Group A Escherichia coli-Related Purpura Fulminans: an Unusual Manifestation Due to an Unusual Strain?

We describe an exceptional case of life-threatening group A Escherichia coli-induced purpura fulminans. Genotyping of common polymorphisms in genes involved in innate immunity or coagulation did not reveal known susceptibility to such a manifestation. Genetic analysis of the strain revealed an unusual conserved virulence plasmidic region, pointing out its potential virulence.     

Total body irradiation–high-dose cytosine arabinoside and melphalan followed by allogeneic bone marrow transplantation from HLA-identical siblings in the treatment of children with acute lymphoblastic leukaemia after relapse while receiving chemotherapy: a Société Française de Greffe de Moelle study

We investigated the use of a new conditioning regimen followed by allogeneic bone marrow transplantation (BMT) for treating children with acute lymphoblastic leukaemia (ALL) after relapse within 6 months of the completion of therapy. One hundred and sixteen children with acute lymphoblastic leukaemia in second or subsequent complete remission (CR) underwent allogeneic bone marrow transplantation from HLA-identical siblings after a preparative regimen comprising total body irradiation (TBI), high-dose cytosine arabinoside and melphalan (TAM regimen). The Kaplan-Meier product-limit estimate (mean ± SE) of disease-free survival (DFS) at 7 years was 59.5 ± 9% (95% confidence interval). The estimated chance of relapse was 22.5 ± 15% with a median follow-up of 88.5 months (range 51–132). 26 patients (22.4%) died with no evidence of recurrent leukaemia, mainly from interstitial pneumonitis, veno-occlusive disease or acute graft-versus-host disease (GVHD). Three factors significantly affected DFS: acute GVHD, site of relapse and, for children in second remission after a marrow relapse, the disease status at the time of transplantation. The DFS were 59.02 ± 12.6%, 37.5 ± 19.8% and 77.4 ± 15% among patients in CR2 after a marrow relapse, in CR3 or in untreated partial marrow relapse, and in CR2 after an isolated CNS relapse, respectively. The lowest DFS was seen in children with acute GVHD grades 3–4. Two significant factors were associated with relapse: the marrow status at the time of transplantation and chronic GVHD. The relapse rate was lower among children in CR2 or with chronic GVHD. We conclude that transplantation after the TAM regimen is an effective therapy for this population with acceptable toxicity, particularly for children in second remission after a very early marrow relapse, or those with early isolated CNS involvement.     

Quantitative PCR technique for the identification of microrearrangements of the AZFc region

Purpose: The AZFc region spans about 3.5 Mb and contains many amplicons causing recombination events. Several papers have reported the occurrence of AZFc partial deletions resulting from non allelic homologous recombination (NAHR) (“gr-gr”, “b1-b3” or “b2-b3” deletions), particularly in infertile patients. DAZ genes are present in 4 copies and rearrangements involve a modification of the number of DAZ genes. Methods: In addition to STS plus/minus PCR, we developed a quantitative technique using real time PCR (Q-PCR) to determine the number of DAZ genes. Fourteen DNA controls were selected to validate the use of Q-PCR to detect AZFc microrearrangements, and sperm DNA samples from 30 fertile men were studied. Results: Rearrangements of 14 controls were well identified with Q-PCR, and 2 AZFc partial deletions were detected in fertile men (1 “gr-gr” and 1 “b2-b3”). Conclusion: Q-PCR represents a well-adapted method to detect microrearrangements of the Y-chromosome, complementary to STS analysis.     

Mode of delivery and fecal incontinence at midlife: a study of 2,640 women in the Gazel cohort

OBJECTIVE: To estimate obstetric risk factors of fecal incontinence among middle-aged women. METHODS: We conducted a mail survey of the Gazel cohort of volunteers for epidemiologic research. In 2000, a questionnaire on anal incontinence was mailed to 3,114 women who were then between the ages of 50 and 61 years; 2,640 (85%) women returned the completed questionnaire. Fecal incontinence was defined by involuntary loss of stool. Logistic regression was used to estimate the effect of obstetric and general risk factors. RESULTS: Prevalence of fecal incontinence in the past 12 months was 9.5% (250). Significant risk factors for fecal incontinence were completion of high school (adjusted odds ratio [OR] 1.5, 95% confidence interval [CI] 1.1-2.0), self-reported depression (OR 2.1, 95% CI 1.6-2.7), overweight or obesity measured by body mass index (BMI) (OR 1.5 for BMI of 25-30, 95% CI 1.1-2.0; OR 1.6 for BMI more than 30, 95% CI 1.1-2.5), surgery for urinary incontinence (OR 3.5, 95% CI 2.0-6.1), and anal surgery (OR 1.7, 95% CI 1.1-2.9). No obstetric variable (parity, mode of delivery, birth weight, episiotomy, or third-degree perineal tear) was significant. Prevalence of fecal incontinence was similar for nulliparous, primiparous, secundiparous, and multiparous women (11.3%, 9.0%, 9.0%, and 10.4%, respectively), and among parous women, it was similar for women with spontaneous vaginal, instrumental (at least one), or only cesarean deliveries (9.3%, 10.0%, and 6.6%, respectively). CONCLUSION: In our population of women in their 50s, fecal incontinence was not associated with either parity or mode of delivery.     

