Mercury in seafood is a neurotoxicant that threatens human health. Dynamic rates of mercury emission, re-emission, and atmospheric deposition warrant studies into mercury concentrations in fish ...because many are consumed by humans and can serve as sentinels of mercury levels in the environment. We modeled trends in total mercury content in an apex marine fish predator, Atlantic blue marlin Makaira nigricans, whose muscle tissues were opportunistically sampled from North Carolina (USA) sportfishing tournaments over a discontinuous time period: between 1975 and 77 and 1998–2021 (n = 148). The model-estimated influence of marlin weight on total mercury concentration was constant across years (shared slope) allowing for comparisons of weight-corrected mercury concentrations among years. Weight-corrected total mercury concentrations revealed an inter-decadal decline of approximately 45 % between the 1970s and late 1990s and then variable but relatively stable concentrations through 2021. The mean (SD) wet weight concentration of total mercury was 9.47 (4.11) from 1975 to 77 and 4.17 (2.61) from 2020 to 2021. Methylmercury and selenium were measured on a subset of fish to address questions related to human health and consumption. Methylmercury levels (mean = 0.72 μg/g) were much lower than total mercury (mean = 4.69 μg/g) indicating that total mercury is not a good proxy for methylmercury in Atlantic blue marlin. Selenium, examined as a Se:Hg molar ratio and as a selenium health benefit value (HBVSe), showed high protective value against mercury toxicity. Long-term trends in the concentration of mercury in blue marlin should continue to be monitored to determine whether policies to mitigate anthropogenic contributions to global mercury are achieving their intended goals and to provide information to inform safe human consumption.
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•Long-term studies of offshore marine apex predators are valuable for indexing ambient heavy metal concentrations.•Atlantic blue marlin muscle collected from 1975 to 2021 was analyzed for total mercury, methylmercury, and selenium.•Total mercury concentrations declined from the 1970s to late 1990s, but remained approximately constant during this century.•Methylmercury is a small percentage of total mercury in Atlantic blue marlin, which is not typically observed in fish.•High selenium concentrations in Atlantic blue marlin tissue may substantially offset mercury toxicity in human consumers.
The slow (<1 Hz) rhythm is a defining feature of the electroencephalogram during sleep. Since cortical circuits can generate this rhythm in isolation, it is assumed that the accompanying slow ...oscillation in thalamocortical (TC) neurons is largely a passive reflection of neocortical activity. Here we show, however, that by activating the metabotropic glutamate receptor (mGluR), mGluR1a, cortical inputs can recruit intricate cellular mechanisms that enable the generation of an intrinsic slow oscillation in TC neurons in vitro with identical properties to those observed in vivo. These mechanisms rely on the “window” component of the T-type Ca
2+ current and a Ca
2+-activated, nonselective cation current. These results suggest an active role for the thalamus in shaping the slow (<1 Hz) sleep rhythm.
Metabotropic glutamate receptors (mGluRs) play a crucial role in regulation of phasic inhibition within the visual thalamus. Here we demonstrate that mGluR-dependent modulation of interneuron GABA ...release results in dynamic changes in extrasynaptic GABA(A) receptor (eGABA(A)R)-dependent tonic inhibition in thalamocortical (TC) neurons of the rat dorsal lateral geniculate nucleus (dLGN). Application of the group I selective mGluR agonist dihydroxyphenylglycine produces a concentration-dependent enhancement of both IPSC frequency and tonic GABA(A) current (I(GABA)tonic) that is due to activation of both mGluR1a and mGluR5 subtypes. In contrast, group II/III mGluR activation decreases both IPSC frequency and I(GABA)tonic amplitude. Using knock-out mice, we show that the mGluR-dependent modulation of I(GABA)tonic is dependent upon expression of δ-subunit containing eGABA(A)Rs. Furthermore, unlike the dLGN, no mGluR-dependent modulation of I(GABA)tonic is present in TC neurons of the somatosensory ventrobasal thalamus, which lacks GABAergic interneurons. In the dLGN, enhancement of IPSC frequency and I(GABA)tonic by group I mGluRs is not action potential dependent, being insensitive to TTX, but is abolished by the L-type Ca(2+) channel blocker nimodipine. These results indicate selective mGluR-dependent modulation of dendrodendritic GABA release from F2-type terminals on interneuron dendrites and demonstrate for the first time the presence of eGABA(A)Rs on TC neuron dendritic elements that participate in "triadic" circuitry within the dLGN. These findings present a plausible novel mechanism for visual contrast gain at the thalamic level and shed new light upon the potential role of glial ensheathment of synaptic triads within the dLGN.
