Israeli neonatal herpes simplex infection: Unique epidemiology and clinical profile.

To gather national level data on Israeli neonatal HSV (NHSV) infection and to evaluate the distinct clinical characteristics of NHSV and neonatal enteroviral meningitis (NEM). Israeli NHSV patients, hospitalized between January 2015 and April 2022 in 22 medical centers were assessed, together with NEM patients, hospitalized at Sheba Medical Center during the same period. NHSV demographic and clinical characteristics were documented and compared to those of NEM. Eighty-five NHSV (73% males) and 130 NEM (62% males) patients were included. The incidence of NHSV was 5.9/100 000 live births, the common phenotype and HSV type were SEM (53%) and HSV1 (91%), respectively. Horizontal transmission was suspected in 50% cases (of which 67% underwent a Jewish ritual circumcision with direct wound sucking, 33% had relatives with highly suspicious herpetic lesions). Compared with NEM, NHSV tends to present with rash (14% vs. 60%, p-value < 0.01) and seizures (0% vs. 6%, p-value 0.02), while fever, irritability and poor feeding appear more frequently in NEM (94% vs. 18%, p-value < 0.01; 37% vs. 1%, p-value < 0.01; 25% vs. 1%, p-value < 0.01 respectively). Of NEM patients, 28% were treated with acyclovir. Our results mark a decrease in the incidence rate of NHSV in Israel and a prominent mode of horizontal infection acquisition. We underscore the unique localized phenotype of NHSV, in contrast to enterovirus, which tends to cause a systemic disease with constitutional symptoms. These findings should be considered when evaluating the need for comprehensive empirical treatment for HSV in the context of neonatal fever, or according to a certain clinical presentation.

Changes in Exhaled Carbon Dioxide during the Menstrual Cycle and Menopause.

Introduction: The menstrual cycle (MC) reflects multifaceted hormonal changes influencing women's metabolism, making it a key aspect of women's health. Changes in hormonal levels throughout the MC have been demonstrated to influence various physiological parameters, including exhaled carbon dioxide (CO2). Lumen is a small handheld device that measures metabolic fuel usage via exhaled CO2. This study leverages exhaled CO2 patterns measured by the Lumen device to elucidate metabolic variations during the MC, which may hold significance for fertility management. Additionally, CO2 changes are explored in menopausal women with and without hormonal replacement therapy (HRT). Methods: This retrospective cohort study analyzed exhaled CO2 data from 3,981 Lumen users, including eumenorrheal women and menopausal women with and without HRT. Linear mixed models assessed both CO2 changes of eumenorrheal women during the MC phases and compared between menopausal women with or without HRT. Results: Eumenorrheic women displayed cyclical CO2 patterns during the MC, characterized by elevated levels during the menstrual, estrogenic and ovulation phases and decreased levels during post-ovulation and pre-menstrual phases. Notably, despite variations in cycle length affecting the timing of maximum and minimum CO2 levels within a cycle, the overall pattern remained consistent. Furthermore, CO2 levels in menopausal women without HRT differed significantly from those with HRT, which showed lower levels. Conclusion: This study reveals distinct CO2 patterns across MC phases, providing insights into hormonal influences on metabolic activity. Menopausal women exhibit altered CO2 profiles in relation to the use or absence of HRT. CO2 monitoring emerges as a potential tool for tracking the MC and understanding metabolic changes during menopause.

The Association of Macronutrient Consumption and BMI to Exhaled Carbon Dioxide in Lumen Users: Retrospective Real-World Study.

