Human Nasal and Lung Tissues Infected Ex Vivo with SARS-CoV-2 Provide Insights into Differential Tissue-Specific and Virus-Specific Innate Immune Responses in the Upper and Lower Respiratory Tract.

The nasal mucosa constitutes the primary entry site for respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the imbalanced innate immune response of end-stage coronavirus disease 2019 (COVID-19) has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here, we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues ex vivo, coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with a rapid increase in tissue-associated viral subgenomic mRNA and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon-stimulated genes, cytokines, and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tracts that are specific to SARS-CoV-2. The studies shed light on the role of the nasal mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19. IMPORTANCE In order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here, we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues infected in parallel with SARS-CoV-2 and influenza virus, we found distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal mucosal infection model can be employed to assess the impact of viral evolutionary changes and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens.

Human Nasal Turbinate Tissues in Organ Culture as a Model for Human Cytomegalovirus Infection at the Mucosal Entry Site.

The initial events of viral infection at the primary mucosal entry site following horizontal person-to-person transmission have remained ill defined. Our limited understanding is further underscored by the absence of animal models in the case of human-restricted viruses, such as human cytomegalovirus (HCMV), a leading cause of congenital infection and a major pathogen in immunocompromised individuals. Here, we established a novel ex vivo model of HCMV infection in native human nasal turbinate tissues. Nasal turbinate tissue viability and physiological functionality were preserved for at least 7 days in culture. We found that nasal mucosal tissues were susceptible to HCMV infection, with predominant infection of ciliated respiratory epithelial cells. A limited viral spread was demonstrated, involving mainly stromal and vascular endothelial cells within the tissue. Importantly, functional antiviral and proleukocyte chemotactic signaling pathways were significantly upregulated in the nasal mucosa in response to infection. Conversely, HCMV downregulated the expression of nasal epithelial cell-related genes. We further revealed tissue-specific innate immune response patterns to HCMV, comparing infected human nasal mucosal and placental tissues, representing the viral entry and the maternal-to-fetal transmission sites, respectively. Taken together, our studies provide insights into the earliest stages of HCMV infection. Studies in this model could help evaluate new interventions against the horizontal transmission of HCMV.IMPORTANCE HCMV is a ubiquitous human pathogen causing neurodevelopmental disabilities in congenitally infected children and severe disease in immunocompromised patients. The earliest stages of HCMV infection in the human host have remained elusive in the absence of a model for the viral entry site. Here, we describe the establishment and use of a novel nasal turbinate organ culture to study the initial steps of viral infection and the consequent innate immune responses within the natural complexity and the full cellular repertoire of human nasal mucosal tissues. This model can be applied to examine new antiviral interventions against the horizontal transmission of HCMV and potentially that of other viruses.

Bison phylogeography constrains dispersal and viability of the Ice Free Corridor in western Canada.

The Ice Free Corridor has been invoked as a route for Pleistocene human and animal dispersals between eastern Beringia and more southerly areas of North America. Despite the significance of the corridor, there are limited data for when and how this corridor was used. Hypothetical uses of the corridor include: the first expansion of humans from Beringia into the Americas, northward postglacial expansions of fluted point technologies into Beringia, and continued use of the corridor as a contact route between the north and south. Here, we use radiocarbon dates and ancient mitochondrial DNA from late Pleistocene bison fossils to determine the chronology for when the corridor was open and viable for biotic dispersals. The corridor was closed after ∼23,000 until 13,400 calendar years ago (cal y BP), after which we find the first evidence, to our knowledge, that bison used this route to disperse from the south, and by 13,000 y from the north. Our chronology supports a habitable and traversable corridor by at least 13,000 cal y BP, just before the first appearance of Clovis technology in interior North America, and indicates that the corridor would not have been available for significantly earlier southward human dispersal. Following the opening of the corridor, multiple dispersals of human groups between Beringia and interior North America may have continued throughout the latest Pleistocene and early Holocene. Our results highlight the utility of phylogeographic analyses to test hypotheses about paleoecological history and the viability of dispersal routes over time.

Inferring demographic structure with moccasin size data from the Promontory Caves, Utah.