Two types of GABAergic interneurone are known to express cholecystokinin-related peptides in the isocortex: basket cells, which preferentially innervate the somata and proximal dendrites of pyramidal ...cells; and double bouquet cells, which innervate distal dendrites and dendritic spines. In the hippocampus, cholecystokinin immunoreactivity has only been reported in basket cells. However, at least eight distinct GABAergic interneurone types terminate in the dendritic domain of CA1 pyramidal cells, some of them with as yet undetermined neurochemical characteristics. In order to establish whether more than one population of cholecystokinin-expressing interneurone exist in the hippocampus, we have performed whole-cell current clamp recordings from interneurones located in the stratum radiatum of the hippocampal CA1 region of developing rats. Recorded neurones were filled with biocytin to reveal their axonal targets, and were tested for the presence of pro-cholecystokinin immunoreactivity.
The results show that two populations of cholecystokinin-immunoreactive interneurones exist in the CA1 area (
n=15 positive cells). Cholecystokinin-positive basket cells (53%) preferentially innervate stratum pyramidale and adjacent strata oriens and radiatum. A second population of cholecystokinin-positive cells, previously described as Schaffer collateral-associated interneurones Vida et al. (1998) J. Physiol. 506, 755–773, have axons that ramify almost exclusively in strata radiatum and oriens, overlapping with the Schaffer collateral/commissural pathway originating from CA3 pyramidal cells. Two of seven of the Schaffer collateral-associated cells were also immunopositive for calbindin. Soma position and orientation in stratum radiatum, the number and orientation of dendrites, and the passive and active membrane properties of the two cell populations are only slightly different. In addition, in stratum radiatum and its border with lacunosum of perfusion-fixed hippocampi, 31.6±3.8% (adult) or 26.8±2.9% (postnatal day 17–20) of cholecystokinin-positive cells were also immunoreactive for calbindin.
Therefore, at least two populations of pro-cholecystokinin-immunopositive interneurones, basket and Schaffer collateral-associated cells, exist in the CA1 area of the hippocampus, and are probably homologous to cholecystokinin-immunopositive basket and double bouquet cells in the isocortex. It is not known if the GABAergic terminals of double bouquet cells are co-aligned with specific glutamatergic inputs. However, in the hippocampal CA1 area, it is clear that the terminals of Schaffer collateral-associated cells are co-stratified with the glutamatergic input from the CA3 area, with as yet unknown functional consequences. The division of the postsynaptic neuronal surface by two classes of GABAergic cell expressing cholecystokinin in both the hippocampus and isocortex provides further evidence for the uniform synaptic organisation of the cerebral cortex.
Abstract Background High-dose oestrogen (HDE) is effective but toxic in postmenopausal women with advanced breast cancer (ABC). Prolonged oestrogen deprivation sensitises BC cell lines to estrogen ...and we hypothesised that third-generation aromatase inhibitors (AIs) would sensitise BCs to low-dose estradiol (LDE). Methods A single-arm phase II study of LDE (2 mg estradiol valerate daily) in postmenopausal women with estrogen receptor-positive (ER+) ABC. The primary end-point was clinical benefit (CB) rate. If LDE was ineffective, HDE was offered. If LDE was effective, retreatment with the pre-LDE AI was offered on progression. Results Twenty-one patients were recruited before the trial was closed early due to slow accrual; 19 were assessable for efficacy and toxicity. CB was seen in 5 in 19 patients (26%; 95% confidence interval 9.1–51.2%), all with prolonged SD (median duration 16.8 months; range 11.0–29.6). Treatment was discontinued for toxicity in 4 in 19 patients (21%) and 8 in 11 women without hysterectomy experienced vaginal bleeding (VB). After primary LDE failure, three patients received HDE and one achieved a partial response (PR). Following CB on LDE, four patients restarted pre-LDE AI and three achieved CB including one PR. Those with CB to LDE had a significantly longer duration of first-line endocrine therapy for ABC than those without (54.9 versus 16.8 months; p < 0.01) Conclusion LDE is an effective endocrine option in women with evidence of prolonged sensitivity to AI therapy. LDE is reasonably well tolerated although VB is an issue. Re-challenge with the pre-LDE AI following progression confirms re-sensitisation as a true phenomenon.