BACKGROUND: Metabolic flexibility is the ability of the body to rapidly switch between fuel sources based on their accessibility and metabolic requirements. High metabolic flexibility is associated with improved health outcomes and a reduced risk of several metabolic disorders. Metabolic flexibility can be improved through lifestyle changes, such as increasing physical activity and eating a balanced macronutrient diet. Lumen is a small handheld device that measures metabolic fuel usage through exhaled carbon dioxide (CO2), which allows individuals to monitor their metabolic flexibility and make lifestyle changes to enhance it. OBJECTIVE: This retrospective study aims to examine the postprandial CO2 response to meals logged by Lumen users and its relationship with macronutrient intake and BMI. METHODS: We analyzed deidentified data from 2607 Lumen users who logged their meals and measured their exhaled CO2 before and after those meals between May 1, 2023, and October 18, 2023. A linear mixed model was fitted to test the association between macronutrient consumption, BMI, age, and gender to the postprandial CO2 response, followed by a 2-way ANOVA. RESULTS: The model demonstrated significant associations (P<.001) between CO2 response after meals and both BMI and carbohydrate intake (BMI: ß=-0.112, 95% CI -0.156 to -0.069; carbohydrates: ß=0.046, 95% CI 0.034-0.058). In addition, a 2-way ANOVA revealed that higher carbohydrate intake resulted in a higher CO2 response compared to low carbohydrate intake (F2,2569=24.23; P<.001), and users with high BMI showed modest responses to meals compared with low BMI (F2,2569=5.88; P=.003). CONCLUSIONS: In this study, we show that Lumen's CO2 response is influenced both by macronutrient consumption and BMI. The results of this study highlight a distinct pattern of reduced metabolic flexibility in users with obesity, indicating the value of Lumen for assessing postprandial metabolic flexibility.

ZnT1 induces a crosstalk between T-type and L-type calcium channels through interactions with Raf-1 kinase and the calcium channel ß2 subunit.

ZnT1 is a major zinc transporter that regulates cellular zinc homeostasis. We have previously shown that ZnT1 has additional functions that are independent of its activity as a Zn2+ extruder. These include inhibition of the L-type calcium channel (LTCC) through interaction with the auxiliary ß-subunit of the LTCC and activation of the Raf-ERK signaling leading to augmented activity of the T-type calcium channel (TTCC). Our findings indicate that ZnT1 increases TTCC activity by enhancing the trafficking of the channel to the plasma membrane. LTCC and TTCC are co-expressed in many tissues and have different functions in a variety of tissues. In the current work, we investigated the effect of the voltage-gated calcium channel (VGCC) ß-subunit and ZnT1 on the crosstalk between LTCC and TTCC and their functions. Our results indicate that the ß-subunit inhibits the ZnT1-induced augmentation of TTCC function. This inhibition correlates with the VGCC ß-subunit-dependent reduction in ZnT1-induced activation of Ras-ERK signaling. The effect of ZnT1 is specific, as the presence of the ß-subunit did not change the effect of endothelin-1 (ET-1) on TTCC surface expression. These findings document a novel regulatory function of ZnT1 serving as a mediator in the crosstalk between TTCC and LTCC. Overall, we demonstrate that ZnT1 binds and regulates the activity of the ß-subunit of VGCC and Raf-1 kinase and modulates surface expression of the LTCC and TTCC catalytic subunits, consequently modulating the activity of these channels.

The efficacy of a home-use metabolic device (Lumen) in response to a short-term low and high carbohydrate diet in healthy volunteers.