The moccasin assemblage Julian Steward recovered from the Promontory caves in 1930-31 provides a novel example in which material culture can be used to understand the structure of an AD thirteenth century population. Several studies shed light on the relationship between shoe size, foot size, and stature. We develop an anthropometric model for understanding the composition of the Promontory Cave population by using moccasin size as a proxy for foot size. We then predict the stature of the individual who would have worn a moccasin. Stature is closely related to age for children, subadults and adult males. Although there are predictable sex and age factors biasing moccasin discard practices, moccasin dimensions suggest a relatively large proportion of children and subadults occupied the Promontory caves. This bison and antelope hunting population appears to have thrived during its stay on Promontory Point.

Complementary medicine for fatigue and cortisol variability in breast cancer survivors: a randomized controlled trial.

BACKGROUND: Fatigue is a chief complaint in cancer patients, and warrants effective treatment. Biofield therapies are complementary medicine approaches used by cancer populations. There is little information about their efficacy. METHODS: This blinded, randomized controlled trial examined the effects of 4 weeks (eight 1-hour sessions) of biofield healing compared with mock healing and a waitlist control group on fatigue in 76 fatigued breast cancer survivors (stages I-IIIa). Secondary outcomes were diurnal cortisol variability (via estimates of cortisol slope), depression, and quality of life (QOL). Treatment belief was assessed to explore whether belief predicted outcomes. Data were analyzed via hierarchical linear modeling. RESULTS: There were no significant differences between biofield healing and mock healing on belief; 75% thought they received biofield healing. Compared with controls, biofield healing significantly decreased total fatigue (P < .0005, Cohen's d = 1.04), as did mock healing (P = .02, Cohen's d = 0.68), with no significant differences between biofield healing and mock healing. Cortisol slope significantly decreased for biofield healing versus both mock healing and control (P < .04 in both cases; Cohen's d = 0.58). Belief predicted changes in QOL over and above group (P = .004, Cohen's d = 0.84). Belief did not impact fatigue or cortisol variability. CONCLUSIONS: Nonspecific factors are important in responses to biofield interventions for fatigue. Belief predicts QOL responses but not fatigue or cortisol variability. Biofield therapies increase cortisol variability independent of belief and other nonspecific factors. There is a need to further examine the effects of specific processes of biofield healing on outcomes for cancer populations.

Method for appraising model validity of randomised controlled trials of homeopathic treatment: multi-rater concordance study.

BACKGROUND: A method for assessing the model validity of randomised controlled trials of homeopathy is needed. To date, only conventional standards for assessing intrinsic bias (internal validity) of trials have been invoked, with little recognition of the special characteristics of homeopathy. We aimed to identify relevant judgmental domains to use in assessing the model validity of homeopathic treatment (MVHT). We define MVHT as the extent to which a homeopathic intervention and the main measure of its outcome, as implemented in a randomised controlled trial (RCT), reflect 'state-of-the-art' homeopathic practice. METHODS: Using an iterative process, an international group of experts developed a set of six judgmental domains, with associated descriptive criteria. The domains address: (I) the rationale for the choice of the particular homeopathic intervention; (II) the homeopathic principles reflected in the intervention; (III) the extent of homeopathic practitioner input; (IV) the nature of the main outcome measure; (V) the capability of the main outcome measure to detect change; (VI) the length of follow-up to the endpoint of the study. Six papers reporting RCTs of homeopathy of varying design were randomly selected from the literature. A standard form was used to record each assessor's independent response per domain, using the optional verdicts 'Yes', 'Unclear', 'No'. Concordance among the eight verdicts per domain, across all six papers, was evaluated using the kappa (κ) statistic. RESULTS: The six judgmental domains enabled MVHT to be assessed with 'fair' to 'almost perfect' concordance in each case. For the six RCTs examined, the method allowed MVHT to be classified overall as 'acceptable' in three, 'unclear' in two, and 'inadequate' in one. CONCLUSION: Future systematic reviews of RCTs in homeopathy should adopt the MVHT method as part of a complete appraisal of trial validity.

A randomized controlled study to evaluate the efficacy of noninvasive limb cover for chronic phantom limb pain among veteran amputees.

