Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling.

Adipose tissue macrophages (ATM) adapt to changes in their energetic microenvironment. Caloric excess, in a range from transient to diet-induced obesity, could result in the transition of ATMs from highly oxidative and protective to highly inflammatory and metabolically deleterious. Here, we demonstrate that Interferon Regulatory Factor 5 (IRF5) is a key regulator of macrophage oxidative capacity in response to caloric excess. ATMs from mice with genetic-deficiency of Irf5 are characterised by increased oxidative respiration and mitochondrial membrane potential. Transient inhibition of IRF5 activity leads to a similar respiratory phenotype as genomic deletion, and is reversible by reconstitution of IRF5 expression. We find that the highly oxidative nature of Irf5-deficient macrophages results from transcriptional de-repression of the mitochondrial matrix component Growth Hormone Inducible Transmembrane Protein (GHITM) gene. The Irf5-deficiency-associated high oxygen consumption could be alleviated by experimental suppression of Ghitm expression. ATMs and monocytes from patients with obesity or with type-2 diabetes retain the reciprocal regulatory relationship between Irf5 and Ghitm. Thus, our study provides insights into the mechanism of how the inflammatory transcription factor IRF5 controls physiological adaptation to diet-induced obesity via regulating mitochondrial architecture in macrophages.

Waveguide-based absorption measurement system for visible wavelength applications.

We present a miniaturized waveguide-based absorption measurement system operating at a wavelength of 635 nm, based on a silicon nitride integrated photonic platform, suitable for lab-on-chip applications. We experimentally demonstrate a high correlation between the bulk dye concentration and the measured absorption loss levels in the waveguides. We explain a photonic design process for choosing the ideal waveguide to minimize the coefficient of variation on the analyte concentration. The approach is designed for camera readout, allowing multiple readouts and easy integration for lab-on chip cartridge approach.

A Critical Disconnect: Residency Selection Factors Lack Correlation With Intern Performance.

BACKGROUND: Emergency medicine (EM) residency programs want to employ a selection process that will rank best possible applicants for admission into the specialty. OBJECTIVE: We tested if application data are associated with resident performance using EM milestone assessments. We hypothesized that a weak correlation would exist between some selection factors and milestone outcomes. METHODS: Utilizing data from 5 collaborating residency programs, a secondary analysis was performed on residents trained from 2013 to 2018. Factors in the model were gender, underrepresented in medicine status, United States Medical Licensing Examination Step 1 and 2 Clinical Knowledge (CK), Alpha Omega Alpha (AOA), grades (EM, medicine, surgery, pediatrics), advanced degree, Standardized Letter of Evaluation global assessment, rank list position, and controls for year assessed and program. The primary outcomes were milestone level achieved in the core competencies. Multivariate linear regression models were fitted for each of the 23 competencies with comparisons made between each model's results. RESULTS: For the most part, academic performance in medical school (Step 1, 2 CK, grades, AOA) was not associated with residency clinical performance on milestones. Isolated correlations were found between specific milestones (eg, higher surgical grade increased wound care score), but most had no correlation with residency performance. CONCLUSIONS: Our study did not find consistent, meaningful correlations between the most common selection factors and milestones at any point in training. This may indicate our current selection process cannot consistently identify the medical students who are most likely to be high performers as residents.

[Renal aspects of sodium glucose cotransporter 2 inhibitors]. / Les inhibiteurs du cotransporteur SGLT2 comme nouveau traitement du diabète: aspects rénaux.

It has been known for centuries that the kidneys play a role in glucose homeostasis, yet the underlying tubular mechanisms have only been recently identified by studying patients with familial glucosuria. These insights have lead to the commercialization of a novel class of oral antidiabetic agents named gliflozines. Gliflozines induce renal glucosuria by blocking the Na-glucose cotransporter SGLT2, localized in the proximal tubule, and allow a reduction of 0.5 to 1% of glycated hemoglobin. They also diminish proximal sodium reabsorption, and reduce the glomerular hyperfiltration that is often seen in the early stages of diabetes. Preliminary data suggest that they may decrease blood pressure and have renoprotective effects. This article provides an overview of the role of kidneys in glucose homeostasis and the renal effects of SGLT2-inhibitors.