BACKGROUND: Based on stoichiometric assumptions, and real-time assessment of expired carbon dioxide (%CO2) and flow rate, the Lumen device provides potential for consumers/athletes to monitor metabolic responses to dietary programs outside of laboratory conditions. However, there is a paucity of research exploring device efficacy. This study aimed to evaluate Lumen device response to: i) a high-carbohydrate meal under laboratory conditions, and ii) a short-term low- or high-carbohydrate diet in healthy volunteers. METHODS: Following institutional ethical approval, 12 healthy volunteers (age: 36 ± 4 yrs; body mass: 72.1 ± 3.6 kg; height: 1.71 ± 0.02 m) performed Lumen breath and Douglas bag expired air measures under fasted laboratory conditions and at 30 and 60 min after a high-carbohydrate (2 g·kg-1) meal, along with capilliarized blood glucose assessment. Data were analyzed using a one-way ANOVA, with ordinary least squares regression used to assess the model between Lumen expired carbon dioxide percentage (L%CO2) and respiratory exchange ratio (RER). In a separate phase, 27 recreationally active adults (age: 42 ± 2 yrs; body mass: 71.9 ± 1.9 kg; height: 1.72 ± 0.02 m) completed a 7-day low- (~20% of energy intake [EI]; LOW) or high-carbohydrate diet (~60% of EI; HIGH) in a randomized, cross-over design under free-living conditions. L%CO2 and derived Lumen Index (LI) were recorded daily across morning (fasted and post-breakfast) and evening (pre/post meal, pre-bed) periods. Repeated measures ANOVA were employed for main analyses, with Bonferroni post-hoc assessment applied (P ≤ 0.05). RESULTS: Following the carbohydrate test-meal, L%CO2 increased from 4.49 ± 0.05% to 4.80 ± 0.06% by 30 min, remaining elevated at 4.76 ± 0.06% by 60 min post-feeding (P < 0.001, ηp2 = 0.74). Similarly, RER increased by 18.1% from 0.77 ± 0.03 to 0.91 ± 0.02 by 30 min post-meal (P = 0.002). When considering peak data, regression analysis demonstrated a significant model effect between RER and L%CO2 (F = 5.62, P = 0.03, R2 = 0.20). Following main dietary interventions, no significant interactions (diet × day) were found. However, main diet effects were evident across all time-points assessed, highlighting significant differences for both L%CO2 and LI between LOW and HIGH conditions (P < 0.003). For L%CO2, this was particularly noted under fasted (4.35 ± 0.07 vs. 4.46 ± 0.06%, P = 0.001), pre-evening meal (4.35 ± 0.07 vs. 4.50 ± 0.06%, P < 0.001), and pre-bed time-points (4.51 ± 0.08 vs. 4.61 ± 0.06%, P = 0.005). CONCLUSION: Our findings demonstrated that a portable, home-use metabolic device (Lumen) detected significantly increased expired %CO2 in response to a high-carbohydrate meal, and may be useful in tracking mean weekly changes to acute dietary carbohydrate modifications. Additional research is warranted to further determine the practical and clinical efficacy of the Lumen device in applied compared to laboratory settings.

The Effects of Metabolism Tracker Device (Lumen) Usage on Metabolic Control in Adults with Prediabetes: Pilot Clinical Trial.

INTRODUCTION: Prediabetes is a risk factor for type 2 diabetes mellitus (T2DM). However, it may be reversed via lifestyle changes. Lumen is a novel handheld device that measures exhaled CO2 producing results in agreement with those of indirect calorimetry when assessing metabolic fuel usage. The aim of this study was to examine the effects of following Lumen's personalized, measurement-guided lifestyle intervention program on anthropometric and metabolic variables in adults with prediabetes. METHODS: A 12-week single-arm intervention study was conducted in 27 participants. Body composition and blood markers were measured at the start and end of the study. Each participant took a daily morning (fasted) measurement and received feedback on their metabolic state (i.e., their degree of fat vs. carbohydrate oxidation). Participants were then provided with personalized daily guidelines for their carbohydrate, fat, and protein consumption, along with recommended lifestyle changes. RESULTS: Intention-to-treat analysis revealed a significant decrease in body weight (5.99 kg, p < 0.001), comprising a significant reduction in percentage body fat (2.93%, p < 0.001) and waist circumference (6.23 cm, p < 0.001). Significant reductions were also observed in glycated hemoglobin A1c (0.27%, p < 0.001), triglycerides (0.45 mg/dL, p < 0.001), and systolic blood pressure (0.5 mm Hg, p < 0.05). CONCLUSION: In a 12-week pilot study of participants with prediabetes, Lumen usage significantly improved multiple metabolic parameters, demonstrating its potential to deliver better clinical outcomes for patients with T2DM and metabolic syndrome.

