Role of Endothelium/Nitric Oxide and Cyclic AMP in Isoproterenol Potentiation of 17ß-Estradiol-Mediated Vasorelaxation

Background: Calcitonin gene-related peptide (CGRP) is known to have an extremely potent and prolonged vasodilator effect on the coronary arteries. Studies have shown that CGRP increased coronary blood flow and alleviated reperfusion injury in vitro. It is still unknown, however, whether exogenous CGRP has a protective effect on the reperfusion heart associated with cardiopulmonary bypass (CPB). Methods: An in vivo porcine model of CPB was established. Twenty pigs, 10 controls and 10 CGRP used animals (CGRP group), were performed a median sternotomy followed by a standard CPB. All the hearts were arrested for 45 minutes. In the CGRP group, 1mg/kg CGRP was added into the cardioplegia, and another 1mg/kg was reperfused just before the aortic cross-clamp was removed. In both groups, myocardial microvascular perfusion, coronary arterial microvessel diameter and microvessel blood flow were detected by a laser doppler flowmeter and a contact microscope with TV monitor on five consecutive time perioperatively. Result: Myocardial microvascular perfusion was significantly higher and coronary arterial microvessel diameter was larger in the CGRP group on every point of time of reperfusion compared to those in the control group. In the CGRP group, microvessel blood flow also improved significantly than that in the control group during reperfusion. Conclusion: CGRP improves myocardial microcirculation during cardiac ischemia-reperfusion associated with CPB and could become a new, potent myocardial protector.     

Ultra-protective tidal volume: how low should we go?

Applying tidal volumes of less than 6 mL/kg might improve lung protection in patients with acute respiratory distress syndrome. In a recent article, Retamal and colleagues showed that such a reduction is feasible with conventional mechanical ventilation and leads to less tidal recruitment and overdistension without causing carbon dioxide retention or auto-positive end-expiratory pressure. However, whether the compensatory increase in the respiratory rate blunts the lung protection remains unestablished.Further reducing tidal volumes beyond the standard 6 mL/kg is an appealing goal in patients with acute respiratory distress syndrome (ARDS) [1]. Such reduction could decrease the tidal stretch imposed on the lung, potentially attenuating further the ventilator-induced lung injury [2]. In fact, tidal volumes of less than 6.5 mL/kg and as low as 4 mL/kg were recently associated with increased survival in patients with ARDS [3]. One of the main obstacles to such a strategy is the potential for carbon dioxide (CO₂) retention and severe acidosis. To avoid this, specialized techniques, such as high-frequency oscillatory ventilation and extracorporeal CO₂ removal, have been previously tested with mixed results [4-6].In the previous issue of Critical Care, Retamal and colleagues proposed that lower tidal volumes could be used with conventional positive-pressure ventilation without leading to CO₂ retention [1]. A reduction in tidal volume from 6 to 4 mL/kg was feasible with a decrease in the instrumental dead space and an increase in the respiratory rate. In patients with ARDS, the dead space is a marker of disease severity [7]. Consequently, very low tidal volumes can be difficult to use in practice, especially in very sick patients, because the necessary increase in respiratory rate might cause significant auto-positive end-expiratory pressure (auto-PEEP). Luckily, patients with severe ARDS also tend to have low lung compliance [8], making their lungs inflate and deflate fast. Therefore, this restrictive ventilatory pattern allows the safe use of high respiratory rates without leading to significant auto-PEEP.Retamal and colleagues [1] should be congratulated for their careful design of the ventilator protocol in the 4 mL/kg phase, which allowed an effective CO₂ elimination. The bottom line is that if one decides to use very low tidal volumes with high respiratory rates, attention to the details is invaluable. First, the removal of any dispensable dead space, including substituting an external heated humidifier by the heat-moisture exchanger, is imperative. Second, the use of volume-controlled ventilation helps to keep short inspiratory times. Peak airway pressures may increase, but the preserved expiratory time guarantees low auto-PEEP and, consequently, low plateau pressures. For safety, plateau pressures and auto-PEEP should be measured periodically. Third, in selected cases with high recruitability, the alveolar dead space can be minimized through recruitment maneuvers and higher PEEP values. Finally, the use of a short end-inspiratory pause is encouraged to improve the CO₂ elimination [9]. These measures will improve the safety and optimize the CO₂ elimination of a strategy with very low tidal volumes, even with higher-than-normal respiratory rates.However, even successfully avoiding CO₂ retention, this strategy has yet to be proven effective in terms of further lung protection. We believe that two aspects should be taken into consideration. The first is whether the strategy attenuated the mechanisms of lung injury. The authors performed computed tomography scans in all patients at tidal volumes of both 4 and 6 mL/kg and showed that the amount of cyclic recruitment-derecruitment and hyperinflation decreased after reducing the tidal volume. Although the absolute reduction was small (less than 1% of the lung weight), this finding is suggestive of decreased injury per breath. The second aspect is that an increased respiratory rate can be injurious per se [10]. It would be important to know whether the compensatory increase of the respiratory rate blunted the protective effect per breath of the tidal volume reduction.This tradeoff was emphasized recently in a model of the energy delivered by the ventilator as a surrogate for the potential lung damage [11]. Decreases in tidal volume require disproportionate increases in respiratory rate to maintain alveolar ventilation, and so more energy can be delivered to the lungs even at reduced stress and strain per breath. Though purely theoretical, this hypothesis helps reconcile our expectation of a further protective effect of very low tidal volumes with the recent findings of harmful or null effect of oscillatory high-frequency ventilation [5,6]. In these trials, it is possible that the reduction in lung injury per breath was offset by the very high respiratory rates applied.Finally, Retamal and colleagues [1] followed their patients for 5 to 30 minutes only. Since lower tidal volumes tend to promote atelectasis, especially under insufficient PEEP [12], a longer observation time perhaps would have shown an increase in atelectasis and driving pressures, opposing the benefits initially achieved.In conclusion, we are convinced that a strategy with very low tidal volumes (4 mL/kg) is feasible with conventional positive-pressure ventilation. This strategy could be used in patients with high plateau pressures or high driving pressures with standard 6 mL/kg tidal volumes, but we need more data in terms of lung protection before we can recommend this strategy to every patient with ARDS.     

