Hfe Actions in Kupffer Cells Are Dispensable for Hepatic and Systemic Iron Metabolism.

Mutations in the HFE/Hfe gene cause Hereditary Hemochromatosis (HH), a highly prevalent genetic disorder characterized by elevated iron deposition in multiple tissues. HFE acts in hepatocytes to control hepcidin expression, whereas HFE actions in myeloid cells are required for cell-autonomous and systemic iron regulation in aged mice. To address the role of HFE specifically in liver-resident macrophages, we generated mice with a selective Hfe deficiency in Kupffer cells (HfeClec4fCre). The analysis of the major iron parameters in this novel HfeClec4fCre mouse model led us to the conclusion that HFE actions in Kupffer cells are largely dispensable for cellular, hepatic and systemic iron homeostasis.

The first report of meningitis in a Greenland shark (Somniosus microcephalus).

The Greenland shark (Somniosus microcephalus) is a large species of shark found in the North Atlantic and Arctic Oceans and is believed to be the longest living vertebrate. Relatively little is known about its biology, abundance, health or diseases. In March 2022, only the third reported UK stranding of this species occurred and it was the first to undergo post-mortem examination. The animal was a sexually immature female, measuring 3.96 m in length and 285 kg in weight, and was in poor nutritional state. Gross findings included haemorrhages in the skin and soft tissues, particularly of the head, and silt in the stomach suggestive of live stranding, bilateral corneal opacity, slightly turbid cerebrospinal fluid (CSF) and patchy congestion of the brain. Histopathological findings included keratitis and anterior uveitis, fibrinonecrotic and lymphohistiocytic meningitis of the brain and proximal spinal cord and fibrinonecrotizing choroid plexitis. A near pure growth of a Vibrio organism was isolated from CSF. This is believed to be the first report of meningitis in this species.

Electrocution Risk of Capacitive Discharge Shocks: Application to Electric Vehicle Charging.

It is difficult to electrocute (induce ventricular fibrillation) with capacitive discharge shocks. With small capacitance values, the high voltages required for the necessary charge are rarely seen in industrial situations (e.g. electric vehicle charging stations). On the other hand, with large capacitance values, the discharge time is so great that the shock couples inefficiently with the cardiac cells. The update to IEC 60479-2 sets the C1 "mostly-safe" charge limit of 3 mC for a short "impulse function" pulse. We calculated the equivalent capacitor stored charge for an arbitrary capacitance value using the simple single membrane time constant model for the cardiac response. The peak membrane response was set equal to that of the 3 mC impulse function response to calculate the safe values for stored charge, voltage, and energy. The total stored charge, per se, cannot be used simplistically to estimate the danger of a capacitive discharge shock. A capacitive-discharge shock cannot be accurately compared to a rectangular shock with a duration equal to the shock time constant. The greater the capacitance, the larger the fraction of wasted charge in coupling to the heart and thus the shorter equivalent duration compared to the shock time constant. For a capacitive discharge shock this translates to a stored charge of 3 mC increasing up to 9 mC for a 10 capacitor using the assumed 575 load for an electric-vehicle (EV) charging station. In the area of interest for 1 - 10 the safe voltage ranges from 1300 to 4700 V, which includes the 1500-VDCscope of EV charger standard IEC 61851-23. For C > 100 the voltage asymptote is 700 V.

Iron effects versus metabolic alterations in hereditary hemochromatosis driven bone loss.

Hereditary hemochromatosis (HH) is a genetic disorder in which mutations affect systemic iron homeostasis. Most subtypes of HH result in low hepcidin levels and iron overload. Accumulation of iron in various tissues can lead to widespread organ damage and to various complications, including liver cirrhosis, arthritis, and diabetes. Osteoporosis is another frequent complication of HH, and the underlying mechanisms are poorly understood. Currently, it is unknown whether iron overload in HH directly damages bone or whether complications associated with HH, such as liver cirrhosis or hypogonadism, affect bone secondarily. This review summarizes current knowledge of bone metabolism in HH and highlights possible implications of metabolic dysfunction in HH-driven bone loss. We further discuss therapeutic considerations managing osteoporosis in HH.

Hands-on defibrillation with safety drapes: Analysis of compressions and an alternate current pathway.