OBJECTIVE: To assess the efficacy of a noninvasive limb cover for treating chronic phantom limb pain (PLP). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Outpatient clinic. PARTICIPANTS: We randomly assigned 57 subjects to 2 groups: true noninvasive limb cover (n=30) and sham noninvasive limb cover (n=27). Inclusion criteria included age of 18 years or greater, upper or lower extremity amputation with healed residual limb, and 3 or more episodes of PLP during the previous 6 weeks. INTERVENTIONS: Subjects received 2 true or sham noninvasive limb covers to be worn over the prosthesis and residual limbs 24 hours a day for 12 weeks. MAIN OUTCOME MEASURES: Primary outcome measure was the numerical pain rating scale of PLP level (0-10). Secondary outcomes included overall pain level (0-10), PLP frequency per week, and the Veterans RAND 12-Item Health Survey (VR-12). We collected data at baseline and at 6- and 12-week follow-up visits. RESULTS: Demographic and clinical characteristics were not significantly different between groups. The true noninvasive limb cover group reported nonsignificant reductions in PLP from 5.9±1.9 at baseline to 3.9±1.7 at the 12-week follow-up. The sham noninvasive limb cover group also had nonsignificant reducations in PLP from 6.5±1.8 to 4.2±2.3. PLP did not differ significantly between the 2 groups at 6 weeks (mean difference, 0.8; 95% confidence interval [CI], -1.4 to 3) or at 12 weeks (mean difference, 0.2; 95% CI, -1.9 to 2.3). Similarly, overall pain level, PLP episodes per week, and VR-12 physical and mental health component scores did not differ between the 2 groups at 6 and 12 weeks. CONCLUSIONS: A true noninvasive limb cover did not significantly decrease PLP levels or the frequency of PLP episodes per week, overall bodily pain levels, or VR-12 physical and mental health component scores compared with a sham noninvasive limb cover in our veteran amputee sample.

Enzyme stabilization by glass-derived silicates in glass-exposed aqueous solutions.

OBJECTIVES: To analyze the solutes leaching from glass containers into aqueous solutions, and to show that these solutes have enzyme activity stabilizing effects in very dilute solutions. METHODS: Enzyme assays with acetylcholine esterase were used to analyze serially succussed and diluted (SSD) solutions prepared in glass and plastic containers. Aqueous SSD preparations starting with various solutes, or water alone, were prepared under several conditions, and tested for their solute content and their ability to affect enzyme stability in dilute solution. RESULTS: We confirm that water acts to dissolve constituents from glass vials, and show that the solutes derived from the glass have effects on enzymes in the resultant solutions. Enzyme assays demonstrated that enzyme stability in purified and deionized water was enhanced in SSD solutions that were prepared in glass containers, but not those prepared in plastic. The increased enzyme stability could be mimicked in a dose-dependent manner by the addition of silicates to the purified, deionized water that enzymes were dissolved in. Elemental analyses of SSD water preparations made in glass vials showed that boron, silicon, and sodium were present at micromolar concentrations. CONCLUSIONS: These results show that silicates and other solutes are present at micromolar levels in all glass-exposed solutions, whether pharmaceutical or homeopathic in nature. Even though silicates are known to have biological activity at higher concentrations, the silicate concentrations we measured in homeopathic preparations were too low to account for any purported in vivo efficacy, but could potentially influence in vitro biological assays reporting homeopathic effects.

A new ground and reference technique for invasive EEG recordings.

OBJECTIVE: To demonstrate a subdermal wire electrode technique for establishing a ground (GND) and reference (REF) during long-term EEG monitoring (LTM) with intracranial electrodes. Usually, a separate GND and REF are required and this GND&REF pair can be selected contacts in the invasive electrode arrays themselves, special invasive electrodes, or standard surface disc electrodes which require frequent maintenance. We investigated the use of a pair of chronic Subdermal Wire Electrodes (SWE) for use as GND&REF. METHODS: A pair of SWEs as GND&REF was tested in nine patients undergoing invasive EEG monitoring. SWE impedances were monitored in two patients and compared to disc electrode impedances. RESULTS: Without maintenance, SWE impedances remained low and stable during the entire recording period (up to 20 days), whereas disc electrodes showed rapid impedance increase after the first day. In all nine patients, the consistent and durable integrity of the GND&REF pair of SWE allowed for a good quality EEG recording. No local skin complications were observed. CONCLUSIONS: A pair of SWE electrodes provides a GND&REF system that is easy to place, maintain, and provides a high quality recording with long-term stability when coupled with referential based EEG recording system from invasive electrodes. SIGNIFICANCE: A more efficient means of establishing a GND&REF pair during the monitoring of patients with invasive electrodes is described.