A Handheld Metabolic Device (Lumen) to Measure Fuel Utilization in Healthy Young Adults: Device Validation Study.

BACKGROUND: Metabolic carts measure the carbon dioxide (CO2) produced and oxygen consumed by an individual when breathing to assess metabolic fuel usage (carbohydrates versus fats). However, these systems are expensive, time-consuming, and only available in health care laboratory settings. A small handheld device capable of determining metabolic fuel usage via CO2 from exhaled air has been developed. OBJECTIVE: The aim of this study is to evaluate the validity of a novel handheld device (Lumen) for measuring metabolic fuel utilization in healthy young adults. METHODS: Metabolic fuel usage was assessed in healthy participants (n=33; mean age 23.1 years, SD 3.9 years) via respiratory exchange ratio (RER) values obtained from a metabolic cart as well as % CO2 from the Lumen device. Measurements were performed at rest in two conditions: fasting, and after consuming 150 grams of glucose, in order to determine changes in metabolic fuel usage. Reduced major axis regression and simple linear regression were performed to test for agreement between RER and Lumen % CO2. RESULTS: Both RER and Lumen % CO2 significantly increased after glucose intake (P<.001 for both) compared with fasting conditions, by 0.089 and 0.28, respectively. Regression analyses revealed an agreement between the two measurements (F1,63=18.54; P<.001). CONCLUSIONS: This study shows the validity of Lumen for detecting changes in metabolic fuel utilization in a comparable manner with a laboratory standard metabolic cart, providing the ability for real-time metabolic information for users under any circumstances.

Pressure-selective modulation of NMDA receptor subtypes may reflect 3D structural differences.

Professional deep-water divers exposed to high pressure (HP) above 1.1 MPa suffer from High Pressure Neurological Syndrome (HPNS), which is associated with CNS hyperexcitability. We have previously reported that HP augments N-methyl-D-aspartate receptor (NMDAR) synaptic responses, increases neuronal excitability, and potentially causes irreversible neuronal damage. We now report that HP (10.1 MPa) differentially affects eight specific NMDAR subtypes. GluN1(1a or 1b) was co-expressed with one of the four GluN2(A-D) subunits in Xenopus laevis oocytes. HP increased ionic currents (measured by two electrode voltage clamps) of one subtype, reduced the current in four others, and did not affect the current in the remaining three. 3D theoretical modeling was aimed at revealing specific receptor domains involved with HP selectivity. In light of the information on the CNS spatial distribution of the different NMDAR subtypes, we conclude that the NMDAR's diverse responses to HP may lead to selective HP effects on different brain regions. These discoveries call for further and more specific investigation of deleterious HP effects and suggest the need for a re-evaluation of deep-diving safety guidelines.

ZnT-1 enhances the activity and surface expression of T-type calcium channels through activation of Ras-ERK signaling.