BACKGROUND: Hands-on defibrillation (HOD) could theoretically improve the efficacy of cardiopulmonary resuscitation (CPR) though a few mechanisms. Polyethylene drapes could potentially facilitate safe HOD, but questions remain about the effects of CPR on polyethylene's conductance and the magnitude of current looping through rescuers' arms in contact with patients. METHODS: This study measured the leakage current through 2 mil (0.002 in.) polyethylene through two different current pathways before and after 30 min of continuous compressions on a CPR mannequin. The two pathways analyzed were the standardized IEC (International Electrotechnical Commission) leakage current analysis and a setup analyzing a current pathway looping through a rescuer's arms and returning to the patient. First, ten measurements involving the two pathways were obtained on a single polyethylene drape. 30 min of continuous compressions were applied to the drape on a CPR mannequin after which the ten measurements were repeated. RESULTS: Twenty patients undergoing elective cardioversion for atrial fibrillation (18/20) or atrial flutter (2/20) at Emory University Hospital underwent analysis all receiving 200 J shocks (age 38-101, 35% female). Through the IEC measurement method the peak leakage current mean was 0.70 +/- 0.02 mA before compressions and 0.59 +/- 0.19 mA after compressions. Only three of the ten measurements assessing current passing through a rescuer's arms had detectable current and each was of low magnitude. All measurements were well below the maximum IEC recommendations of 3.5 mA RMS and 5.0 mA peak. CONCLUSIONS: Polyethylene may facilitate safe HOD even after long durations of compressions. Current looping through a rescuer's arms is likely of insignificant magnitude.

Ventricular Fibrillation Threshold vs Alternating Current Shock Duration.

INTRODUCTION: International basic safety limits for utility-frequency electrical currents have long been set by the International Electrotechnical Commission 60479-1 standard. These were inspired by a linear-section plot proposed by Biegelmeier in 1980 with current given as a function of the shock duration. This famous plot has contributed to safe electrical circuit design internationally and has properly earned significant amount of respect over its 35 years of life. However, some possible areas for improvement have been suggested. METHODS: We searched for all animal studies of ventricular fibrillation threshold versus duration that used a forelimb to hindlimb connection that had at least 3 durations tested. We found 6 such studies and they were then used to calculate a new C3 curve after normalizing the data. RESULTS: A rational function model fit the animal data with r2 = .96. Such a correlation calculation tends to underweight the smaller values, so we also correlated the log threshold values and this had a correlation of r2=.94. CONCLUSION: Existing ventricular fibrillation threshold current versus duration data can be fitted with a simple rational function. This can provide a useful update to IEC 60479-1.

Output of Electronic Muscle Stimulators: Physical Therapy and Police Models Compared.

INTRODUCTION: Both physical therapists and police officers use electrical muscle stimulation. The typical physical therapist unit is attached with adhesive patches while the police models use needle-based electrodes to penetrate clothing. There have been very few papers describing the outputs of these physical therapy EMS (electrical muscle stimulator) units. METHODS: We purchased 6 TENS/EMS units at retail and tested them with loads of 500 Ω, 2 kΩ, and 10 kΩ. RESULTS: For the typical impedance of 500 Ω, the EMS units delivered the most current followed by the electrical weapons; TENS units delivered the least current. At higher im-pedances (> 2 kΩ) the electrical weapons delivered more current than the EMS units, which is explained by the higher voltage-compliance of their circuits. Some multi channel EMS units deliver more calculated muscle stimula tion than the multi-channel weapons. CONCLUSION: Present therapeutic electrical muscle stimula-tors can deliver more current than present law-enforcement muscle stimulators.

Humidity and Ventricular Fibrillation: When Wet Welding can be Fatal.

INTRODUCTION: Arc welding is generally considered very safe electrically. There have been electrocution cases with welders in high humidity environments. When dry, the flux coatings tend to have sufficient electrical resistance to limit the current below that required for the induction of VF (ventricular fibrillation). METHODS: We tested 4 welding electrodes for resistance in both dry and wet conditions. To estimate the cardiac current density - in a worst-case scenario - we used a 20k element finite-element bioimpedance model with 1 cm of skin and fat along with 1 cm of muscle before the heart of 5 cm dimensions. Between the heart and a metal plate we assumed 5 cm of lung and 1 cm of skin and fat. RESULTS: Welding electrode flux is highly resistive when dry. However, when saturated with moisture the resistance is almost negligible as far as dangerous currents in a human. The FEM model calculated a current density of > 7 mA/cm2 on the ventricular epicardium with a source of 80 V at the welding rod. CONCLUSION: In conditions of high humidity, a supine operator, in contact with a coated welding electrode to the precordial region of the body can be fibrillated with the AC open-circuit voltage. Most reported DC fatalities were probably due to pseudo-DC outputs that were merely rectified AC without smoothing.

Control of impulsivity by Gi-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex.

Pathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

Safety of a High-Efficiency Electrical Fence Energizer.

