Effects of cholinergic modulation on responses of neocortical neurons to fluctuating input

Neocortical neurons in vivo are spontaneously active and intracellular recordings have revealed strongly fluctuating membrane potentials arising from the irregular arrival of excitatory and inhibitory synaptic potentials. In addition to these rapid fluctuations, more slowly varying influences from diffuse activation of neuromodulatory systems alter the excitability of cortical neurons by modulating a variety of potassium conductances. In particular, acetylcholine, which effects learning and memory, reduces the slow alterhyperpolarization, which contributes to spike frequency adaptation. We used whole-cell patch-clamp recordings of pyramidal neurons in neocortical slices and computational simulations to show, first, that when fluctuating inputs were added to a constant current pulse, spike frequency adaptation was reduced as the amplitude of the fluctuations was increased. High- frequency, high-amplitude fluctuating inputs that resembled in vivo conditions exhibited only weak spike frequency adaptation. Second, bath application of carbachol, a cholinergic agonist, significantly increased the firing rate in response to a fluctuating input but minimally displaced the spike times by < 3 ms, comparable to the spike jitter observed when a visual stimulus is repeated under in vivo conditions. These results suggest that cholinergic modulation may preserve information encoded in precise spike timing, but not in interspike intervals, and that cholinergic mechanisms other than those involving adaptation may contribute significantly to cholinergic modulation of learning and memory.      

Parental mosaicism and autosomal dominant mutations causing structural abnormalities of collagen I are frequent in families with osteogenesis imperfecta type III/IV

Abstract Protein-chemical and molecular studies were conducted on all osteogenesis imperfecta (OI) type III/IV patients referred to our hospital during the last 15 y. Of a total of 16 OI type III/IV patients studied, 15 patients were heterozygous for a mutation in one of the two genes coding for collagen I, COL1A1 or COL1A2. Cultured fibroblasts from these 15 patients produced both normal and abnormal collagen I molecules, pointing to a dominant-negative effect of the mutation. Nine mutations had not been described previously. Parental mosaicism was demonstrated in three families. In the 16th child the causative mutation was not found. In conclusion, OI type III/IV in most patients of Western European ancestry is caused by dominant mutations in the genes for collagen I, and recurrence of OI is caused in most cases by parental gonadal mosaicism.     

Obesity: Risk Factor for Increased Resource Utilization at Bidirectional Glenn

Background

Underweight infants with single‐ventricle cardiac physiology have been shown to have increased morbidity, mortality, and resource utilization. The purpose of this study was to determine whether patients who were overweight, as defined by weight‐for‐length z score >90th percentile, were similarly at risk for increased resource utilization, as defined by mechanical ventilation hours (VHs) and intensive care unit length of stay (ICU LOS).

Methods

We evaluated resource utilization for 109 patients from our institution who underwent bidirectional Glenn surgery from January 2010 to June 2015 and met prespecified inclusion criteria. Patients were divided into 3 groups: underweight (z score, <5th percentile), normal weight (z score, 5th–90th percentile), and overweight (z score, >90th percentile).

Results

ICU LOS was longer in the overweight group (median, 18.5 days) when compared with the under‐ and normal‐weight groups (median LOS, 11 and 9 days, respectively) but did not reach statistical significance. VHs were also increased in the overweight group (median, 72 hours) when compared with the underweight (median, 27 hours) and normal weight (median, 25 hours) groups. This increase in VHs was statistically significant (P = .03).

Conclusions

This study suggests that patients with single‐ventricle physiology who are overweight at the time of their bidirectional Glenn surgery may be at risk for increased resource utilization as compared with those who meet or fail to meet their caloric recommendations. These findings represent an underappreciated risk factor in this already‐vulnerable patient population, providing potential opportunity for intervention and improved outcomes.     

Activation of human platelets by immune complexes prepared with cationized human IgG

The present study shows that the ability of soluble immune complexes (IC), prepared with human IgG and rabbit IgG antibodies against human IgG, to trigger platelet activation was markedly higher for IC prepared with cationized human IgG (catIC) compared with those prepared with untreated human IgG (cIC). CatIC induced platelet aggregation and adenosine triphosphate release in washed platelets (WP), gel-filtered platelets (GFP), or platelet-rich plasma (PRP) at physiologic concentrations of platelets (3 x 10(8)/mL) and at low concentrations of catIC (1 to 30 micrograms/mL). On the contrary, under similar experimental conditions, cIC did not induce aggregation in PRP, WP, or GFP. Low aggregation responses were only observed using high concentrations of both WP (9 x 10(8)/mL) and cIC (500 micrograms/mL). Interestingly, catIC were also able to induce platelet activation under nonaggregating conditions, as evidenced by P-selectin expression. Cationized human IgG alone did not induce platelet aggregation in PRP but triggered either WP or GFP aggregation. However, the concentration needed to induce these responses, was about eightfold higher than those required for catIC. The responses induced either by catIC or cationized human IgG were completely inhibited by treatment with heparin, dextran sulphate, EDTA, prostaglandin E1, or IV3, a monoclonal antibody against the receptor II for the Fc portion of IgG (Fc gamma RII). The data presented in this study suggest that IgG charge constitutes a critical property that conditions the ability of IC to trigger platelet activation.     

In vivo behavior of human radioiodinated antithrombin III: distribution among three physiologic pools

It has recently been shown that antithrombin III (AT) distributes between plasma, a noncirculating vascular-associated pool and an extravascular pool in rabbit. Study of the in vivo behavior of autologous human 131I-AT demonstrates that in humans AT also distributes among three pools that are analogous to those found in rabbit. From the in vivo kinetic behavior of the 131I-labeled AT, the fractions of total-body AT in the plasma, noncirculating vascular- associated, and extravascular pools were calculated to be 0.393 +/- 0.015, 0.109 +/- 0.016, and 0.496 +/- 0.014, respectively. From three- exponential plasma radioactivity disappearance curves, an average plasma fractional catabolic rate, j3, of 0.576 +/- 0.034 day-1 was obtained for five healthy young men. This is almost identical to the result obtained if plasma 131I-AT disappearance is assumed to fit a two- exponential curve (0.546 +/- 0.038), where the constant C2 from *Ap(t) = C1e-a1t + C2e-a2t is assumed to be equal to 1 - C1. The fraction of the total vascular AT catabolized daily, j3.5, was calculated to be 0.457 +/- 0.034, and the fractional catabolic rate of total-body AT, jT, averaged 0.2271 +/- 0.0176. The results give further support to a model of in vivo behavior in which the vascular AT distributes between plasma and an endothelial receptor. Thus, the latter may serve to mediate activation of AT for its reaction with coagulation proteases and to mediate its entrance into the endothelial cell, where it is either transported to the extravascular fluids or is catabolized.