Priming with a very low dose of DNA complexed with cationic block copolymers followed by protein boost elicits broad and long-lasting antigen-specific humoral and cellular responses in mice

Cationic block copolymers spontaneously assemble via electrostatic interactions with DNA molecules in aqueous solution giving rise to micellar structures that protect the DNA from enzymatic degradation both in vitro and in vivo. In addition, we have previously shown that they are safe, not immunogenic and greatly increased antigen-specific CTL responses following six intramuscular inoculations of a very low dose (1 μg) of the vaccine DNA as compared to naked DNA. Nevertheless, they failed to elicit detectable humoral responses against the antigen. To gain further insight in the potential application of this technology, here we show that a shorter immunization protocol based on two DNA intramuscular inoculations of 1 μg of DNA delivered by these copolymers and a protein boost elicits in mice broad (both humoral and cellular) and long-lasting responses and increases the antigen-specific Th1-type T cell responses and CTLs as compared to priming with naked DNA. These results indicate that cationic block copolymers represent a promising adjuvant and delivery technology for DNA vaccination strategies aimed at combating intracellular pathogens.     

Treatment of ABO Hemolytic Disease with Synthetic Blood Group Trisaccharides

Thirteen infants, 10 with A-O and 3 with B-O hemolytic disease of the newborn (ABO-HDN), were treated with synthetic A or B blood group trisaccharides (ATS, BTS) which cause dissociation of maternal antibody bound to infant red cells. The clinical outcome was compared with that of a control group of 21 infants treated with phototherapy during the preceding year. Exchange transfusion was required in 2 out of 13 infants in the experimental group and in 7 in the control group. A randomized prospective controlled study is necessary to confirm these results.     

Intermale aggression and infanticide in aged C57BL/6J male mice: Behavioral deficits are not related to serum testosterone (T) levels and are not recovered by supplemental T

Healthy aged adul (24–26 months of age) and young adult (2–4 months of age) C57BL/6J male mice were assessed for intermale aggression, pup-killing behavior (infanticide), and circulating levels of testosterone (T). When compared to young adult male mice, aged adult males were highly variable in the exhibition of both androgen-dependent behaviors. Significant numbers of aged males exhibited deficits in aggression and pup-killing while other animals were as behaviorally active as their young male counterparts. Assessment of serum T showed that aging did not produce a reduction in levels of the steroid and individual variability in androgen-dependent behavior of aged males was not related to plasma levels of the hormone. When aged non-aggressive and non-killer males were exposed to supplemental T by way of subcutaneously implanted silastic capsules, circulating levels of the steroid were elevated but T-dependent behavior was not recovered. These findings, in combination with those previously reported for copulatory behavior, indicate that the deficits observed in the androgen-dependent behavior of aged male mice cannot be attributed to a breakdown in the production of testicular androgens. While neural refractoriness to T may account in part for deficits in androgen-dependent behavior of aged males, the variability that is observed in the reproductive behaviors of aged male rodents ultimately may be related to other sources of variation such as perinatal environment.     