INTRODUCTION: Our primary goal was to evaluate the performance of a new high-efficiency electric fence energizer unit using resistive load changes. Our secondary goal was to test for compliance with the classical energy limits and the newer charge-based limits for output. METHODS: We tested 4 units of the Nemtek Druid energizer with 2 channels each. We used a wide load-resistance range to cover the worst-case scenario of a barefoot child making a chest contact (400 Ω) up to an adult merely touching the fence (2 kΩ). RESULTS: The energy output was quite consistent between the 8 sources. Even at the lowest resistance, 400 Ω, the outputs were well below the IEC 60335-2-76 limit of 5 J/pulse. The charge delivered was also quite consistent. Even at the lowest resistance, 400 Ω, the outputs (679 ± 23 µC) were well below the proposed limits of 4 mC for short pulses. CONCLUSIONS: The high-efficiency electric fence energizers satisfied all relevant safety limits. Charge, energy, voltage, and current outputs were consistent between channels and units.

Perceived Electrical Injury: Misleading Symptomology Due to Multisensory Stimuli.

BACKGROUND: An electrical accident victim's recollection is often distorted by Bayesian inference in multisensory integration. For example, hearing the sound and seeing the bright flash of an electrical arc can create the false impression that someone had experienced an electrical shock. These subjects will often present to an emergency department seeking either treatment or reassurance. CASE REPORTS: We present seven cases in which the subjects were startled by an electrical shock (real or perceived) and injury was reported. Calculations of the current and path were used to allocate causality between the shock and a history of chronic disease or previous trauma. In all seven cases, our analysis suggests that no current was passed through the body. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Symptomology seen as corroborating may actually be confounding. Witness and survivor descriptions of electrical shocks are fraught with subjectivity and misunderstanding. Available current is usually irrelevant and overemphasized, such as stress on a 100-ampere welding source, which is orders of magnitude beyond lethal limits. History can also be biased for a number of reasons. Bayesian inference in multisensory perception can lead to a subject sincerely believing they had experienced an electrical shock. Determination of the current pathway and calculations of the amplitude and duration of the shock can be critical for understanding the limits and potential causation of electrical injury.

High Impedance Electrical Accidents: Importance of Source and Subject Impedance.

In most cases, the diagnosis of an electrical injury or electrocution is straightforward. However, there is a necessity for much closer analysis in many cases. There exist sophisticated electrical safety standards that predict outcomes for shocks of various currents applied to different parts of the body. Unfortunately, the actual current is almost never known in an accident investigation. A common source of errors is the assumption that the source (including the return) has zero impedance. Another surprisingly common problem is the erroneous assumption that the body current is equal to the source current capability. METHODS: We used the following methodology for analyzing such cases: (1) Determine body pathway, (2) Estimate body pathway impedance, (3) Determine source voltage, (4) Determine source impedance, (5) Calculate delivered current using total pathway impedance, and (6) Ignore available current as it is largely confounding in most cases. RESULTS: We analyzed 6 difficult cases using the above methodology. This includes 2 subtle situations involving pairs of matched case-control subjects where a subject was electrocuted while his work partner was not. CONCLUSIONS: Careful calculations of the amplitude and duration of the shock is required for understanding the limits and potential causation of such electrical injury. This requires the determination of both the source and body pathway impedance. Available current is usually irrelevant and overemphasized.

Electric fence standards comport with human data and AC limits.

INTRODUCTION: The ubiquitous electric fence is essential to modern agriculture and has saved lives by reducing the number of livestock automobile collisions. Modern safety standards such as IEC 60335-2-76 and UL 69 have played a role in this positive result. However, these standards are essentially based on energy and power (RMS current), which have limited direct relationship to cardiac effects. We compared these standards to bioelectrically more relevant units of charge and average current in view of recent work on VF (ventricular fibrillation) induction and to existing IEC AC current limits. METHODS AND RESULTS: There are 3 limits for normal (low) pulsing rate: IEC energy limit, IEC current limit, and UL current limit. We then calculated the delivered charge allowed for each pulse duration for these limits and then compared them to a charge-based safety model derived from published human ventricular-fibrillation induction data. Both the IEC and UL also allow for rapid pulsing for up to 3 minutes. We calculated maximum outputs for various pulse durations assuming pulsing at 10, 20, and 30 pulses per second. These were then compared to standard utility power safety (AC) limits via the conversion factor of 7.4 to convert average current to RMS current for VF risk. The outputs of TASER electrical weapons (typically < 100 µC and ~100 µs duration) were also compared. CONCLUSIONS: The IEC and UL electric fence energizer normal rate standards are conservative in comparison with actual human laboratory experiments. The IEC and UL electric fence energizer rapid-pulsing standards are consistent with accepted IEC AC current limits for commercially used pulse durations.