[Contrast-induced nephropathy]. / Néphropathie au produit de contraste.

Iodine and gadolinium-based contrast induced nephropathy is the third leading cause of hospital-acquired acute kidney injury. It is essentially observed in patients with defined risk factors and is associated with increased morbidity and mortality. The prevention of contrast induced nephropathy consists in volume expansion through intravenous sodium chloride 0.9% or sodium bicarbonate 1.4%. Comparative randomized controlled trials appear to show a benefit in favor of sodium bicarbonate over saline fluids. According to last evidence, N-acetylcysteine does not provide additional benefit over intravenous fluids.

[Myoclonia in an oldest old woman: a frequent and reversible etiology]. / Myoclonies chez une personne très âgée; une cause fréquente et réversible.

A 98-year-old woman was referred to our hospital because of myoclonia. The concentration of calcium and vitamin D in the serum was low. In this context, we concluded of neuromuscular irritability secondary to hypocalcaemia. The symptoms disappeared after a treatment of intravenous calcium. This case shows how important it is to investigate electrolytes in case of neuromuscular irritability symptoms in elderly people.

Comparison of sludge and clinical isolates of Listeria monocytogenes.

AIMS: Listeria monocytogenes strains isolated in the same geographical area from sewage sludge and from patients presenting with listeriosis were compared. METHODS AND RESULTS: All isolates were typed by serotyping, phage typing and SmaI/ApaI pulsed-field gel electrophoresis (PFGE). Among the sludge isolates (n=32), 22 subtypes could be distinguished by the combination of all typing methods. The human isolates (n=11) were distributed into 10 subtypes which clearly differed from those observed among sludge isolates, except for one cluster formed by two related human isolates which showed high similarity in PFGE patterns (SmaI: 92%; ApaI: 89.5%) with one sludge isolate. CONCLUSION: These results suggest the existence of an epidemiological link between sludge and human isolates, but they may also be reflecting the distribution of L. monocytogenes types within the environment. SIGNIFICANCE AND IMPACT OF THE STUDY: Sludge and human L. monocytogenes may be related but further epidemiological studies are necessary to elucidate this point.

Repeated seizure-associated long-lasting changes of N-methyl-D-aspartate receptor properties in the developing rat brain.

Glutamate NMDA receptor has been implicated in brain developmental processes as well as in excitotoxicity and seizure mediation. A previous study has shown that an acute episode of seizures for 30 min in rats altered NMDA receptor characteristics, mainly in the very immature animal. In order to assess whether receptor modifications may also account for long-lasting cerebral disabilities, medium- and long-term consequences of repeated seizures in developing rats on brain NMDA receptor properties were investigated. Seizures were induced once a day for 3 consecutive days, either from post-natal day 5 (P5) to P7 or from P15 to P17. NMDA receptors were then analysed at P15, P25 and P60 (adulthood) by measuring specific binding of [3H]MK-801 on brain membrane preparations. In addition, allosteric modulation of NMDA receptors by exogenous glutamate and glycine was investigated. Seizures from P5 to P7 led to a 22% increase in the density of [3H]MK-801 binding sites measured at P15, but did not affect NMDA receptor density or affinity at P25 or P60. P15-P17 seizures led to a 21% decrease in the density of binding sites and to a 33% decrease in receptor dissociation constant at P25, while they were without effect at P60. Moreover, P5-P7 and P15-P17 seizures were both associated with a suppression of the glutamate/glycine-induced receptor activation at P60. These modifications might account for long-term alterations in cerebral excitability or plasticity after early convulsive disorders, with regards to altered cognitive capacities, epileptogenesis and brain susceptibility to recurrent seizures.

Medium- and long-term alterations of brain A1 and A2A adenosine receptor characteristics following repeated seizures in developing rats.