Neonatal treatment with 192 IgG-saporin produces long-term forebrain cholinergic deficits and reduces dendritic branching and spine density of neocortical pyramidal neurons

The role of basal forebrain-derived cholinergic afferents in the development of neocortex was studied in postnatal rats. Newborn rat pups received intraventricular injections of 192 IgG-saporin. Following survival periods ranging from 2 days to 6 months, the brains were processed to document the cholinergic lesion and to examine morphological consequences. Immunocytochemistry for choline acetyltransferase (ChAT) and in situ hybridization for ChAT mRNA demonstrate a loss of approximately 75% of the cholinergic neurons in the medial septum and nucleus of the diagonal band of Broca in the basal forebrain. In situ hybridization for glutamic acid decarboxylase mRNA reveals no loss of basal forebrain GABAergic neurons. Acetylcholinesterase histochemistry demonstrates a marked reduction of the cholinergic axons in neocortex. Cholinergic axons are reduced throughout the cortical layers; this reduction is more marked in medial than in lateral cortical areas. The thickness of neocortex is reduced by approximately 10%. Retrograde labeling of layer V cortico-collicular pyramidal cells reveals a reduction in cell body size and also a reduction in numbers of branches of apical dendrites. Spine densities on apical dendrites are reduced by approximately 20-25% in 192 IgG- saporin-treated cases; no change was detected in number of spines on basal dendrites. These results indicate a developmental or maintenance role for cholinergic afferents to cerebral cortical neurons.      

