Non-additive effects of electrical stimulation of the dorsolateral prefrontal cortex and the vestibular system on muscle sympathetic nerve activity in humans.

Sinusoidal galvanic vestibular stimulation (sGVS) induces robust modulation of muscle sympathetic nerve activity (MSNA) alongside perceptions of side-to-side movement, sometimes with an accompanying feeling of nausea. We recently showed that transcranial alternating current stimulation (tACS) of the dorsolateral prefrontal cortex (dlPFC) also modulates MSNA, but does not generate any perceptions. Here, we tested the hypothesis that when the two stimuli are given concurrently, the modulation of MSNA would be additive. MSNA was recorded from 11 awake participants via a tungsten microelectrode inserted percutaneously into the right common peroneal nerve at the fibular head. Sinusoidal stimuli (± 2 mA, 0.08 Hz, 100 cycles) were applied in randomised order as follows: (i) tACS of the dlPFC at electroencephalogram (EEG) site F4 and referenced to the nasion; (ii) bilateral sGVS applied to the vestibular apparatuses via the mastoid processes; and (iii) tACS and sGVS together. Previously obtained data from 12 participants supplemented the data for stimulation protocols (i) and (ii). Cross-correlation analysis revealed that each stimulation protocol caused significant modulation of MSNA (modulation index (paired data): 35.2 ± 19.4% for sGVS; 27.8 ± 15.2% for tACS), but there were no additive effects when tACS and sGVS were delivered concurrently (32.1 ± 18.5%). This implies that the vestibulosympathetic reflexes are attenuated with concurrent dlPFC stimulation. These results suggest that the dlPFC is capable of blocking the processing of vestibular inputs through the brainstem and, hence, the generation of vestibulosympathetic reflexes.

Differential control of sympathetic outflow to muscle and skin during physical and cognitive stressors.

PURPOSE: Sympathetic nerve activity towards muscle (MSNA) and skin (SSNA) regulates various physiological parameters. MSNA primarily functions in blood pressure and flow, while SSNA operates in thermoregulation. Physical and cognitive stressors have been shown to have effects on both types of sympathetic activity, but there are inconsistencies as to what these effects are. This article aims to address the discrepancies in the literature and compare MSNA and SSNA responses. METHODS: Microelectrode recordings were taken from the common peroneal nerve in 29 participants: MSNA (n = 21), SSNA (n = 16) and both MSNA and SSNA (n = 8). Participants were subjected to four different 2-min stressors: two physical (isometric handgrip task, cold pressor test) and two cognitive (mental arithmetic task, Stroop colour-word conflict test), the latter of which saw participants separated into responders and non-responders to the stressors. It was hypothesised that the physical stressors would have a greater effect on MSNA than SSNA, while the cognitive stressors would operate conversely. RESULTS: Peristimulus time histogram (PSTH) analysis showed the mental arithmetic task to significantly increase both MSNA and SSNA; the isometric handgrip task and cold pressor test to increase MSNA, but not SSNA; and Stroop test to have no significant effects on changing MSNA or SSNA from baseline. Additionally, stress responses did not differ between MSNA and SSNA in participants who had both sets of data recorded. CONCLUSIONS: This study has provided evidence to support the literature which claims cognitive stressors increase sympathetic activity, and provides much needed SSNA data in response to stressors.

Top-down control of vestibular inputs by the dorsolateral prefrontal cortex.

The vestibular apparatus provides spatial information on the position of the head in space and with respect to gravity. Low-frequency sinusoidal galvanic vestibular stimulation (sGVS), a means of selectively changing the firing of vestibular afferents, induces a frequency-dependent perception of sway and, in some individuals, induces nausea. Given that vestibular afferents project to the insular cortex-which forms part of the vestibular cortex-and that the insula receives inputs from the dorsolateral prefrontal cortex (dlPFC), we tested the hypothesis that electrical stimulation of the dlPFC can modulate vestibular inputs. Sinusoidal electrical stimulation (± 2 mA, 0.08 Hz, 100 cycles) was delivered via surface electrodes over (1) the mastoid processes alone (sGVS), (2) electroencephalogram (EEG) site F4 (right dlPFC) and the nasion or (3) to each site concurrently (sGVS + dlPFC) in 23 participants. The same stimulation protocol was used in a separate study to investigate EEG site F3 (left dlPFC) instead of F4 in 13 participants. During sGVS, all participants reported perceptions of sway and 13 participants also reported nausea, neither sensation of which occurred as a result of dlPFC stimulation. Interestingly, when sGVS and dlPFC stimulations were delivered concurrently, vestibular perceptions and sensations of nausea were almost completely abolished. We conclude that the dlPFC provides top-down control of vestibular inputs and further suggests that dlPFC stimulation may provide a novel means of controlling nausea.