In order to assess long-lasting consequences of recurrent seizures during development, the effects of repeated seizures in developing rats were investigated on brain adenosine A1 and A2A receptors. The characteristics of A1 and A2A receptors were analyzed by measuring the binding of the selective agonists [3H]CHA (N6-cyclohexyladenosine) and [3H]CGS 21680 (2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamido adenosine), respectively, on cerebral membrane preparations, whereas receptor coupling to G-proteins was examined by using a GTP analogue (Gpp(NH)p; guanylyl-5'-imidodiphosphate). Seizures were induced by bicuculline once a day at two different developmental stages: either from postnatal day 5 to postnatal day 7 (P5-P7) or from P15 to P17. Adenosine receptors were then studied at P15, P25 and P60. P5-P7 seizures led to an increase in A1 receptor density at P60 and to a decrease in their coupling to G-proteins at P15, but they did not affect A2A receptors. P15-P17 seizures decreased the coupling of A1 receptors to G-proteins at P25 and P60, reduced the density of A2A receptors at P25 and increased their affinity at P60. These results depict a persistent sensitivity of both A1 and A2A brain adenosine receptors to repeated seizures, with selective receptor alterations according to the cerebral maturational stage when seizures occur. In respect to the neuromodulatory and anticonvulsant properties of adenosine, such changes might be implicated in long-term functional brain reorganization after early seizures and future susceptibility to convulsive disorders.

Medium- and long-term effects of repeated bicuculline-induced seizures in developing rats on local cerebral energy metabolism.

To assess long-term metabolic consequences of recurrent ictal events arising during development, seizures were repeatedly generated in rats at different stages of cerebral maturation. Seizures were induced by i.p. injections of bicuculline for three consecutive days, starting from postnatal day 5 (P5), when the brain is very immature, or from P15, a period at which the brain is more structurally organized. Local cerebral metabolic rates for glucose were measured in 74 structures at P15, P25 and in adults (P60), by the autoradiographic method using 2-D-[14C]deoxyglucose. Repeated seizures in P5 to P7 pups led to a reduction (16-34%) of glucose consumption at P15, mainly significant in sensory, motor and functionally non-specific areas as well as in cerebellar nuclei. Selective decreases in metabolic activity were still recorded in adults, mostly in auditory system (20%) and cerebellar nuclei (27%). Seizures generated from P15 to P17 led to an overall mortality rate of 62% (versus 22% at P5 to P7). Surviving animals exhibited reduced metabolic rates for glucose (by 7-27%) at P25, significant in 23 structures, and depicting pronounced changes in limbic, hypothalamic, sensory and white matter areas, whereas brain functional activity finally returned to basal values at P60. Therefore, while younger rats seemed to better tolerate repeated bicuculline-induced seizures than older animals, the reverse was true for long-term metabolic effects, and the more immature the brain when seizures arise, the more persistent the functional consequences.

Long-term consequences of neonatal exposure to diazepam on cerebral glucose utilization, learning, memory and anxiety.

The long-term consequences of neonatal exposure to diazepam (DZP) on behavioral abilities and local cerebral glucose utilization (LCGU) in 12 brain regions involved in the control of memory and anxiety were studied in adult rats. Rat pups received a daily subcutaneous injection of 10 mg/kg DZP or of the dissolution vehicle from postnatal day (P) 2 to 21. Learning and memory were tested in P60-P70 rats over 5 consecutive days in a T maze and an eight-arm maze while anxiety and reaction to novelty were tested in a two-compartment box with a two-step staircase on the enriched side. LCGU was measured in the P60 rat by the quantitative autoradiographic [14C]deoxyglucose method. In the T maze, when performed without delay between the two trials, the rate of alternation was significantly lower in DZP- than in vehicle-exposed rats on the first 2 days of testing and similar in both groups on days 3-5. In the procedure with a 30 s intertrial delay, the rate of alternation was similar in DZP- and vehicle-treated rats on all days of testing. In the eight-arm maze, DZP-treated rats were more active, i.e., entered more arms per minute than control animals. The number of arms entered before the first error was lower on day 1 and higher on day 3 in DZP- compared to vehicle-exposed rats. In the two-compartment box, DZP-treated rats crossed more often and spent more time than controls on the lower step of the staircase while control rats made more rearings and spent more time than DZP-exposed rats in the well protected corner of the box. LCGU were decreased by early DZP exposure in six regions which were mammillary body, septum, visual and prefrontal cortices, dorsomedian caudate nucleus and mediodorsal thalamus. In conclusion, postnatal DZP treatment induced at adulthood an increase in activity, a delay in task acquisition but no learning-memory impairment and reduced the level of anxiety allowing active responding to novelty. These quite subtle behavioral changes were accompanied by discrete metabolic decreases in regions mediating anxiety, reflecting a change in the level of anxiety and emotionality.

