Electrocardiographic ST-segment changes during acute, severe isovolemic hemodilution in humans

BACKGROUND: Controversy exists regarding the lowest blood hemoglobin concentration that can be safely tolerated. The authors studied healthy resting humans to test the hypothesis that acute isovolemic reduction of blood hemoglobin concentration to 5 g/dl would produce an imbalance in myocardial oxygen supply and demand, resulting in myocardial ischemia. METHODS: Fifty-five conscious healthy human volunteers were studied. Isovolemic removal of aliquots of blood reduced blood hemoglobin concentration from 12.8 +/- 1.2 to 5.2 +/- 0.5 g/dl (mean +/- SD). Removed blood was replaced simultaneously with intravenous fluids to maintain constant isovolemia. Hemodynamics and arterial oxygen content (Cao2) were measured before and after removal of each aliquot of blood. Electrocardiographic (ECG) changes were monitored continuously using a Holter ECG recorder for detection of myocardial ischemia. RESULTS: During hemodilution, transient, reversible ST-segment depression developed in three subjects as seen on the electrocardiogram during hemodilution. These changes occurred at hemoglobin concentrations of 5-7 g/dl while the subjects were asymptomatic. Two of three subjects with ECG changes had significantly higher heart rates than those without ECG changes at the same hemoglobin concentrations. When evaluating the entire study period, the subjects who had ECG ST-segment changes had significantly higher maximum heart rates than those without ECG changes, despite having similar baseline values. CONCLUSION: With acute reduction of hemoglobin concentration to 5 g/dl, ECG ST-segment changes developed in 3 of 55 healthy conscious adults and were suggestive of, but not conclusive for, myocardial ischemia. The higher heart rates that developed during hemodilution may have contributed to the development of an imbalance between myocardial supply and demand resulting in ECG evidence of myocardial ischemia. However, these ECG changes appear to be benign because they were reversible and not accompanied by symptoms.     

ROLE OF INTERMEDIARY BIOMARKERS IN DETERMINING THE ANTICANCER EFFICACY OF MARINE COMPOUNDS

In the present study, two of the probable an umor marine compounds, manzamine A and sarcophine, were screened using benzo[a]pyrene (BP)-derived DNA adduct formation in MCF-7 cells as intermediary biomarker. Briefly, MCF-7 cells were treated with the compounds for 24 h followed by treatment with BP (0.5 μM). After 24h incubation, cellular DNA was isolated and analyzed for BP-derived DNA adducts by ³²P-postlabeling technique. Manzamine A and sarcophine increased the BP-DNA adducts by 2 to 4-folds. Further, manzamine A (50 μM) substantially down regulated the expression of p53 while sarcophine (50 μM) slightly induced the level of p21. The residual DNA repair ability was almost completely abolished by manzamine A while sarcophine was ineffective. Based on our preliminary results, these compounds may be classified as potential genotoxic.     

ER-resident STIM1/2 couples Ca2+ entry by NMDA receptors to pannexin-1 activation

Pannexin-1 (Panx1) is a large-pore ion and solute permeable channel highly expressed in the nervous system, where it subserves diverse processes, including neurite outgrowth, dendritic spine formation, and N-methyl D-aspartate (NMDA) receptor (NMDAR)-dependent plasticity. Moreover, Panx1 dysregulation contributes to neurological disorders, including neuropathic pain, epilepsy, and excitotoxicity. Despite progress in understanding physiological and pathological functions of Panx1, the mechanisms that regulate its activity, including its ion and solute permeability, remain poorly understood. In this study, we identify endoplasmic reticulum (ER)-resident stromal interaction molecules (STIM1/2), which are Ca²⁺ sensors that communicate events within the ER to plasma membrane channels, as binding and signaling partners of Panx1. We demonstrate that Panx1 is activated to its large-pore configuration in response to stimuli that recruit STIM1/2 and map the interaction interface to a hydrophobic region within the N terminus of Panx1. We further characterize a Panx1 N terminus–recognizing antibody as a function-blocking tool able to prevent large-pore Panx1 activation by STIM1/2. Using either the function-blocking antibody or re-expression of Panx1 deletion mutants in Panx1 knockout (KO) neurons, we show that STIM recruitment couples Ca²⁺ entry via NMDARs to Panx1 activation, thereby identifying a model of NMDAR-STIM-Panx1 signaling in neurons. Our study highlights a previously unrecognized and important role of the Panx1 N terminus in regulating channel activation and membrane localization. Considering past work demonstrating an intimate functional relation between NMDARs and Panx1, our study opens avenues for understanding activation modality and context-specific functions of Panx1, including functions linked to diverse STIM-regulated cellular responses.

