Bone marrow-resident memory T cells survive pretransplant chemotherapy and contribute to early immune reconstitution of patients with acute myeloid leukemia given mafosfamide-purged autologous bone marrow transplantation

OBJECTIVE: Studies of memory T cells transferred with the graft are relevant to better understand the early immune reconstitution of patients given autologous bone marrow transplantation (A-BMT). A critical question is whether memory T cells resident in bone marrow (BM) of patients with hematological malignancies are resistant to either pretransplant chemotherapy or ex vivo pharmacological purging. PATIENTS AND METHODS: To address these issues, we evaluated the frequency of tetanus-toxoid (TT)-specific proliferating T-cell precursors (TT-PTCp) in BM and peripheral blood (PB) of eight patients with acute myeloid leukemia (AML) given A-BMT after in vitro purging of BM with mafosfamide. Patients were studied at the time of BM harvesting and five of them also after A-BMT. RESULTS: The range of TT-PTCp frequencies found after A-BMT were comparable with those observed in PB and in BM at the time of harvesting and did not differ significantly from those of eight age-matched healthy subjects who donated BM for a human leukocyte antigen-identical sibling. TT-PTCp frequencies in BM, studied before and after ex vivo purging, appeared not to be affected by incubation with mafosfamide. We also compared the T-cell receptor (TCR)-Vbeta-repertoire usage of TT-specific T-cell lines (TT-TCL) in BM of patients at the time of harvesting and in their PB 2 months after transplantation. The same TCR-clonotypes were detected in TT-TCL at time of harvesting and after A-BMT. CONCLUSION: These data indicate that BM-resident memory T cells of patients with AML are resistant to both pretransplant chemotherapy and ex vivo pharmacological purging and may contribute to immune reconstitution after A-BMT.     

Electrophysiological responses to visuospatial regularity

Humans are quicker to detect reflectional than rotational or translational symmetry, despite the fact that these patterns are equally regular. We were interested in the neural correlates of these perceptual effects. Participants viewed random, reflection, rotation, and translation patterns while we recorded EEG from the scalp. Half the participants classified the pattern regularity overtly, the other half did not explicitly attend to pattern regularity but reported rare oddball trials, where two squares were embedded among the dots. The amplitude of a symmetry‐related ERP known as the sustained posterior negativity was most pronounced for reflection, then rotation and translation. We suggest that reflectional symmetry, despite its biological significance, may not be processed by unique visual mechanisms, but instead it could be a preferred stimulus for a more general regularity‐sensitive network in the extrastriate visual cortex.     

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

In pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections, the translocation of microbial products from the gastrointestinal (GI) tract to portal and systemic circulation has been proposed as a major driver of the chronic immune activation that is associated with disease progression. Consistently, microbial translocation is not present in nonpathogenic SIV infections of natural host species. In vivo studies demonstrated that HIV/SIV-associated microbial translocation results from a series of immunopathological events occurring at the GI mucosa: (i) early and severe mucosal CD4⁺ depletion, (ii) mucosal immune hyperactivation/persistent inflammation; (iii) damage to the integrity of the intestinal epithelium with enterocyte apoptosis and tight junction disruption; and (iv) subverted the gut microbiome, with a predominance of opportunistic bacteria. Direct in situ evidence of microbial translocation has been provided for SIV-infected rhesus macaques showing translocated microbial products in the intestinal lamina propria and distant sites. While the mechanisms by which microbial translocation causes immune activation remain controversial, a key pathogenic event appears to be innate immunity activation via Toll-like receptors and other pathogen recognition receptors. Accumulating clinical observations suggest that microbial translocation might affect HIV disease progression, response to therapy, and non-AIDS comorbidities. Given its detrimental effect on overall immunity, several interventions to prevent/block microbial translocation are currently under investigation as novel therapeutic agents for HIV/AIDS.     

Nerve ultrasound in hereditary transthyretin amyloidosis: red flags and possible progression biomarkers

Journal of Neurology - Diagnostic delay of hereditary transthyretin amyloidosis (ATTRv, v for variant) prevents timely treatment and, therefore, concurs to the mortality of the disease. The aim of...     