Continuity of care between obstetrical and pediatric preventive care: indicators of nonattendance at the first well-child appointment.

This study evaluates appointment behavior for first well-child visits for first-born children and identifies factors that target infants at increased likelihood for missing their first pediatric appointment. Timely appointments were not scheduled for 10.3% of newborns; 20.1% of those scheduling did not keep the first appointment. Younger, less educated mothers who did not remember when they had learned about well-baby care, and mothers of infants born in the newborn intensive care unit were unlikely to schedule the appointment; young mothers learning about well care from friends or relatives and who chose a pediatrician without a previous prenatal visit were more likely to miss the child's first appointment. Prenatal pediatric visits as well as prenatal classes and written materials may improve compliance with the first well-child appointment.

Brain maturation of high-affinity adenosine A2 receptors and their coupling to G-proteins.

The neuromodulator adenosine is acting through specific receptors, A1 and A2, coupled to their effector systems via G-proteins. The regulatory effects of adenosine on locomotor activity have been attributed to an interaction with A2 striatal receptors. The postnatal development of adenosine A2a receptors was analysed in rat striatal membranes and by quantitative autoradiography in brain sections using [3H]CGS 21680 as specific probe. At the concentration of radioligand used (5 nM), A2a sites were concentrated in the striatum at all ages, with minor developmental alterations in the expression pattern within the striatal regions. In membrane preparations, Scatchard analysis showed that the density of CGS 21680 binding sites was low at birth, around 3% of the adult value, and then increased, mostly between birth and 5 days and then from 15 days to adulthood. Concomitantly, the receptor affinity decreased sharply during brain development, Kd values varying from 2 to 15.5 nM. The addition of a GTP analogue, guanylyl-5'-imidodiphosphate (Gpp(NH)p, 10 microM), to the assay medium reduced significantly the receptor affinity throughout the postnatal development, reflecting a coupling to G-proteins at all ages, but it also suggested a weaker association at birth. These data show that the developmental properties of A2a receptors contrast with those of A1 receptors, and emphasize the role played by adenosine through its A2 receptors in the maturation of striatum-related cerebral pathways.

Behavioral and metabolic consequences of neonatal exposure to diazepam in rat pups.

The short-term consequences of a neonatal exposure to diazepam (DZP) on neurobehavioral development and postnatal changes in local cerebral metabolic rates for glucose (LCMRglcs) in selected regions were studied in rats. Rat pups received a daily subcutaneous injection of 10 mg/kg DZP or of the dissolution vehicle from Postnatal Day 2 (P2) to 21 (P21). DZP did not affect the static righting reflex tested at P4 but increased suspension time at P10 and time to complete a 180 degrees pivoting on an inclined plane at P9. In a locomotor coordination test performed at P20, swimming or climbing on a vertical pole was not affected by DZP while the drug impaired the ability of the rat to place its hind-paws on the horizontal platform after climbing. Likewise, DZP induced marked decreases (19-45%) in LCMRglcs in most structures studied at P10, P14, and P21. The results of the present study show that neonatal DZP treatment induces motor deficits that appear to be quite subtle, to concern mainly posture and body balance. They are not apparent in tasks such as swimming or climbing but become obvious in more difficult tasks such as achieving a horizontal quadruped position on a platform after a climbing phase. Decreases in cerebral energy metabolism appear to be mainly located in areas controlling posture and body balance and are partly correlated with the locomotor impairments recorded in the present study.