Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

X-linked chronic granulomatous disease (CGD) is associated with defective phagocytosis, life-threatening infections, and inflammatory complications. We performed a clinical trial of lentivirus-based gene therapy in four patients (NCT02757911). Two patients show stable engraftment and clinical benefits, whereas the other two have progressively lost gene-corrected cells. Single-cell transcriptomic analysis reveals a significantly lower frequency of hematopoietic stem cells (HSCs) in CGD patients, especially in the two patients with defective engraftment. These two present a profound change in HSC status, a high interferon score, and elevated myeloid progenitor frequency. We use elastic-net logistic regression to identify a set of 51 interferon genes and transcription factors that predict the failure of HSC engraftment. In one patient, an aberrant HSC state with elevated CEBPβ expression drives HSC exhaustion, as demonstrated by low repopulation in a xenotransplantation model. Targeted treatments to protect HSCs, coupled to targeted gene expression screening, might improve clinical outcomes in CGD

System-level determinants of immunization coverage disparities among health districts in Burkina Faso: a multiple case study

<p>Abstract</p> <p>Background</p> <p>Despite rapid and tangible progress in vaccine coverage and in premature mortality rates registered in sub-Saharan Africa, inequities to access remain firmly entrenched, large pockets of low vaccination coverage persist, and coverage often varies considerably across regions, districts, and health facilities' areas of responsibility. This paper focuses on system-related factors that can explain disparities in immunization coverage among districts in Burkina Faso.</p> <p>Methods</p> <p>A multiple-case study was conducted of six districts representative of different immunization trends and overall performance. A participative process that involved local experts and key actors led to a focus on key factors that could possibly determine the efficiency and efficacy of district vaccination services: occurrence of disease outbreaks and immunization days, overall district management performance, resources available for vaccination services, and institutional elements. The methodology, geared toward reconstructing the evolution of vaccine services performance from 2000 to 2006, is based on data from documents and from individual and group interviews in each of the six health districts. The process of interpreting results brought together the field personnel and the research team.</p> <p>Results</p> <p>The districts that perform best are those that assemble a set of favourable conditions. However, the leadership of the district medical officer (DMO) appears to be the main conduit and the rallying point for these conditions. Typically, strong leadership that is recognized by the field teams ensures smooth operation of the vaccination services, promotes the emergence of new initiatives and offers some protection against risks related to outbreaks of epidemics or supplementary activities that can hinder routine functioning. The same is true for the ability of nurse managers and their teams to cope with new situations (epidemics, shortages of certain stocks).</p> <p>Conclusion</p> <p>The discourse on factors that determine the performance or breakdown of local health care systems in lower and middle income countries remains largely concentrated on technocratic and financial considerations, targeting institutional reforms, availability of resources, or accessibility of health services. The leadership role of those responsible for the district, and more broadly, of those we label "the human factor", in the performance of local health care systems is mentioned only marginally. This study shows that strong and committed leadership promotes an effective mobilization of teams and creates the conditions for good performance in districts, even when they have only limited access to supports provided by external partners.</p> <p>Abstract in French</p> <p>See the full article online for a translation of this abstract in French.</p

Glial Fibrillary Acidic Protein Autoimmunity: A French Cohort Study

Background and ObjectivesTo report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies.MethodsWe retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers.ResultsWe identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies.DiscussionGFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome

A reassessment of the Hypoglossum group (Delesseriaceae, Rhodophyta), with a critique of its genera

A reassessment of the Hypoglossum group (Delesseriaceae, Rhodophyta), with a critique of its genera. Eight genera are assigned to the Hypoglossum Kützing, Phitymophora J. Agardh, Pseudobranchioglossum Bodard, and Zellera Martens. The circumscription of the group is emended to include forms with network-forming ( Zellera ) an dspirally twisted ( Duckerella ) thalli. The definition of the group is lalso modified to include members (e.g. some species of Hypoglossum ) in which tetrasporangia are produced by primary cells as in the Caloglossa group. Exogenous branching, a distinguishing feature of the closely related Caloglossa group, never occurs in the Hypoglossum group.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47938/1/10152_2006_Article_BF02365624.pd

Antidepressant-like effect of tramadol in the unpredictable chronic mild stress procedure: Possible involvement of the noradrenergic system

PubMedID: 17912046Tramadol, which inhibits the reuptake of noradrenaline and serotonin, is effective in animal models of depression. Its antidepressant-like effects may be mediated mainly by the noradrenergic system. This study investigated the role of the noradrenergic system in the antidepressant-like effects of tramadol and desipramine in the unpredictable chronic mild stress model. We assessed the involvement of ß-adrenoreceptors, particularly ß2-receptors in the activity of these drugs. In addition, we measured the level of noradrenaline and its metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the locus coeruleus, hypothalamus, hippocampus and cerebellum in stressed mice. Unpredictable chronic mild stress induced a degradation of coat state and decreased grooming behaviour in the splash test, which was reversed by the chronic administration of tramadol (20 mg/kg) and desipramine (10 mg/kg). The nonselective ß-adrenoreceptor antagonist propranolol (5 mg/kg, intraperitoneally) and the selective ß2-receptor antagonist ICI 118,551 (2 mg/kg, intraperitoneally) reversed the antidepressant-like effects of tramadol and desipramine. Moreover, chronic tramadol and desipramine treatment increased the level of noradrenaline (NA) and MHPG in the locus coeruleus but not in the cerebellum, whereas only MHPG level was increased in the hypothalamus. Tramadol, however, increased the levels of MHPG and NA in the hippocampus, whereas desipramine only increased NA level. These data support the view that the noradrenergic system plays an important role in the antidepressant-like action of tramadol. © 2007 Lippincott Williams & Wilkins, Inc

Effects of 5,7-dihydroxytryptamine lesion of the dorsal raphe nucleus on the antidepressant-like action of tramadol in the unpredictable chronic mild stress in mice

PubMedID: 18581097Rationale: Tramadol is a centrally acting clinically effective analgesic, with a weak opioid receptor affinity. It shows antidepressant-like effects in animal models such as forced swimming test, learned helplessness, and unpredictable chronic mild stress (UCMS) and enhances the concentrations of noradrenaline (NA) and serotonin (5-HT) by interfering with their reuptake and release mechanisms, like some antidepressants. Objectives: The aim of this study was to explore whether the antidepressant-like effects of tramadol is affected by the serotonergic system. For this purpose, the effects of a lesion of the dorsal raphe nucleus (DRN) by 5,7-dihydroxytryptamine (5,7-DHT) on the action of tramadol (20 mg/kg, i.p.) on depression-related behavior and neurochemical correlates were investigated in mice. From the third week onward, we administered tramadol chronically during 4 weeks. Results: Tramadol reversed the physical and behavioral abnormalities induced by the UCMS. Furthermore, the lesion of the DRN by 5,7-DHT antagonized the antidepressant-like effects of tramadol on the coat state, in the splash test but not in the resident-intruder test. The results obtained by high-pressure liquid chromatography showed that the level of 5-HT was reduced by the lesion in some brain regions without affecting the level of NA. Moreover, while the UCMS regimen diminished the level of 5-HT, tramadol increased the level of this neurotransmitter in certain regions. Conclusions: These results seem to indicate that the serotonergic system is critically involved in the antidepressant-like effects of tramadol in the UCMS in mice. © 2008 Springer-Verlag