Real world experience with teriflunomide in multiple sclerosis: the TER-Italy study

Journal of Neurology - To identify baseline factors associated with disease activity in patients with relapsing–remitting multiple sclerosis (RRMS) under teriflunomide treatment. This was an...     

The female pelvic floor through midlife and aging

Female pelvic floor is a complex functional unit involved in multiple functions that extend beyond the sole support of pelvic organs. Pelvic floor dysfunction globally affects micturition, defecation and sexual activity. Evolutionary modifications such ad adaptation to upright standing, walking and the need to deliver fetuses with larger head diameters made the fascial and muscle support of the pelvic floor vulnerable, therefore predisposing women to pelvic organ prolapse and incontinence. Different than in males, the female pelvic floor undergoes a number of adaptive changes related to life and endocrine events. Most of the clinical manifestations of these changes become apparent after menopause and throughout aging in women. This review article summarizes the key aspects of the pathophysiology and the clinics of the modifications of the pelvic floor in women through midlife and beyond. A particular focus is given to the relationship between urinary and bowel dysfunction.     

Epidemiological studies on Echinococcus in Pampas fox (Lycalopex gymnocercus) and European hare (Lepus europaeus) in Buenos Aires province, Argentina

In Argentina, hydatid disease caused by Echinococcus granulosus is widespread. The south of Buenos Aires province, Argentina, is one of the three regions where hydatidosis is endemic. Although domestic dogs and sheep are considered to be the main hosts for E. granulosus, the potential role of wildlife in the local transmission of E. granulosus has not been investigated. The aim of this study was to estimate the hydatidosis/echinococcosis prevalence in European hare (Lepus europaeus) and Pampas fox (Lycalopex gymnocercus), two abundant species with a strong predator–prey relationship in rural areas of Buenos Aires province using different diagnostic tests. A total of 61 fox intestines were examined, finding that 52 (85.2 %) harbored at least one helminth species. However, no adult or immature form of Echinococcus sp. was found in the intestinal contents. Coproparasitological analysis and Copro–ELISA followed by Copro–PCR were used as supplementary diagnostic tests. Only one (1.7 %) of 59 fecal samples was positive to Taeniidae eggs by coproparasitological analysis, but this same sample was negative by the Copro–ELISA test. The analysis by Copro–ELISA showed 6 of 57 (10.6 %) positive samples, but the Copro–PCR tests carried out on these samples were negative to E. granulosus. A total of 6,808 lungs, 3,576 livers, and 3,542 hearts of hunted hares were examined and palpated, but no structure resembling hydatid cysts were detected. Our results suggest that hares and Pampas foxes are not currently important wild reservoirs of E. granulosus in the studied area.     

Photoparoxysmal response in ADCK3 autosomal recessive ataxia: a case report and literature review

Mutations in AarF domain‐containing kinase 3 (ADCK3) are responsible for the most frequent form of hereditary coenzyme Q10 (CoQ10) deficiency (Q10 deficiency‐4), which is mainly associated with autosomal recessive cerebellar ataxia type 2 (ARCA2). Clinical presentation is characterized by a variable degree of cerebellar atrophy and a broad spectrum of associated symptoms, including muscular involvement, movement disorders, neurosensory loss, cognitive impairment, psychiatric symptoms and epilepsy. In this report, we describe, for the first time, a case of photoparoxysmal response in a female patient with a mutation in ADCK3. Disease onset occurred in early childhood with gait ataxia, and mild‐to‐moderate degeneration. Seizures appeared at eight years and six months, occurring only during sleep. Photoparoxysmal response was observed at 14 years, almost concomitant with the genetic diagnosis (c.901C>T;c.589‐3C>G) and the start of CoQ10 oral supplementation. A year later, disease progression slowed down, and photosensitivity was attenuated. A review of the literature is provided focusing on epileptic features of ADCK3‐related disease as well as the physiopathology of photoparoxysmal response and supposed cerebellar involvement in photosensitivity. Moreover, the potential role of CoQ10 oral supplementation is discussed. Prospective studies on larger populations are needed to further understand these data.