Spikelets, or fast prepotentials as they are frequently referred to, are a common feature of the electrophysiology of central neurones and are invariably correlated with the presence of electrotonic ...coupling via gap junctions (
Dudek et al., 1998; Perez Velazquez and Carlen, 2000). Here we report that in the presence of the metabotropic glutamate receptor agonists,
trans-ACPD or DHPG, thalamocortical neurones of the cat dorsal lateral geniculate nucleus maintained
in vitro exhibit stereotypical spikelets that possess similar properties to those described in other brain areas. These spikelets were routinely observed in the presence of antagonists of fast chemical synaptic transmission, were resistant to the application of a variety of voltage-dependent Ca
2+ channel blockers but were abolished by tetrodotoxin. In addition, spikelets were reversibly blocked by the putative gap junction blocker carbenoxolone and were nearly always accompanied by dye-coupling. These results indicate that thalamocortical neurones may be electrotonically coupled via gap junctions with spikelets representing attenuated action potentials from adjoining cells. We suggest that the presence of electrotonic communication between thalamocortical neurones would have major implications for the understanding of both physiological (
Steriade et al., 1993; Sillito et al., 1994; Alonso et al., 1996; Neuenschwander and Singer, 1996; Weliky and Katz, 1999) and pathological (
Steriade and Contreras, 1995; Pinault et al., 1998) synchronised electrical activity in the thalamus.
Tonic GABA
A
receptor-mediated inhibition is typically generated byδ subunit-containing extrasynaptic receptors. Because the δ subunit is highly expressed in the thalamus, we tested whether ...thalamocortical (TC) neurons of the dorsal lateral geniculate nucleus (dLGN) and ventrobasal complex exhibit tonic inhibition. Focal application of gabazine (GBZ) (50 μ
m
) revealed the presence of a 20 pA tonic current in 75 and 63% of TC neurons from both nuclei, respectively. No tonic current was observed in GABAergic neurons of the nucleus reticularis thalami (NRT). Bath application of 1μ
m
GABA increased tonic current amplitude to ∼70 pA in 100% of TC neurons, but it was still not observed in NRT neurons. In dLGN TC neurons, the tonic current was sensitive to low concentrations of the δ subunit-specific receptor agonists allotetrahydrodeoxycorticosterone (100 n
m
) and 4,5,6,7-tetrahydroisoxazolo5,4-c-pyridin-3-ol (THIP) (100 n
m
) but insensitive to the benzodiazepine flurazepam (5 μ
m
). Bath application of low concentrations of GBZ (25–200 n
m
) preferentially blocked the tonic current, whereas phasic synaptic inhibition was primarily maintained. Under intracellular current-clamp conditions, the preferential block of the tonic current with GBZ led to a small depolarization and increase in input resistance. Using extracellular single-unit recordings, block of the tonic current caused the cessation of low-threshold burst firing and promoted tonic firing. Enhancement of the tonic current by THIP hyperpolarized TC neurons and promoted burst firing. Thus, tonic current in TC neurons generates an inhibitory tone. Its modulation contributes to the shift between different firing modes, promotes the transition between different behavioral states, and predisposes to absence seizures.