The Central Network Involved in the Processing of Vestibular Inputs and the Generation of Vestibulosympathetic Reflexes Controlling Blood Pressure in Humans.

The vestibular apparatus is highly specialized for detecting linear and angular acceleration, contributing importantly to perception of our position in the gravitational field and to motion in the three spatial axes. Beginning in the inner ear, spatial information is relayed toward higher cortical regions for processing, though the specific locations at which this action takes place remain somewhat ambiguous. This article aims to highlight brain regions known to be involved in the processing of spatial information, as well as those that contribute to a less widely documented function of the vestibular system-its capacity to regulate blood pressure via vestibulosympathetic reflexes. As we go from lying to standing, there is a proportional increase in muscle sympathetic nerve activity (MSNA) to the legs that prevents the fall in blood pressure associated with the pooling of blood toward the feet. While feedback from baroreceptors is partially responsible, vestibulosympathetic reflexes operate in a feed-forward manner to compensate for postural changes in the gravitational field. The cortical and subcortical network comprising the central sympathetic connectome shares certain elements with the vestibular system, and it is known that vestibular afferents project via the vestibular nuclei to the rostral ventrolateral medulla (RVLM)-the final output nucleus for generating MSNA. Here we consider how vestibular afferents interact with other components of the central sympathetic connectome, with particular emphasis on the potential roles of the insula and dorsolateral prefrontal cortex (dlPFC) as possible core integrative sites for vestibular and higher cortical processes. © 2023 American Physiological Society. Compr Physiol 13:4811-4832, 2023.

The role of the dorsolateral prefrontal cortex in control of skin sympathetic nerve activity in humans.

The dorsolateral prefrontal cortex (dlPFC) is primarily involved in higher order executive functions, with there being evidence of lateralization. Brain imaging studies have revealed its link to the generation of skin sympathetic nerve activity (SSNA), which is elevated in states of emotional arousal or anxiety. However, no studies have directly explored dlPFC influences on SSNA. Transcranial alternating current stimulation (-2 to 2 mA, 0.08 Hz, 100 cycles) was applied between the left or right dlPFC and nasion via surface electrodes. Spontaneous bursts of SSNA were recorded from the common peroneal nerve via a tungsten microelectrode in 21 healthy participants. The modulation index was calculated for each stimulation paradigm by constructing cross-correlation histograms between SSNA and the sinusoidal stimulus. Stimulation of the dlPFC caused significant modulation of SSNA, but there was no significant difference in the median modulation index across sides. Stimulation also caused cyclic modulation of skin blood flow and sweat release. We have shown for the first time that stimulation of the dlPFC causes modulation of SSNA, also reflected in the effector-organ responses. This supports a role for the dlPFC in the control of SSNA, which likely contributes to the ability of emotions to bring about cutaneous vasoconstriction and sweat release.

Stimulation of the dorsolateral prefrontal cortex modulates muscle sympathetic nerve activity and blood pressure in humans.

