Comparison of different invasive hemodynamic methods for AV delay optimization in patients with cardiac resynchronization therapy: Implications for clinical trial design and clinical practice

Background

Reproducibility and hemodynamic efficacy of optimization of AV delay (AVD) of cardiac resynchronization therapy (CRT) using invasive LV dp/dt_max are unknown.

Method and results

25 patients underwent AV delay (AVD) optimisation twice, using continuous left ventricular (LV) dp/dt_max, systolic blood pressure (SBP) and pulse pressure (PP). We compared 4 protocols for comparing dp/dt_max between AV delays:

Immediate absolute: mean of 10 s recording of dp/dt_max acquired immediately after programming the tested AVD,

Delayed absolute: mean of 10 s recording acquired 30 s after programming AVD,

Single relative: relative difference between reference AVD and the tested AVD,

Multiple relative: averaged difference, from multiple alternations between reference and tested AVD.

We assessed for dp/dt_max, LVSBP and LVPP, test–retest reproducibility of the optimum.Optimization using immediate absolute dp/dt_max had poor reproducibility (SDD of replicate optima = 41 ms; R² = 0.45) as did delayed absolute (SDD 39 ms; R² = 0.50). Multiple relative had better reproducibility: SDD 23 ms, R² = 0.76, and (p < 0.01 by F test).Compared with AAI pacing, the hemodynamic increment from CRT, with the nominal AV delay was LVSBP 2% and LVdp/dt_max 5%, while CRT with pre-determined optimal AVD gave 6% and 9% respectively.

Conclusions

Because of inevitable background fluctuations, optimization by absolute dp/dt_max has poor same-day reproducibility, unsuitable for clinical or research purposes. Reproducibility is improved by comparing to a reference AVD and making multiple consecutive measurements. More than 6 measurements would be required for even more precise optimization — and might be advisable for future study designs. With optimal AVD, instead of nominal, the hemodynamic increment of CRT is approximately doubled.     

The role of long-range connections on the specificity of the macaque interareal cortical network

We investigated the influence of interareal distance on connectivity patterns in a database obtained from the injection of retrograde tracers in 29 areas distributed over six regions (occipital, temporal, parietal, frontal, prefrontal, and limbic). One-third of the 1,615 pathways projecting to the 29 target areas were reported only recently and deemed new-found projections (NFPs). NFPs are predominantly long-range, low-weight connections. A minimum dominating set analysis (a graph theoretic measure) shows that NFPs play a major role in globalizing input to small groups of areas. Randomization tests show that (i) NFPs make important contributions to the specificity of the connectivity profile of individual cortical areas, and (ii) NFPs share key properties with known connections at the same distance. We developed a similarity index, which shows that intraregion similarity is high, whereas the interregion similarity declines with distance. For area pairs, there is a steep decline with distance in the similarity and probability of being connected. Nevertheless, the present findings reveal an unexpected binary specificity despite the high density (66%) of the cortical graph. This specificity is made possible because connections are largely concentrated over short distances. These findings emphasize the importance of long-distance connections in the connectivity profile of an area. We demonstrate that long-distance connections are particularly prevalent for prefrontal areas, where they may play a prominent role in large-scale communication and information integration.     

Cell membrane structures during exocytosis

Exocytosis is a key biological process that controls the neurotransmission and release of hormones from cells. In endocrine cells, hormones are packed into secretory vesicles and released into the extracellular environment via openings in the plasma membrane, a few hundred nanometers wide, which form as a result of fusion of the membranes of the granule and cell. The complex processes and dynamics that result in the formation of the fusion pore, as well as its structure, remain scantly understood. A number of different exocytosis mechanisms have been postulated. Furthermore, the possibility exists that several mechanisms occur simultaneously. We present here an investigation of the cell membrane dynamics during exocytosis in anterior pituitary cells, especially gonadotropes, which secrete LH, a hormone central to ovulation. Gonadotrope enrichment was achieved using immunolabeled magnetic nanobeads. Three complementary imaging techniques were used to realize a fine structure study of the dynamics of the exocytosis-like sites occurring during secretion. Living pituitary and gonadotrope-enriched cells were imaged with atomic force microscopy, as well as cells that had been fixed to obtain better resolution. Atomic force microscopy, along with scanning and transmission electron microscopy, studies of these cells revealed that there are at least two different site configurations: simple single fusion pores and a complex association of pores consisting of a simple primary site combined with secondary attachments.     

