Central nervous system tumors and agricultural exposures in the prospective cohort AGRICAN

Studies in farmers suggest a possible role of pesticides in the occurrence of Central Nervous System (CNS) tumors but scientific evidence is still insufficient. Using data from the French prospective agricultural cohort AGRICAN (Agriculture & Cancer), we investigated the associations between exposure of farmers and pesticide users to various kinds of crops and animal farming and the incidence of CNS tumors, overall and by subtypes. Over the 2005–2007, 181,842 participants completed the enrollment questionnaire that collected a complete job calendar with lifetime history of farming types. Associations were estimated using proportional hazards models with age as underlying timescale. During a 5.2 years average follow‐up, 273 incident cases of CNS tumors occurred, including 126 gliomas and 87 meningiomas. Analyses showed several increased risks of CNS tumors in farmers, especially in pesticide users (hazard ratio = 1.96; 95% confidence interval: 1.11–3.47). Associations varied with tumor subtypes and kinds of crop and animal farming. The main increases in risk were observed for meningiomas in pig farmers and in farmers growing sunflowers, beets and potatoes and for gliomas in farmers growing grasslands. In most cases, more pronounced risk excesses were observed among pesticide applicators. Even if we cannot completely rule out the contribution of other factors, pesticide exposures could be of primary concern to explain these findings.     

Understanding Lennox–Gastaut syndrome: insights from focal epilepsy patients with Lennox–Gastaut features

To delineate the clinical and EEG features of adults with focal epilepsy associated with a generalized paroxysmal fast activity (GPFA) pattern on EEG who developed refractory seizures, notably drop attacks, but do not fulfill the classical triad for the diagnosis of Lennox–Gastaut syndrome (LGS) and provide further insight into LGS mechanisms. Among 957 patients admitted to video-EEG monitoring between 2002 and 2015, we retrospectively research adult patients with refractory focal epilepsy, drop attacks and GPFA on EEG. We collected demographic, anamnestic, and clinical data from medical records. We reviewed for all patients the interictal and ictal video-EEG recordings. We identified ten patients with focal epilepsy and electro-clinical features of LGS. As compared to classical LGS patients, our patients: (1) began epilepsy later (15.4 ± 8 years); (2) exhibited exclusively focal onset seizures, including drop attacks seizures linked to focal asymmetrical tonic posturing seizures; (3) had a stable cognition over time and (4) evolved favourably with a good secondary response to treatments in 80% of cases. Interestingly, all patients exhibited apparent diffuse interictal and ictal EEG abnormalities but a detailed analysis revealed that 50% had asymmetrical GPFA and 70% secondary bilateral synchrony processes. We may hypothesize here that a process of “secondary LGS” occurred which produced a worsening of seizures with the apparition of drop attacks and GPFA on EEG. This study brings arguments to consider that some cases of LGS could be linked to the development of a “secondary epileptic network” driven by a primary focal epileptic zone.     

Bloodstream infection in adults with sickle cell disease: association with venous catheters, Staphylococcus aureus, and bone-joint infections

ABSTRACT:: Although well documented in children with sickle cell disease (SCD), the incidence, cause, and outcome of bloodstream infection (BSI) are poorly defined in adults with SCD. Through a 5-year retrospective analysis of a cohort of 900 patients followed at our institution, we identified 56 episodes of BSI in 47 patients. The incidence rate of BSI was 1.2 episodes per 100 patient-years. As compared to the patients followed in the cohort, those with BSI were more likely to be younger (p = 0.001), to have Hb-S disease (p = 0.008), severe disease (p = 0.001), or additional immunosuppression (p = 0.05). BSI was hospital-acquired in 46% of cases and mainly associated with venous catheters (41%) and Staphylococcus aureus (34%). Pneumococci were rarely identified (10.7%). Despite an adequate duration of antibiotic therapy, the course of BSI was marked by a high frequency of associated bone-joint infection. Bone-joint infection was noted in 18 patients (32% of episodes) and occurred either during the initial BSI episode (13 patients) or 1-6 months after BSI resolution (5 patients). Factors associated with the occurrence of bone-joint infection were previous osteonecrosis (relative risk, 2.5; 95% confidence interval, 1.2-5.3) and S. aureus infection (relative risk, 3.8; 95% confidence interval, 1.8-8.4). In conclusion, BSI is a rare event in adults with SCD compared to children. It mainly occurs in those with a severe underlying disease and a venous catheter. These patients have a high risk of associated bone-joint infection and therefore must be closely monitored.     

Microtubule-associated protein 2 (MAP2) is a neurosteroid receptor

The neurosteroid pregnenolone (PREG) and its chemically synthesized analog 3beta-methoxypregnenolone (MePREG) bind to microtubule-associated protein 2 (MAP2) and stimulate the polymerization of microtubules. PREG, MePREG, and progesterone (PROG; the physiological immediate metabolite of PREG) significantly enhance neurite outgrowth of nerve growth factor-pretreated PC12 cells. However, PROG, although it binds to MAP2, does not increase the immunostaining of MAP2, contrary to PREG and MePREG. Nocodazole, a microtubule-disrupting agent, induces a major retraction of neurites in control cultures, but pretreatment with PREG/MePREG is protective. Decreasing MAP2 expression by RNA interference does not modify PROG action, but it prevents the stimulatory effects of PREG and MePREG on neurite extension, showing that MAP2 is their specific receptor.     