The slow (<1 Hz) rhythm is an electroencephalogram hallmark of resting sleep. In thalamocortical neurons this rhythm correlates with a slow (<1 Hz) oscillation comprising recurring UP and DOWN ...membrane potential states. Recently, we showed that metabotropic glutamate receptor activation brings about an intrinsic slow oscillation in thalamocortical neurons of the cat dorsal lateral geniculate nucleus
in vitro which is identical to that observed
in vivo. The aim of this study was to further assess the properties of this oscillation and compare them with those observed in thalamocortical neurons of three other thalamic nuclei in the cat (ventrobasal complex, medial geniculate body; ventral lateral nucleus) and two thalamic nuclei in rats and mice (lateral geniculate nucleus and ventrobasal complex). Slow oscillations were evident in all of these additional structures and shared several basic properties including, i) the stereotypical, rhythmic alternation between distinct UP and DOWN states with the UP state always commencing with a low-threshold Ca
2+ potential, and ii) an inverse relationship between frequency and injected current so that slow oscillations always increase in frequency with hyperpolarization, often culminating in delta (δ) activity at ∼1–4 Hz. However, beyond these common properties there were important differences in expression between different nuclei. Most notably, 44% of slow oscillations in the cat lateral geniculate nucleus possessed UP states that comprised sustained tonic firing and/or high-threshold bursting. In contrast, slow oscillations in cat ventrobasal complex, medial geniculate body and ventral lateral nucleus thalamocortical neurons exhibited such UP states in only 16%, 11% and 10% of cases, respectively, whereas slow oscillations in the lateral geniculate nucleus and ventrobasal complex of rats and mice did so in <12% of cases. Thus, the slow oscillation is a common feature of thalamocortical neurons that displays clear species- and nuclei-related differences. The potential functional significance of these results is discussed.
There are very few studies about the impact of physicians’ attire on patients’ confidence and trust. The objective of this study was to determine whether the way a doctor dresses is an important ...factor in the degree of trust and confidence among respondents.
A cross-sectional descriptive study using survey methodology was conducted of patients and visitors in the waiting room of an internal medicine outpatient clinic. Respondents completed a written survey after reviewing pictures of physicians in four different dress styles. Respondents were asked questions related to their preference for physician dress as well as their trust and willingness to discuss sensitive issues.
Four hundred respondents with a mean age of 52.4 years were enrolled; 54% were men, 58% were white, 38% were African-American, and 43% had greater than a high school diploma. On all questions regarding physician dress style preferences, respondents significantly favored the professional attire with white coat (76.3%, P <.0001), followed by surgical scrubs (10.2%), business dress (8.8%), and casual dress (4.7%). Their trust and confidence was significantly associated with their preference for professional dress (P <.0001). Respondents also reported that they were significantly more willing to share their social, sexual, and psychological problems with the physician who is professionally dressed (P <.0001). The importance of physician’s appearance was ranked similarly between male and female respondents (P=.54); however, female physicians’ dress appeared to be significantly more important to respondents than male physicians’ dress (P <.001).
Respondents overwhelmingly favor physicians in professional attire with a white coat. Wearing professional dress (ie, a white coat with more formal attire) while providing patient care by physicians may favorably influence trust and confidence-building in the medical encounter.
1
The existence of a non‐negligible steady‐state (‘window’) component of the low threshold, T‐type Ca2+current (IT) and an appropriately large ratio of IT to ILeak conductance (i.e. gT/gLeak) have ...been shown to underlie a novel form of intrinsic bistability that is present in about 15 % of thalamocortical (TC) neurones.
2
In the present experiments, the dynamic clamp technique was used to introduce into mammalian TC neurones in vitro either an artificial, i.e. computer‐generated, IT in order to enhance endogenous IT, or an artificial inward ILeak to decrease endogenous ILeak. Using this method, we were able to investigate directly whether the majority of TC neurones appear non‐bistable because their intrinsic ionic membrane properties are essentially different (i.e. presence of a negligible IT‘window’ component), or simply because they possess a gT or gLeak conductance that is insufficiently large or small, respectively.
3
The validity of the dynamic clamp arrangement and the accuracy of artificial IT were confirmed by (i) recreating the low threshold calcium potential (LTCP) with artificial IT following its block by Ni2+ (0.5–1 mM), and (ii) blocking endogenous LTCPs with an artificial outward IT.
4
Augmentation of endogenous IT by an artificial analog or introduction of an artificial inward ILeak transformed all non‐bistable TC neurones to bistable cells that expressed the full array of bistability‐mediated behaviours, i.e. input signal amplification, slow oscillatory activity and membrane potential bistability.
5
These results demonstrate the existence of a non‐negligible IT‘window’ component in all TC neurones and suggest that rather than being a novel group of neurones, bistable cells are merely representative of an interesting region of dynamical modes in the (gT, gLeak) parameter space that may be expressed under certain physiological or pathological conditions by all TC neurones and other types of excitable cells that possess an IT‘window’ component with similar biophysical properties.
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