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection.

Quinolinate (Quin) is a classic example of a biochemical double-edged sword, acting as both essential metabolite and potent neurotoxin. Quin is an important metabolite in the kynurenine pathway of tryptophan catabolism leading to the de novo synthesis of nicotinamide adenine dinucleotide (NAD+). As a precursor for NAD+, Quin can direct a portion of tryptophan catabolism toward replenishing cellular NAD+ levels in response to inflammation and infection. Intracellular Quin levels increase dramatically in response to immune stimulation [e.g., lipopolysaccharide (LPS) or pokeweed mitogen (PWM)] in macrophages, microglia, dendritic cells, and other cells of the immune system. NAD+ serves numerous functions including energy production, the poly ADP ribose polymerization (PARP) reaction involved in DNA repair, and the activity of various enzymes such as the NAD+-dependent deacetylases known as sirtuins. We used highly specific antibodies to protein-coupled Quin to delineate cells that accumulate Quin as a key aspect of the response to immune stimulation and infection. Here, we describe Quin staining in the brain, spleen, and liver after LPS administration to the brain or systemic PWM administration. Quin expression was strong in immune cells in the periphery after both treatments, whereas very limited Quin expression was observed in the brain even after direct LPS injection. Immunoreactive cells exhibited diverse morphology ranging from foam cells to cells with membrane extensions related to cell motility. We also examined protein expression changes in the spleen after kynurenine administration. Acute (8 h) and prolonged (48 h) kynurenine administration led to significant changes in protein expression in the spleen, including multiple changes involved with cytoskeletal rearrangements associated with cell motility. Kynurenine administration resulted in several expression level changes in proteins associated with heat shock protein 90 (HSP90), a chaperone for the aryl-hydrocarbon receptor (AHR), which is the primary kynurenine metabolite receptor. We propose that cells with high levels of Quin are those that are currently releasing kynurenine pathway metabolites as well as accumulating Quin for sustained NAD+ synthesis from tryptophan. Further, we propose that the kynurenine pathway may be linked to the regulation of cell motility in immune and cancer cells.

Hormetic responses in neural systems: consideration, contexts, and caveats.

Dr. Edward Calabrese asserts that hormetic responses occur in neural systems, and provides ample review of evidence to support this claim. In this essay, we survey Dr. Calabrese's findings, illustrate the somewhat provocative premise of hormesis, and posit that while evidence suggests that amplification of low-dose effects are operative in neural systems, it is equally important to consider observations and claims of hormesis in greater detail, and framed within the "cultural" and epistemic contexts of science. We offer specific caveats to avoid the overgeneralization of findings, oversimplification of putative effects or mechanisms, and the dogmatic adherence to a restrictive methodologic orientation. Finally, we assert that any meaningful discussion of hormesis must be grounded to methodologic rigor, yet openness, and must allow for a self-critical and self-revisionist epistemic approach. We attempt to show that the work presented by Calabrese takes a first and important step toward the initiation of dialectic, allows for the exchange of ideas, strives toward reconciliation of differences and the amelioration of error, and seeks intellectual synthesis.

Clinical and analytical toxicology of dietary supplements: a case study and a review of the literature.