A gene transfer strategy for making bone marrow cells resistant to trimetrexate

Trimetrexate (TMTX) is an anticancer drug with potential advantages over the more commonly used antifolate, methotrexate (MTX); however, its use has been limited by severe myelosuppression. Retroviral vectors containing mutant dihydrofolate reductase (DHFR) genes have been used to protect bone marrow cells from MTX, suggesting a similar approach could be used for TMTX. We first screened six variants of human DHFR to determine which allowed maximal TMTX resistance in fibroblasts. A variant enzyme containing a Leu-to-Tyr mutation in the 22nd codon (L22Y) was best, allowing a 100-fold increase in resistance over controls. Murine hematopoietic progenitor cells transduced with an L22Y- containing retroviral vector also showed high-level TMTX resistance in vitro. Mice reconstituted with L22Y-transduced bone marrow cells were challenged with a 5-day course of TMTX to determine whether hematopoiesis could be protected in vivo. Transfer of the L22Y vector resulted in consistent protection from TMTX-induced neutropenia and reticulocytopenia at levels that correlated with the proviral copy number in circulating leukocytes. We conclude that the L22Y vector is highly effective in protecting hematopoiesis from TMTX toxicity and may provide a means for increasing the therapeutic utility of TMTX in certain cancers.     

Ranking of parameters of pain hypersensitivity according to their discriminative ability in chronic low back pain

Low back pain is associated with plasticity changes and central hypersensitivity in a subset of patients. We performed a case-control study to explore the discriminative ability of different quantitative sensory tests in distinguishing between 40 cases with chronic low back pain and 300 pain-free controls, and to rank these tests according to the extent of their association with chronic pain. Gender, age, height, weight, body mass index, and psychological measures were recorded as potential confounders. We used 26 quantitative sensory tests, including different modalities of pressure, heat, cold, and electrical stimulation. As measures of discrimination, we estimated receiver operating characteristics (ROC) and likelihood ratios. Six tests seemed useful (in order of their discriminative ability): (1) pressure pain detection threshold at the site of most severe pain (fitted area under the ROC, 0.87), (2) single electrical stimulation pain detection threshold (0.87), (3) single electrical stimulation reflex threshold (0.83), (4) pressure pain tolerance threshold at the site of most severe pain (0.81), (5) pressure pain detection threshold at suprascapular region (0.80), and (6) temporal summation pain threshold (0.80). Pressure and electrical pain modalities seemed most promising and may be used for diagnosis of pain hypersensitivity and potentially for identifying individuals at risk of developing chronic low back pain over time.     

永久起搏器在预防心房颤动中的作用

本文总结了用于预防和终止心房颤动的起搏器的类型。窦房结功能异常的病人,心室起搏与较高的心房颤动的发生率相关。有鉴于此,有心房颤动病史、因心动过缓而需要安装起搏器的病人,应该安装双腔或心房起搏生理性起搏器,而不应安装单腔的心室起搏器。     

Role of negative pressure wound therapy in total hip and knee arthroplasty

Negative-pressure wound therapy(NPWT) has been a successful modality of wound management which is in widespread use in several surgical fields. The main mechanisms of action thought to play a role in enhancing wound healing and preventing surgical site infection are macrodeformation and microdeformation of the wound bed, fluid removal, and stabilization of the wound environment. Due to the devastating consequences of infection in the setting of joint arthroplasty, there has been some interest in the use of NPWT following total hip arthroplasty and total knee arthroplasty. However, there is still a scarcity of data reporting on the use of NPWT within this field and most studies are limited by small sample sizes, high variability of clinical settings and end-points. There is little evidence to support the use of NPWT as an adjunctive treatment for surgical wound drainage, and for this reason surgical intervention should not be delayed when indicated. The prophylactic use of NPWT after arthroplasty in patients that are at high risk for postoperative wound drainage appears to have the strongest clinical evidence. Several clinical trialsincluding single-use NPWT devices for this purpose are currently in progress and this may soon be incorporated in clinical guidelines as a mean to prevent periprosthetic joint infections.