Introduction: Muscle sympathetic nerve activity (MSNA) controls the diameter of arterioles in skeletalmuscle, contributing importantly to the beat-to-beat regulation of blood pressure (BP). Although brain imaging studies have shown that bursts of MSNA originate in the rostral ventrolateral medulla, other subcortical and cortical structures-including the dorsolateral prefrontal cortex (dlPFC)-contribute. Hypothesis: We tested the hypothesis that MSNA and BP could be modulated by stimulating the dlPFC. Method: dlPFC. In 22 individuals MSNA was recorded via microelectrodes inserted into the common peroneal nerve, together with continuous BP, electrocardiographic, and respiration.Stimulation of the right (n=22) or left dlPFC (n=10) was achieved using transcranial alternating current (tcACS; +2 to -2mA, 0.08 Hz,100 cycles), applied between the nasion and electrodes over the F3 or F4 EEG sites on the scalp. Results: Sinusoidal stimulation of either dlPFC caused cyclicmodulation of MSNA, BP and heart rate, and a significant increase in BP. Conclusion: We have shown, for the first time, that tcACS of the dlPFC in awake humans causes partial entrainment of MSNA, heart rate and BP, arguing for an important role of this higher-level cortical area in the control of cardiovascular function.

Pesticides and their degradates in groundwater reflect past use and current management strategies, Long Island, New York, USA.

Long Island, New York, has a mix of urban/suburban to agricultural/horticultural land use and nearly 3 million residents that rely on a sole-source aquifer for drinking water. The analysis of shallow groundwater (<40 m below land surface) collected from 54 monitoring wells across Long Island detected 53 pesticides or pesticide degradates. Maximum concentrations for individual pesticides or pesticide degradates ranged from 3 to 368,000 ng/L. The highest concentrations and most frequent pesticide detections occurred in samples collected from the pesticide management (PM) network, set in an agricultural/horticultural area in eastern Long Island with coordinated pesticide management by state and local agencies. The other two networks (Suffolk and Nassau/Queens) were set in suburban and urban areas, respectively, and had less frequent detections and lower pesticide concentrations than the PM network. Pesticide detections and concentration patterns (herbicide, insecticide, or fungicide) differed among the three networks revealing broad differences in land use. The predominance of fungicides metalaxyl, 1H-1,2,4-triazole (propiconazole/myclobutanil degradate), and 4-hydroxychlorothalonil (HCTL, chlorothalonil degradate) in samples from the PM network reflects their intensive use in agricultural settings. Total fungicide concentrations in the PM network ranged from <10 to >300,000 ng/L. The widespread detection of imidacloprid and triazine herbicides, simazine and atrazine, reveal a mixture of current and past use pesticides across the Long Island region. Low concentrations (<200 ng/L) of the triazines in the Suffolk and Nassau/Queens networks may reflect a change in land use and application. Acetanilide herbicides and aldicarb have been discontinued for 20 and 40 years, respectively, yet the concentrations of their degradates were among the highest observed in this study. Acetanilide (total concentrations up to 10,000 ng/L) and aldicarb degradates (up to 270 ng/L) are present in the PM network at much lower concentrations than previous Long Island studies and reflect changes in agricultural practices and pesticide management.

National survey of mentorship in Canadian general surgery residency programs: Where are we and what do we need?

BACKGROUND: The benefits of mentorship on residents are well established. The current state of mentorship in General Surgery (GS) residency programs in Canada is unknown. The objectives of this study were to obtain GS residents' and program directors' (PD) perspectives on resident mentorship. STUDY DESIGN: An electronic survey was developed and distributed to all 601 GS residents in Canada. All 17 PDs were invited for telephone interviews. RESULTS: A total of 179 of the 601 residents responded. Ninety-seven percent (n=173) felt mentorship was important. Only 67% (n=116) identified a mentor and only 53% (n=62) reported a mentorship program. Most who identified a mentor (n=87/110, 79%) were satisfied with the mentorship received. Significant variations in mentorship existed between demographic subgroups and mentorship program types. Overall, residents (n=121, 74%) favoured having a required mentorship program.A total of 11 out of 17 PDs participated in the telephone interviews. The majority of PDs (n=9, 82%) were satisfied with current resident mentorship but most acknowledged that barriers exist (n=8, 73%). CONCLUSION: GS programs in Canada should ensure they are providing equal opportunities for mentorship across demographic subgroups. Programs are encouraged to examine both their program's and their residents' needs as well as local barriers to improve mentorship.