The use of dietary supplements has grown dramatically in the last decade. A large number of dietary and herbal supplements escape regulatory and quality control; components of these preparations are poisonous and may contain, among other toxins, heavy metals. Uncontrolled use of dietary and herbal supplements by special populations, such as the military, may therefore pose a health risk. Clinical symptoms are not always properly attributed to dietary supplements; patients often do not mention supplement use to their health care provider. Therefore, a health risk estimate is hard to make on either the individual or the population level. The literature on this issue was reviewed and discussed in the light of a representative clinical-chemical case study. This case study was performed on a host of preparations that were used by one single individual in the military. Both essential (chromium, copper, zinc, and iron) and poisonous (arsenic, lead, and nickel) trace elements were determined using inductively coupled plasma combined with optical emission spectrometry (ICP-OES) or with mass spectrometry (ICP-MS). Arsenic and lead were detected at exposure levels associated with health risks. These health risks were detected predominantly in hormone-containing supplements and the herbs and botanicals used for performance enhancement. To the extent that this is a representative sample, there is an underestimation of supplement use and supplement risk in the US military, if not in the general population. Since clinical symptoms may be attributed to other causes and, unless patients are specifically asked, health care providers may not be aware of their patients' use of dietary supplements, a strong support of laboratory diagnostics, such as a toxicological screening of blood or urine, is required. In addition, screening of the preparations themselves may be advised.

Should we explore the clinical utility of hormesis?

The idea that low-dose adaptive effects as described in hormesis can be used clinically has been discussed for hundreds if not thousands of years. Paracelsus famous adage that ;the dose makes the poison' and the common folk saying that one can be cured by ;the hair of the dog that bit you' speak to this idea. So why has so little research been done on the possible clinical utility of hormesis? What areas of clinical hormesis seem to be the most promising to explore? This article examines these concepts and proposes some initial areas or research where the possible utility of hormeiss might be investigated.

Free radicals and low-level photon emission in human pathogenesis: state of the art.

Convincing evidence supports a role for oxidative stress in the pathogenesis of many chronic diseases. The model includes the formation of radical oxygen species (ROS) and the misassembly and aggregation of proteins when three tiers of cellular defence are insufficient: (a) direct antioxidative systems, (b) molecular damage repairing systems, and (c) compensatory chaperone synthesis. The aim of the present overview is to introduce (a) the basics of free radical and antioxidant metabolism, (b) the role of the protein quality control system in protecting cells from free radical damage and its relation to chronic diseases, (c) the basics of the ultraweak luminescence as marker of the oxidant status of biological systems, and (d) the research in human photon emission as a non-invasive marker of oxidant status in relation to chronic diseases. In considering the role of free radicals in disease, both their generation and their control by the antioxidant system are part of the story. Excessive free radical production leads to the production of heat shock proteins and chaperone proteins as a second line of protection against damage. Chaperones at the molecular level facilitate stress regulation vis-à-vis protein quali y control mechanisms. The manifestation of misfolded proteins and aggregates is a hallmark of a range of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amylotrophic lateral sclerosis, polyglutamine (polyQ) diseases, diabetes and many others. Each of these disorders exhibits aging-dependent onset and a progressive, usually fatal clinical course. The second part reviews the current status of human photon emission techniques and protocols for recording the human oxidative status. Sensitive photomultiplier tubes may provide a tool for non-invasive and continuous monitoring of oxidative metabolism. In that respect, recording ultraweak luminescence has been favored compared to other indirect assays. Several biological models have been used to illustrate the technique in cell cultures and organs in vivo. This initiated practical applications addressing specific human pathological issues. Systematic studies on human emission have presented information on: (a) procedures for reliable measurements, and spectral analysis, (b) anatomic intensity of emission and left-right symmetries, (c) biological rhythms in emission, (d) physical and psychological influences on emission, (e) novel physical characteristics of emission, and (f) the identification of ultraweak photon emission with the staging of ROS-related damage and disease. It is concluded that both patterns and physical properties of ultraweak photon emission hold considerable promise as measure for the oxidative status.

Scalp sensor for simultaneous acoustic emission detection and electroencephalography during transcranial ultrasound.

Focused ultrasound is now capable of noninvasively penetrating the intact human skull and delivering energy to specific areas of the brain with millimeter accuracy. The ultrasound energy is supplied in high-intensities to create brain lesions or at low-intensities to produce reversible physiological interventions. Conducting acoustic emission detection (AED) and electroencephalography (EEG) during transcranial focused ultrasound may lead to several new brain treatment and research applications. This study investigates the feasibility of using a novel scalp senor for acquiring concurrent AED and EEG during clinical transcranial ultrasound. A piezoelectric disk is embedded in a plastic cup EEG electrode to form the sensor. The sensor is coupled to the head via an adhesive/conductive gel-dot. Components of the sensor prototype are tested for AED and EEG signal quality in a bench top investigation with a functional ex vivo skull phantom.