Glutamatergic signaling plays a critical role in diverse processes linked to learning and memory formation. Ca²⁺ signals generated by the N-methyl D-aspartate (NMDA) subtype of glutamate receptors (NMDARs) are indispensable for several forms of synaptic plasticity, including long-term potentiation (LTP), a prototypic form of plasticity linked to memory formation (1–3). NMDAR-initiated Ca²⁺ signals (e.g., time course, amplitude, and spatial spread) are shaped by secondary events, including those engendered via the endoplasmic reticulum (ER) (4, 5). Ca²⁺ entry via NMDARs can promote Ca²⁺-induced Ca²⁺ release from ER stores by stimulating ryanodine (RyRs) (6–8) and/or IP3 receptors (IP3Rs) (9). In turn, NMDAR-initiated Ca²⁺ store depletion recruits ER-resident and Ca²⁺-sensing STIM proteins (10) to negatively regulate L-type voltage-gated Ca²⁺ channels (VGCCs) (13). This establishes the notion that Ca²⁺ entry via NMDARs can stimulate ER- and STIM-dependent cascades that regulate secondary routes of Ca²⁺ entry, thereby sculpting intracellular Ca²⁺ dynamics and in turn the cellular functions influenced by them. As part of a broader search to identify candidate Ca²⁺ channels able to respond to ER signaling dynamics, we found that Pannexin-1 (Panx1) can be activated through ER-based signaling following sarcoendoplasmic reticulum calcium adenosine triphosphatase (ATPase) (SERCA) pump inhibition by thapsigargin. This led us to consider the role of STIM1/2 as a candidate Panx1 activation mechanism.Panx1 is a large-pore nonselective ion and solute permeable channel with prominent central nervous system (CNS) expression (14, 15). Panx1 activation has been linked to pathophysiological disorders, such as excitotoxicity, stroke, migraine, chronic pain, and epilepsy (16–18). However, Panx1 also mediates physiological processes in the CNS, including contributions to neural development (19, 20), spine formation (21, 22), and NMDAR-dependent synaptic plasticity (23, 24). In this context, there remains an important gap in understanding the mechanisms by which Panx1 can mediate such disparate physiological and pathological functions. Intriguingly, evidence suggests that Panx1 ion versus solute permeability may be mediated by distinct channel pore configurations (i.e., small anion vs. large solute permeable) recruited via distinct activation modalities (25). Thus, identifying novel activation mechanisms is fundamental to understanding context- and modality-specific channel function.Here, we uncover a mechanism by which Panx1 is activated in response to ER-initiated signaling, which we demonstrate is dependent on Panx1 interaction with ER-resident STIM1/2. STIM1/2 recruitment and activation stimulates large-pore Panx1 opening, evident on the basis of increased permeability to Ca²⁺ and the large inorganic ion N-methyl-D-glucamine (NMDG). We map the STIM1/2 binding interface to a hydrophobic region in the N terminus of Panx1, a region not previously linked to channel gating. Our detailed structure-function analysis reveals that the Panx1 N-terminal region is necessary for its STIM1/2 responsiveness, but not for its responsiveness to hypotonic stress, demonstrating that this region mediates modality-specific regulation of Panx1 function. Using reverse genetics, ectopic rescue with Panx1 N-terminal deletion mutants, as well as a function inhibiting antibody targeting the critical N-terminal region of Panx1 identified by us, we demonstrate that NMDARs activate Panx1 in hippocampal neurons in a manner contingent upon ER-initiated signaling and reliant upon STIM proteins. Collectively, our data reveal the molecular mechanism by which STIM1/2 activates Panx1 and establishes a previously unrecognized essential role of its N-terminal region in regulating the transition of Panx1 to its large-pore solute permeable state. Our work will benefit studies aimed at understanding diverse functions of Panx1, including those linked to NMDAR-dependent signaling, stimulated in a modality- and context-specific manner by STIM proteins.     