NO enhances presynaptic currents during cerebellar mossy fiber-granule cell LTP

Nitric oxide (NO) is a candidate retrograde messenger in long-term potentiation (LTP). The NO metabolic pathway is expressed in the cerebellar granule cell layer but its physiological role remained unknown. In this paper we have investigated the role of NO in cerebellar mossy fiber-granule cell LTP, which has postsynaptic N-methyl-d-aspartate (NMDA) receptor-dependent induction. Pre- and postsynaptic current changes were simultaneously measured by using extracellular focal recordings, and NO release was monitored with an electrochemical probe in P21 rat cerebellar slices. High-frequency mossy fiber stimulation induced LTP and caused a significant NO release (6.2 +/- 2.8 nM; n = 5) in the granular layer that was dependent on NMDA receptor as well as on nitric oxide synthase (NOS) activation. Preventing NO production by perfusing the NOS inhibitor 100 microM NG-nitro-l-arginine (L-NNA), blocking extracellular NO diffusion by 10 microM MbO2, or inhibiting the NO target guanylyl cyclase (sGC) with 10 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-dione (ODQ) prevented LTP. Moreover, the NO donor 10 microM 2-(N,N-diethylamino)-diazenolate-2-oxide.Na (DEA-NO) induced LTP, which was mutually occlusive with LTP generated by high-frequency stimulation, prevented by ODQ, and insensitive to NMDA channel blockade (50 microM APV + 25 microM 7-Cl-kyn) or interruption of mossy fiber stimulation. Thus NO is critical for LTP induction at the cerebellar mossy fiber-granule cell relay. Interestingly, LTP manipulations were accompanied by consensual changes in the presynaptic current, suggesting that NO acts as a retrograde signal-enhancing presynaptic terminal excitability.     

The Association Between Neighborhood Social Vulnerability and COVID-19 Testing,Positivity, and Incidence in Alabama and Louisiana

Racial/ethnic and socioeconomic disparities in COVID-19 burden have been widely reported. Using data from the state health departments of Alabama and Louisiana aggregated to residential Census tracts, we assessed the relationship between social vulnerability and COVID-19 testing rates, test positivity, and incidence. Data were cumulative for the period of February 27, 2020 to October 7, 2020. We estimated the association of the 2018 Social Vulnerability Index (SVI) overall score and theme scores with COVID-19 tests, test positivity, and cases using multivariable negative binomial regressions. We adjusted for rurality with 2010 Rural–Urban Commuting Area codes. Regional effects were modeled as fixed effects of counties/parishes and state health department regions. The analytical sample included 1160 Alabama and 1105 Louisiana Census tracts. In both states, overall social vulnerability and vulnerability themes were significantly associated with increased COVID-19 case rates (RR 1.57, 95% CI 1.45–1.70 for Alabama; RR 1.36, 95% CI 1.26–1.46 for Louisiana). There was increased COVID-19 testing with higher overall vulnerability in Louisiana (RR 1.26, 95% CI 1.14–1.38), but not in Alabama (RR 0.95, 95% CI 0.89–1.02). Consequently, test positivity in Alabama was significantly associated with social vulnerability (RR 1.66, 95% CI 1.57–1.75), whereas no such relationship was observed in Louisiana (RR 1.05, 95% CI 0.98–1.12). Social vulnerability is a risk factor for COVID-19 infection, particularly among racial/ethnic minorities and those in disadvantaged housing conditions without transportation. Increased testing targeted to vulnerable communities may contribute to reduction in test positivity and overall COVID-19 disparities.

     

Paracetamol: a focus for the general pediatrician

Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever in children. This drug has multiple mechanisms of action, but its pharmacodynamic is still not well known. The central nervous system is the main site of action and it mirrors the paracetamol effect compartment. The recommended dosages and routes of administration should be different whether paracetamol is used for the treatment of pain or fever. For example, the rectal route, while being efficacious for the treatment of fever, should be avoided in pain management. Paracetamol is a safe drug, but some clinical conditions and concomitant drugs, which are frequent in clinical practice, may increase the risk of paracetamol toxicity. Therefore, it is important to optimize its administration to avoid overdoses and maximize its effect. The principal mediator of the paracetamol toxicity is the N-acetyl-p-benzo-quinone imine (NAPQI), a toxic product of the paracetamol metabolism, which could bind cysteine groups on proteins forming paracetamol–protein adduct in the liver. Conclusion: Although frequently prescribed, the concept of “effect compartment concentration” and the possible co-factors that could cause toxicity at recommended doses are not familiar to all pediatricians and general practitioners. We reviewed the literature concerning paracetamol mechanisms of action, we highlighted some relevant pharmacodynamic concepts for clinical practice, and we summarized the possible risk factors for toxicity at therapeutic dosages.