Rodents monitor their error in self-generated duration on a single trial basis

A fundamental question in neuroscience is what type of internal representation leads to complex, adaptive behavior. When faced with a deadline, individuals’ behavior suggests that they represent the mean and the uncertainty of an internal timer to make near-optimal, time-dependent decisions. Whether this ability relies on simple trial-and-error adjustments or whether it involves richer representations is unknown. Richer representations suggest a possibility of error monitoring, that is, the ability for an individual to assess its internal representation of the world and estimate discrepancy in the absence of external feedback. While rodents show timing behavior, whether they can represent and report temporal errors in their own produced duration on a single-trial basis is unknown. We designed a paradigm requiring rats to produce a target time interval and, subsequently, evaluate its error. Rats received a reward in a given location depending on the magnitude of their timing errors. During the test trials, rats had to choose a port corresponding to the error magnitude of their just-produced duration to receive a reward. High-choice accuracy demonstrates that rats kept track of the values of the timing variables on which they based their decision. Additionally, the rats kept a representation of the mapping between those timing values and the target value, as well as the history of the reinforcements. These findings demonstrate error-monitoring abilities in evaluating self-generated timing in rodents. Together, these findings suggest an explicit representation of produced duration and the possibility to evaluate its relation to the desired target duration.

In neuroscience, a fundamental question is how rich the internal representation of an individual’s experience must be to yield adaptive behavior. Let us consider a hungry individual in need of finding food fast: The individual may adopt a trial-and-error foraging strategy to maximize reward but may also, to maximize its efficiency, represent rich experiential variables, such as how much time it takes to reach a source of food. Both representing elapsed time and monitoring its inherent uncertainty plays an important role in adaptive behavior, learning, and decision making (1). When representing these variables, the sources of uncertainty are both exogenous (stimuli driven) and endogenous (neural implementation). The mapping of exogenous sources of temporal uncertainty has been well described in timing behavior: For instance, mice can adjust their behaviors to the width of the distribution of temporal intervals provided through external stimuli (2). On the other hand, the endogenous sources of uncertainty for time perception are less understood and more difficult to address.Evidence that animals are sensitive and have access to the internal uncertainty of elapsed time comes from a task in which the individual must produce a required target duration using a lever press or a key press (1, 3, 4). In a task in which individuals must produce an interval of fixed duration to obtain a reward (Fig. 1A), a plausible strategy to maximize reward would be to set the produced duration to be longer than the required target duration so as to allow a margin of error [internal target duration; (5)]. This is because the larger an individual’s representational uncertainty, the larger the margin of error to maximize the reward. Consistent with this, studies have shown that the magnitude of error in produced intervals varies with the magnitude of temporal uncertainties (6, 7), and participants with larger temporal uncertainty set larger margins of errors [Fig. 1B and SI Appendix, Fig. S2; (1, 7)]. The observed optimization of timing behavior begs the question of how rich the representation of elapsed time must be.Open in a separate windowFig. 1.The TP task and error-monitoring protocol. (A) Schematic of a box arrangement with a lever available in the middle of the panel and reward ports on the left and right side of the lever. Reward availability was signaled by the port lit, depicted by the lightbulbs. Reward delivery was triggered by rats’ nose poke in the reward port. Depending on the group assignment, rats had to either hold the lever pressed for a minimum of 3.2 s (HOLD group) or press the lever twice with a minimal delay (3.2 s) between two presses (PRESS group). (B) TP performance, in error-monitoring test sessions, follows Weber’s law for both groups, with signatures of optimality. (Upper) Probability density functions over TPs for each individual rat in HOLD (blue) and PRESS (red) groups. Thresholds Θ (blue and red dashed lines for HOLD and PRESS groups, respectively) are plotted for each individual. (Bottom Left) Average probability density functions over TPs for HOLD and PRESS groups superimposed. Note the distribution shift and width shrinkage for HOLD group. (Bottom Right) For each rat, µ(TP) is plotted against σ(TP). Both at the individual and at the group level the PRESS rats showed larger µ(TP) and σ(TP), visible as an upward right shift of the red curve. This pattern indicates that rats make their choices optimally, taking into account their level of TP variability. The results hold within each rat and across sessions (SI Appendix, Fig. S3). (C) Schematic depiction of how rewards were assigned to specific parts of TP distribution. Green color is used for “small error” (SE) trials and orange color for “large error” (LE) trials. Red color indicates TPs that were out of reward range. The arrows indicate probabilistic assignment of TP type (SE or LE) to left and right ports, on training trials. On test trials, the food–port assignments remained, but both ports were available and, thus, the amount of reward was driven by the rat’s choice. (D) Schematic of a trial structure. From the top to bottom, the succession of task events is depicted. They alternate along TP axis (color bar with red, green, and orange) and show different scenarios that are determined by the rats’ performance on TP in single trials. ITI is the last event in a single-trial sequence.A trial-and-error strategy would predict that near-optimal behavior can be parsimoniously explained by adaptation so that timing behavior would fluctuate around the required duration. The representational view would predict that uncertainty and trial-to-trial errors are experiential variables used by the animals to monitor their timing behavior.To settle the question of whether rodents can monitor their timing errors relative to their target on a trial-by-trial basis, we developed a task inspired by human work. Humans required to generate a time interval can also reliably report the magnitude of their errors and their sign (8) (i.e., they can evaluate by how much [magnitude] their generated duration was too short or too long [sign], with respect to the target duration). Humans can also report how confident they are in their timing behavior (9). We tested here these temporal cognitive abilities in rats, which were required to produce a time interval and correctly report, in order to obtain a reward, the magnitude of their timing errors on some test trials. We show that rats correctly reported the magnitude of their timing error, suggesting that their timing behavior uses explicit representations of time intervals together with their uncertainty around the internal target duration.     