Use and evaluation of assistive technologies for upper limb function in tetraplegia

ContextMore than half of all spinal cord injuries (SCI) occur at the cervical level leading to loss of upper limb function, restricted activity and reduced independence. Several technologies have been developed to assist with upper limb functions in the SCI population.ObjectiveThere is no clear clinical consensus on the effectiveness of the current assistive technologies for the cervical SCI population, hence this study reviews the literature in the years between 1999 and 2019.MethodsA systematic review was performed on the state-of-the-art assistive technology that supports and improves the function of impaired upper limbs in cervical SCI populations. Combinations of terms, covering assistive technology, SCI, and upper limb, were used in the search, which resulted in a total of 1770 articles. Data extractions were performed on the selected studies which involved summarizing details on the assistive technologies, characteristics of study participants, outcome measures, and improved upper limb functions when using the device.ResultsA total of 24 articles were found and grouped into five categories, including neuroprostheses (invasive and non-invasive), orthotic devices, hybrid systems, robots, and arm supports. Only a few selected studies comprehensively reported characteristics of the participants. There was a wide range of outcome measures and all studies reported improvements in upper limb function with the devices.ConclusionsThis study highlighted that assistive technologies can improve functions of the upper limbs in SCI patients. It was challenging to draw generalizable conclusions because of factors, such as heterogeneity of recruited participants, a wide range of outcome measures, and the different technologies employed.     

Performance of Microchannel Heat Sink Made of Silicon Material with the Two-Sided Wedge

New designs of the microchannel with a two-sided wedge shape at the base were studied numerically. Five different wedge angles ranging from 3° to 15° were incorporated into the microchannel design. Simulation of this novel microchannel was carried out using Computational Fluid Dynamics (CFD). Three-dimensional models of the microchannel heat sink were created, discretized, and based on Navier–Stokes and energy equations; laminar numerical solutions were obtained for heat transfer and pressure drop. Flow characteristics of water as coolant in a microchannel were studied. It was observed that numerical results are in good agreement with experimental results. It was found that the Nusselt number and friction factor are significantly varied with the increase in Reynolds number. The Nusselt number varies in the following ranges of 5.963–8.521, 5.986–8.550, 6.009–8.568, 6.040–8.609, and 6.078–8.644 at 3°, 6°, 9°, 12°, and 15°, respectively. The microchannel with a wedge angle of 15° was found to be better in terms of Nusselt number and thermo-hydraulic performance. The enhancement in the Nusselt number is found as 1.017–1.036 for a wedge angle of 15°; however, friction factors do not show the perceptible values at distinct values of wedge angle. Moreover, the thermo-hydraulic performance parameters (THPP) were evaluated and found to be maximum in the range of 1.027–1.045 for a wedge angle of 15°. However, minimum THPP was found in the range of 1.005–1.0185 for a wedge angle of 3°.     

Heart Failure after Laboratory Confirmed Influenza Infection (FLU-HF)

Background:Influenza has been shown to exacerbate heart failure (HF). Importantly, no study to date has examined the relationship between HF hospitalizations (HFH) with laboratory confirmed influenza infections. This study evaluated the association between laboratory confirmed influenza infection and HFH in the two largest hospitals in Saskatchewan, Canada.Methods:We used a retrospective self-controlled case series design to evaluate the association between laboratory-confirmed influenza infection and HFH. We compared the incidence ratio for HFH during the influenza risk interval with the control interval. We defined the influenza risk interval as the seven days after a laboratory confirmed influenza result and the control interval as one year before and after the risk interval.Results:We identified 114 HFH that occurred within one year before and after a positive test result for influenza between April 1, 2010, and April 30, 2018. Of these, 28 (28 admissions per week) occurred during the risk interval and 86 (0.853 admissions per week) occurred during the control interval. The incidence ratio of a HFH during the risk interval as compared with the control interval was 33.53 (95% confidence interval [CI], 21.89 to 51.36). A decline in incidence was observed after day seven; between days 8 to 14 and 14 to 28 incidence ratios was 0.91 (95% CI, 0.13 to 6.52) and 0.91 (95% CI, 0.22 to 3.68) respectively.Conclusion:We have observed a significant association between acute influenza infection and HFH. However, further research with a larger sample size and involving a multicenter setting is warranted.Highlights

• Influenza may contribute and exacerbate heart failure events especially during annual influenza season.
• Early identification of influenza among patients with heart failure, could lead to earlier treatment with antiviral medication, reduce unnecessary antibiotic use, and tail off the morbidity and mortality.
• In this study, despite our efficient study design, our sample size was limited to only the two largest hospitals in the province, possibly excluding a significant population in remote areas.