Current evidence allows multiple models for the peopling of the Americas.

Some recent academic and popular literature implies that the problem of the colonization of the Americas has been largely resolved in favor of one specific model: a Pacific coastal migration, dependent on high marine productivity, from the Bering Strait to South America, thousands of years before Clovis, the earliest widespread cultural manifestation south of the glacial ice. Speculations on maritime adaptations and typological links (stemmed points) across thousands of kilometers have also been advanced. A review of the current genetic, archeological, and paleoecological evidence indicates that ancestral Native American population expansion occurred after 16,000 years ago, consistent with the archeological record, particularly with the earliest securely dated sites after ~15,000 years ago. These data are largely consistent with either an inland (ice-free corridor) or Pacific coastal routes (or both), but neither can be rejected at present. Systematic archeological and paleoecological investigations, informed by geomorphology, are required to test each hypothesis.

Can specific biological signals be digitized?

At the request of the United States Defense Advanced Research Projects Agency, we attempted to replicate the data of Professor Jacques Benveniste that digital signals recorded on a computer disc produce specific biological effects. The hypothesis was that a digitized thrombin inhibitor signal would inhibit the fibrinogen-thrombin coagulation pathway. Because of the controversies associated with previous research of Prof. Benveniste, we developed a system for the management of social controversy in science that incorporated an expert in social communication and conflict management. The social management approach was an adaptation of interactional communication theory, for management of areas that interfere with the conduct of good science. This process allowed us to successfully complete a coordinated effort by a multidisciplinary team, including Prof. Benveniste, a hematologist, engineer, skeptic, statistician, neuroscientist and conflict management expert. Our team found no replicable effects from digital signals.

Miniaturized, on-head, invasive electrode connector integrated EEG data acquisition system.

OBJECTIVE: Intracranial electroencephalogram (EEG) monitoring involves recording multi-contact electrodes. The current systems require separate wires from each recording contact to the data acquisition unit resulting in many connectors and cables. To overcome limitations of such systems such as noise, restrictions in patient mobility and compliance, we developed a miniaturized EEG monitoring system with the amplifiers and multiplexers integrated into the electrode connectors and mounted on the head. METHODS: Small, surface-mounted instrumentation amplifiers, coupled with 8:1 analog multiplexers, were assembled into 8-channel modular units to connect to 16:1 analog multiplexer manifold to create a small (55 cm(3)) head-mounted 128-channel system. A 6-conductor, 30 m long cable was used to transmit the EEG signals from the patient to the remote data acquisition system. RESULTS: Miniaturized EEG amplifiers and analog multiplexers were integrated directly into the electrode connectors. Up to 128-channels of EEG were amplified and analog multiplexed directly on the patient's head. The amplified EEG data were obtained over one long wire. CONCLUSIONS: A miniaturized system of invasive EEG recording has the potential to reduce artefact, simplify trouble-shooting, lower nursing care and increase patient compliance. SIGNIFICANCE: Miniaturization technology improves intracranial EEG monitoring and leads to >128-channel capacity.

Metals and health: a clinical toxicological perspective on tungsten and review of the literature.

Tungsten and tungsten compounds are considered toxicologically relatively safe. Concern regarding the potential health and environmental effects of depleted uranium and lead in military applications has lead many countries to explore the possibility of applying toxicologically safer metals. Heavy metal tungsten alloy-based munitions have been therefore introduced as a replacement in munitions and as kinetic energy penetrators. Although the toxicological profiles of all these metals are well known, their internalization as embedded shrapnel may be considered a new route for long-term exposure. Studies in experimental animals and cell culture indicate that pellets based on heavy metal tungsten alloy possess carcinogenic potential previously unseen for depleted uranium and/or lead. Other metals in the tungsten alloy such as nickel or cobalt may contribute to such a risk. Accordingly, the long-term tungsten-related health risk is reason for concern. This article reviews toxicological and clinical literature and provides new perspectives on tungsten and tungsten-based alloys.