Induction of CXCL1 by extracellular matrix and autocrine enhancement by interleukin-1 in rat pancreatic beta-cells

As we showed previously, the extracellular matrix (ECM) derived from rat bladder carcinoma cells (804G-ECM) has positive effects on rat primary beta-cell function and survival in vitro. The aim of this study was to define beta-cell genes induced by this ECM with a specific focus on cytokines. Analysis of differential gene expression by oligonucleotide microarrays, RT-PCR, and in situ hybridization was performed to identify cytokine mRNA induced by this matrix. Four cytokines were overexpressed on 804G-ECM compared with poly-L-lysine: C-X-C motif ligand 1 (CXCL1), CXCL2, interferon-inducible protein-10, and IL-1beta. A time-course experiment indicated that maximal induction by 804G-ECM of CXCL1/2 and interferon-inducible protein-10 occurred at 4 h. Stimulation of CXCL1 release by beta-cells on 804G-ECM was confirmed at the protein level. Moreover, secreted CXCL1 was shown to be functionally active by attracting rat granulocytes. Preventing the interaction of beta1 integrins and laminin-5 (a major component of 804G-ECM) with specific antibodies resulted in a 40-50% inhibition of CXCL1 expression. Using the nuclear factor-kappaB pathway inhibitor Bay 11-7082 it is demonstrated that CXCL1 expression and secretion are dependent on nuclear factor-kappaB activation. IL-1 secreted by beta-cells plated on 804G-ECM was found to be a key soluble mediator because treatment of cells with the IL-1 receptor antagonist significantly reduced both CXCL1 gene expression and secretion. It is concluded that ECM induces expression of cytokines including CXCL1 with amplification by IL-1 acting via a positive autocrine feedback loop.     

Peridomicilary habitat and risk factors for Triatoma infestation in a rural community of the Mexican occident

An examination of peridomestic area organization and triatomine collection in an endemic village for Chagas disease (Jalisco State) identified the habitat of Triatoma longipennis (dominant species) and the risk factors of peridomestic infestation. In 100 visited peridomestic areas, 369 structures (permanent, temporary, and natural) were submitted to active manual research of triatomines. Storage shelters had a higher infestation of T. longipennis than piles of brick and tile; baked clay material had higher degrees of infestation than others. The secondary species Triatoma barberi shares a wide range of peridomicilary habitats with T. longipennis. Peridomestic area infestation risks (evaluated with multivariate logistic regression analysis) are number of closed storage shelters, number of brick and tile piles, number of houses per peridomestic areas, and distance of peridomicile from natural environment. Because both species present great adaptability to different artificial habitats, strategies of control must involved improving the overall management of peridomestic areas to prevent stable colonization.     

Randomized controlled trial of sevoflurane for intubation in neonates

BACKGROUND: Our aim was to determine whether sevoflurane can be used with safety and efficacy for anesthesia during intubation in term and preterm neonates in a prospective randomized-controlled nonblinded study in a tertiary neonatal intensive care unit. METHODS: Thirty-three neonates were randomly allocated to receive sevoflurane (inspired concentrations varying from 2% to 5%) or no medication (preoxygenation with 100% oxygen alone) before intubation. Minute by minute heart rate (HR), mean arterial blood pressure, SpO(2) and number of episodes of bradycardia (HR < 100 b.min(-1)) and desaturation (SpO(2) < 85% for >30 s) were noted from 5 min before to 10 min after intubation. Operator experience, ease and number of attempts were noted. RESULTS: No major adverse events were noted in the study group compared with the control group [hypotension (37.5% vs 37.5%, NS), number of desaturations [37.5% vs 44.5%, NS)]. Hypertension (25%, vs 56.3%P = 0.04) and incidence of bradycardias (8.3% vs 44.4%, P < 0.01) were greater in the control group. Intubation was easier in the study group: no movements: 95.5% vs 28% (P < 0.005); good glottis visualization: 73% vs 33% (P = 0.013). The failure rate was lower in the study group (25% vs 39%), but this difference was not statistically significant. CONCLUSION: Anesthesia for intubation with sevoflurane in neonates is well tolerated, even in the less mature. It facilitates the conditions for intubation and leads to fewer adverse events. Other studies are necessary to confirm these preliminary results.     

Intravenous morphine titration to treat severe pain in the ED

Purpose

We assessed the safety of intravenous morphine titration in the emergency setting.

Methods

A total of 621 consecutive adult patients admitted in the ED with acute severe pain (visual analogue scale pain score >70) were included. Intravenous morphine titration was administered as a bolus of 2 (body weight ≤60 kg) or 3 mg (body weight >60 kg) with 5-minute interval between each bolus. Pain relief was defined as a visual analogue pain score of 30 or lower.

Results

The dose of morphine administered was 0.16 ± 0.10 mg/kg and the median number of boluses was 3. Pain relief was obtained in 512 (82%) patients. Morphine-induced adverse events occurred in 67 patients (11%) without severe adverse event. Titration was interrupted before pain relief had been obtained in 107 (17%) patients. In the remaining 514 patients, pain relief was obtained in 507 (99%) patients. Two variables were significantly associated with no pain relief: major protocol deviation (odds ratio, 17.3; 95% confidence interval, 10.0-30.1) and morphine-induced adverse effect (odds ratio, 13.0; 95% confidence interval, 6.7-25.3).

Conclusion

Intravenous morphine titration is a safe and effective option for severe pain when used according to a strict protocol.