Vertebral microanatomy in squamates: structure, growth and ecological correlates

The histological study of vertebrae in extant squamates shows that the internal vertebral structure in this group differs from that of other tetrapods. Squamate vertebrae are lightly built and basically composed of two roughly concentric osseous tubes--one surrounding the neural canal and the other constituting the peripheral cortex of the vertebra--connected by few thin trabeculae. This structure, which characteristically evokes that of a tubular bone, results from a peculiar remodelling process characterised by an imbalance between local bone resorption and redeposition; in both periosteal and endosteo-endochondral territories, bone is extensively resorbed but not reconstructed in the same proportion by secondary deposits. This process is particularly intense in the deep region of the centrum, where originally compact cortices are made cancellous, and where the endochondral spongiosa is very loose. This remodelling process starts at an early stage of development and remains active throughout subsequent growth. The growth of squamate centra is also strongly asymmetrical, with the posterior (condylar) part growing much faster than the anterior (cotylar) part. Preliminary analyses testing for associations between vertebral structure and habitat use suggest that vertebrae of fossorial taxa are denser than those of terrestrial taxa, those in aquatic taxa being of intermediate density. However, phylogenetically informed analyses do not corroborate these findings, thus suggesting a strong phylogenetic signal in the data. As our analyses demonstrate that vertebrae in snakes are generally denser than those of lizards sensu stricto, this may drive the presence of a phylogenetic signal in the data. More comprehensive sampling of fossorial and aquatic lizards is clearly needed to more rigorously evaluate these patterns.     

Immunogenicity and protective efficacy of tuberculosis DNA vaccines combining mycolyl-transferase Ag85A and phosphate transport receptor PstS-3

DNA vaccines encoding the 32,000 MW mycolyl-transferase Ag85A and the 40,000 MW phosphate-binding protein PstS-3 can elicit protective immune responses against experimental infection with Mycobacterium tuberculosis in C57BL/6 mice. Here we have analysed the vaccine potential of a combination of both antigens using plasmid vectors expressing either a fusion protein of both antigens or the separate proteins driven by two independent promoters (in pBudCE4.1 vector). Comparable levels of Ag85A specific T helper 1 (Th1) type immune responses could be induced by the two combination vaccines and the single vaccine encoding the mycolyl-transferase, whereas induction of PstS-3 specific Th1-mediated responses was impaired in both combination vaccines. In contrast, magnitude of CD8+ mediated responses against the PstS-3 protein was comparable following combination or single DNA vaccination. Antigenic competition was also observed at the antibody level; PstS-3 specific levels being lower in mice vaccinated with the fusion vector and Ag85A specific levels being lower in mice vaccinated with the combination pBudCE4.1 vector (as compared to levels obtained following single plasmid immunization). Protection against M. tuberculosis was only modestly improved in mice vaccinated with the DNA combinations. It is possible that prior activation of Ag85A specific CD4+ T cells directed against this common mycobacterial antigen leads to cross-competition for major histocompatibility complex class II-restricted peptide complexes of the Pst-3 antigen. This may have implications for future combination vaccines using Ag85.     

Nonredundant roles of TIRAP and MyD88 in airway response to endotoxin, independent of TRIF, IL-1 and IL-18 pathways

Inhaled endotoxins induce an acute inflammatory response in the airways mediated through Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). However, the relative roles of the TLR4 adaptor proteins TIRAP and TRIF and of the MyD88-dependent IL-1 and IL-18 receptor pathways in this response are unclear. Here, we demonstrate that endotoxin-induced acute bronchoconstriction, vascular damage resulting in protein leak, Th1 cytokine and chemokine secretion and neutrophil recruitment in the airways are abrogated in mice deficient for either TIRAP or MyD88, but not in TRIF deficient mice. The contribution of other TLR-independent, MyD88-dependent signaling pathways was investigated in IL-1R1, IL-18R and caspase-1 (ICE)-deficient mice, which displayed normal airway responses to endotoxin. In conclusion, the TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin critically depend on the expression of both adaptor proteins, TIRAP and MyD88, suggesting cooperative roles, while TRIF, IL-1R1, IL-18R signaling pathways are dispensable.     

Accumulation of memory T cells from childhood to old age: central and effector memory cells in CD4(+) versus effector memory and terminally differentiated memory cells in CD8(+) compartment

Memory T cells can be classified as central memory (T(CM), CD45RA(neg)CCR7(+)), effector memory (T(EM), CD45RA(neg)CCR7(neg)), and terminally differentiated cells (T(TD), CD45RA(+)CCR7(neg)) with different homing and effector capacities. In 101 healthy subjects aged from 5 to 96 years, distinct dynamics were evidenced between circulating CD4(+) and CD8(+) T cell populations. Naive CD4(+) and CD8(+) T cells decreased linearly with age, CD8(+) twice more rapidly. Memory cells outnumbered naive cells on average at 37.4 in the CD4(+) and 29.5 years of age in the CD8(+) pool. CD4(+) T(CM) and T(EM) cells were positively correlated and increased linearly at a similar rate with age, while CD4(+) T(TD) remained rare. CD8(+) T(EM) and T(TD) accumulated linearly with age, while T(CM) increased only slightly, and each memory subset was negatively correlated to the two others. Almost all CD8(+) T(TD) and some CD8(+) T(EM) had lost CD28 expression. Despite different dynamics, each individual CD4(+) naive and memory subset was correlated to the synonymous CD8(+) subset. Half of the subjects aged 65 years or older were characterized by extremely reduced CD8(+) naive and increased CD8(+) T(TD) cell counts, which could indicate an acceleration of the decay of the immune system from this age onward.