Lithographically Defined, Room Temperature Low Threshold Subwavelength Red-Emitting Hybrid Plasmonic Lasers.

Hybrid plasmonic lasers provide deep subwavelength optical confinement, strongly enhanced light-matter interaction and together with nanoscale footprint promise new applications in optical communication, biosensing, and photolithography. The subwavelength hybrid plasmonic lasers reported so far often use bottom-up grown nanowires, nanorods, and nanosquares, making it difficult to integrate these devices into industry-relevant high density plasmonic circuits. Here, we report the first experimental demonstration of AlGaInP based, red-emitting hybrid plasmonic lasers at room temperature using lithography based fabrication processes. Resonant cavities with deep subwavelength 2D and 3D mode confinement of λ2/56 and λ3/199, respectively, are demonstrated. A range of cavity geometries (waveguides, rings, squares, and disks) show very low lasing thresholds of 0.6-1.8 mJ/cm2 with wide gain bandwidth (610 nm-685 nm), which are attributed to the heterogeneous geometry of the gain material, the optimized etching technique, and the strong overlap of the gain material with the plasmonic modes. Most importantly, we establish the connection between mode confinements and enhanced absorption and stimulated emission, which plays critical roles in maintaining low lasing thresholds at extremely small hybrid plasmonic cavities. Our results pave the way for the further integration of dense arrays of hybrid plasmonic lasers with optical and electronic technology platforms.

High aspect ratio nano-fabrication of photonic crystal structures on glass wafers using chrome as hard mask.

Wafer-scale nano-fabrication of silicon nitride (Si x N y ) photonic crystal (PhC) structures on glass (quartz) substrates is demonstrated using a thin (30 nm) chromium (Cr) layer as the hard mask for transferring the electron beam lithography (EBL) defined resist patterns. The use of the thin Cr layer not only solves the charging effect during the EBL on the insulating substrate, but also facilitates high aspect ratio PhCs by acting as a hard mask while deep etching into the Si x N y . A very high aspect ratio of 10:1 on a 60 nm wide grating structure has been achieved while preserving the quality of the flat top of the narrow lines. The presented nano-fabrication method provides PhC structures necessary for a high quality optical response. Finally, we fabricated a refractive index based PhC sensor which shows a sensitivity of 185 nm per RIU.

Nanowire transistors without junctions.

All existing transistors are based on the use of semiconductor junctions formed by introducing dopant atoms into the semiconductor material. As the distance between junctions in modern devices drops below 10 nm, extraordinarily high doping concentration gradients become necessary. Because of the laws of diffusion and the statistical nature of the distribution of the doping atoms, such junctions represent an increasingly difficult fabrication challenge for the semiconductor industry. Here, we propose and demonstrate a new type of transistor in which there are no junctions and no doping concentration gradients. These devices have full CMOS functionality and are made using silicon nanowires. They have near-ideal subthreshold slope, extremely low leakage currents, and less degradation of mobility with gate voltage and temperature than classical transistors.

New and old cardiovascular risk factors: C-reactive protein, homocysteine, cysteine and von Willebrand factor increase risk, especially in smokers.

BACKGROUND: The relative importance of new risk factors for heart disease singly or in combination is uncertain. We assessed relationships between C-reactive protein, homocysteine, cysteine, von Willebrand factor, activated factor XII and stable heart disease, as well as interaction with established risk factors. METHODS: A case-control study of 260 cases of stable heart disease from the Irish component of the European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE) II cohort and 260 age, sex-matched controls. C-reactive protein, homocysteine, cysteine, von Willebrand factor, activated factor XII and conventional risk factors were assayed or recorded. Interaction effects between new and conventional factors were assessed using additive and multiplicative models. RESULTS: C-reactive protein, homocysteine, cysteine and von Willebrand factor were significantly higher in cases than controls. Comparing the top fifth with the bottom four-fifths showed independent associations between heart disease and C-reactive protein [odds ratio (OR) 1.79; 95% confidence interval (CI) 1.12-2.86; P = 0.01], cysteine (OR 2.00; 95% CI 1.25-3.20; P = 0.004), von Willebrand factor (OR, 3.0; 95% CI 1.9-4.8; P < 0.0001). For homocysteine, the association was independent comparing the top tenth to the bottom nine-tenths (OR 1.95; 95% CI 1.02-3.41; P = 0.04). Activated factor XII was not associated with risk. The association between C-reactive protein and disease was U-shaped and a graded association existed between homocysteine, cysteine, von Willebrand factor and disease. C-reactive protein, homocysteine, cysteine and von Willebrand factor considerably increased risk associated with other factors, particularly smoking. CONCLUSIONS: Independent associations exist between stable heart disease and C-reactive protein, homocysteine, cysteine and von Willebrand factor. Strong combined effects were observed between these and conventional risk factors, particularly smoking. Smoking cessation may profoundly reduce risk associated with other risk factors. We found no evidence of a relationship between activated factor XII and disease.