Associations of Childhood and Perinatal Blood Metals with Children’s Gut Microbiomes in a Canadian Gestation Cohort

Background: The gut microbiome is important in modulating health in childhood. Metal exposures affect multiple health outcomes, but their ability to modify bacterial communities in children is poorly understood.Objectives: We assessed the associations of childhood and perinatal blood metal levels with childhood gut microbiome diversity, structure, species, gene family-inferred species, and potential pathway alterations.Methods: We assessed the gut microbiome using 16S rRNA gene amplicon sequencing and shotgun metagenomic sequencing in stools collected from 6- to 7-year-old children participating in the GESTation and Environment (GESTE) cohort study. We assessed blood metal concentrations [cadmium (Cd), manganese (Mn), mercury (Hg), lead (Pb), selenium (Se)] at two time points, namely, perinatal exposures at delivery (N=70) and childhood exposures at the 6- to 7-y follow-up (N=68). We used multiple covariate-adjusted statistical models to determine microbiome associations with continuous blood metal levels, including linear regression (Shannon and Pielou alpha diversity indexes), permutational multivariate analysis of variance (adonis; beta diversity distance matrices), and multivariable association model (MaAsLin2; phylum, family, species, gene family-inferred species, and pathways).Results: Children’s blood Mn and Se significantly associated with microbiome phylum [e.g., Verrucomicrobiota (coef=−0.305, q=0.031; coef=0.262, q=0.084, respectively)] and children’s blood Mn significantly associated with family [e.g., Eggerthellaceae (coef=−0.228, q=0.052)]-level differences. Higher relative abundance of potential pathogens (e.g., Flavonifractor plautii), beneficial species (e.g., Bifidobacterium longum, Faecalibacterium prausnitzii), and both potentially pathogenic and beneficial species (e.g., Bacteriodes vulgatus, Eubacterium rectale) inferred from gene families were associated with higher childhood or perinatal blood Cd, Hg, and Pb (q<0.1). We found significant negative associations between childhood blood Pb and acetylene degradation pathway abundance (q<0.1). Finally, neither perinatal nor childhood metal concentrations were associated with children’s gut microbial inter- and intrasubject diversity.Discussion: Our findings suggest both long- and short-term associations between metal exposure and the childhood gut microbiome, with stronger associations observed with more recent exposure. Future epidemiologic analyses may elucidate whether the observed changes in the microbiome relate to children’s health. https://doi.org/10.1289/EHP9674