positive patients, naive to Highly Active Antirectroviral therapy (HAART), with no severe psychiatric disorders have been enrolled in the Neuro-ICONA Study. All participants were administered a comprehensive data collection instrument including an addiction behaviour survey, a medical problem list, a psychiatric assessment, a validated neuropsychological test battery. Results: The global prevalence of cognitive impairment and of prominent depressive symptomatology were 17.9 and 15.5%, respectively. A significant difference in the prevalence of prominent depressive symptomatology was observed between patients in HAART and those not taking HAART(14.1 vs. 23.8%; P = 0.05). Conclusion: Depressive and cognitive disorders affect a substantial proportion of HIV-seropositive subjects. The prevalence of prominent depressive symptomatology appears to significantly vary in relationship to the therapeutic protocol

Identification of a Local Sample of Gamma-Ray Bursts Consistent with a Magnetar Giant Flare Origin

International audienceCosmological gamma-ray bursts (GRBs) are known to arise from distinct progenitor channels: short GRBs mostly from neutron star mergers and long GRBs from a rare type of core-collapse supernova (CCSN) called collapsars. Highly magnetized neutron stars called magnetars also generate energetic, short-duration gamma-ray transients called magnetar giant flares (MGFs). Three have been observed from the Milky Way and its satellite galaxies, and they have long been suspected to constitute a third class of extragalactic GRBs. We report the unambiguous identification of a distinct population of four local (99.9% confidence. These properties, the host galaxies, and nondetection in gravitational waves all point to an extragalactic MGF origin. Despite the small sample, the inferred volumetric rates for events above 4 × 1044 erg of Gpc−3 yr−1 make MGFs the dominant gamma-ray transient detected from extragalactic sources. As previously suggested, these rates imply that some magnetars produce multiple MGFs, providing a source of repeating GRBs. The rates and host galaxies favor common CCSN as key progenitors of magnetars