Attenuated total reflectance Fourier transform mid-infrared spectroscopic quantification of sorbitol and sorbose during a Gluconobacter biotransformation process.

Mid-infrared spectroscopy (MIRS) was used to simultaneously detect and predict concentrations of D-sorbitol and L-sorbose during a Gluconobacter suboxydans biotransformation. Quantitative models for both these compounds were developed for the entire time-course of the process and validated externally using samples not included in the original modelling exercise, giving standard errors of prediction of 3.29 and 3.3% for sorbitol and sorbose, respectively, and a correlation coefficient close to 1.

Steady state levels of transforming growth factor-beta1 and -beta2 mRNA and protein expression are elevated in colonic tumors in vivo irrespective of dietary lipids intervention.

Colonic tumors of human origin produce abundant transforming growth factor (TGF)-beta suggesting that TGF-beta is critical to their growth. Dietary lipids regulate a number of growth factors including TGF-beta. Whether elevated TGF-beta levels are consistently expressed in colonic tumors irrespective of the environmental milieu in an in vivo model is not known and forms the main objective of the present study. Male F344 rats were injected with azoxymethane, 10 weeks later, rats bearing preneoplastic lesions were fed a low fat (5% corn oil) diet and 3 high fat (5% corn oil with 18% corn oil, fish oil or beef tallow) diets for 16 weeks. Colonic tumors and mucosae were processed and assessed for TGF-beta status. TGF-beta1 and -beta2 mRNA levels were upregulated in colonic tumors more than in mucosae of all diet groups. Dietary lipids modulated TGF-beta mRNA in both tumors and mucosae, high corn and fish oil diets upregulated TGF-beta1 significantly more than the low fat corn oil or high fat beef tallow diets. Immunohistochemical assessments of tissues with different biological features revealed that TGF-beta1 and -beta2 were elevated in tumors and in selected microscopic preneoplastic lesions compared to normal mucosae. This is the first in vivo study, documenting that developing colonic tumors acquire upregulated TGF-beta phenotype even in the presence of lipid environments capable of differentially regulating TGF-beta in normal mucosae. Elevated expression of TGF-beta in a selected subset of microscopic preneoplastic lesions suggests that TGF-beta plays an important role on both early and late stages of colon carcinogenesis.

Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration.

We studied the role of the matrix metalloproteinase gelatinase B (gelB; MMP-9) in epithelial regeneration using the gelB-deficient mouse. We report the novel finding that, in contrast to other MMPs expressed at the front of the advancing epithelial sheet in wounds of cornea, skin, or trachea, gelB acts to inhibit the rate of wound closure. We determined this to be due to control of cell replication, a novel capacity for MMPs not previously described. We also found that gelB delays the inflammatory response. Acceleration of these processes in gelB-deficient mice is correlated with a delay in signal transduction through Smad2, a transcription factor that inhibits cell proliferation, and in accumulation of epithelial-associated interleukin-1alpha, a cytokine that inhibits Smad2 signaling and promotes the inflammatory response. GelB-deficient mice also reveal defects in remodeling of extracellular matrix at the epithelial basement membrane zone, in particular, failure to effectively remove the fibrin(ogen) provisional matrix. We conclude that gelB coordinates and effects multiple events involved in the process of epithelial regeneration.