Zinc transporter-1 (ZnT-1) is a putative zinc transporter that confers cellular resistance from zinc toxicity. In addition, ZnT-1 has important regulatory functions, including inhibition of L-type calcium channels and activation of Raf-1 kinase. Here we studied the effects of ZnT-1 on the expression and function of T-type calcium channels. In Xenopus oocytes expressing voltage-gated calcium channel (CaV) 3.1 or CaV3.2, ZnT-1 enhanced the low-threshold calcium currents (I(caT)) to 182 ± 15 and 167.95 ± 9.27% of control, respectively (P < 0.005 for both channels). As expected, ZnT-1 also enhanced ERK phosphorylation. Coexpression of ZnT-1 and nonactive Raf-1 blocked the ZnT-1-mediated ERK phosphorylation and abolished the ZnT-1-induced augmentation of I(caT). In mammalian cells (Chinese hamster ovary), coexpression of CaV3.1 and ZnT-1 increased the I(caT) to 166.37 ± 6.37% compared with cells expressing CaV3.1 alone (P < 0.01). Interestingly, surface expression measurements using biotinylation or total internal reflection fluorescence microscopy indicated marked ZnT-1-induced enhancement of CaV3.1 surface expression. The MEK inhibitor PD-98059 abolished the ZnT-1-induced augmentation of surface expression of CaV3.1. In cultured murine cardiomyocytes (HL-1 cells), transient exposure to zinc, leading to enhanced ZnT-1 expression, also enhanced the surface expression of endogenous CaV3.1 channels. Consistently, in these cells, endothelin-1, a potent activator of Ras-ERK signaling, enhanced the surface expression of CaV3.1 channels in a PD-98059-sensitive manner. Our findings indicate that ZnT-1 enhances the activity of CaV3.1 and CaV3.2 through activation of Ras-ERK signaling. The augmentation of CaV3.1 currents by Ras-ERK activation is associated with enhanced trafficking of the channel to the plasma membrane.

ZnT-1 protects HL-1 cells from simulated ischemia-reperfusion through activation of Ras-ERK signaling.

Activation of ERK signaling may promote cardioprotection from ischemia-reperfusion (I/R) injury. ZnT-1, a protein that confers resistance from zinc toxicity, was found to interact with Raf-1 kinase through its C-terminal domain, leading to downstream activation of ERK. In the present study, we evaluated the effects of ZnT-1 in cultured murine cardiomyocytes (HL-1 cells) that were exposed to simulated-I/R. Cellular injury was evaluated by lactate dehydrogenase (LDH) release and by staining for pro-apoptotic caspase activation. Overexpression of ZnT-1 markedly reduced LDH release and caspase activation following I/R. Knockdown of endogenous ZnT-1 augmented the I/R-induced release of LDH and increased caspase activation following I/R. Phospho-ERK levels were significantly increased following I/R in cells overexpressing ZnT-1, while knockdown of ZnT-1 reduced phospho-ERK levels. Pretreatment of cells with the MEK inhibitor PD98059 abolished the protective effect of ZnT-1 following I/R. Accordingly, a truncated form of ZnT-1 lacking the C-terminal domain failed to induce ERK activation and did not protect the cells from I/R injury. In contrast, expression of the C-terminal domain by itself was sufficient to induce ERK activation and I/R protection. Interestingly, the C-terminal of the ZnT-1 did not have protective effect against the toxicity of zinc. In the isolated rat heart, global ischemic injury rapidly increased the endogenous levels of ZnT-1. However, following reperfusion ZnT-1 levels were found to be decreased. Our findings indicate that ZnT-1 may have important role in the ischemic myocardium through its ability to interact with Raf-1 kinase.

The involvement of ZnT-1, a new modulator of cardiac L-type calcium channels, in [corrected] atrial tachycardia remodeling. [corrected].

Atrial fibrillation (AF), the highest occurring cardiac arrhythmia in the Western world, is associated with substantial morbidity and increased mortality. In spite of extensive research, the cause of atrial electrical remodeling, a major factor in the self-perpetuating nature of AF, is still unknown. Downregulation of L-type Ca2+ channel (LTCC) activity is the hallmark of atrial electrical remodeling. ZnT-1 is a ubiquitous membrane protein that was recently suggested to inhibit the LTCC. We have studied and shown that ZnT-1 expression inhibits LTCC function in an oocyte expression system as well as in isolated cardiomyocytes. Our data also show that rapid electrical pacing can augment ZnT-1 expression in culture as well as in the atria of rats in vivo. Finally, in a pilot study, ZnT-1 expression was found to be augmented in the atria of AF patients. These findings position ZnT-1 as a probable missing link in the mechanism underlying atrial tachycardia remodeling.

Molecular basis for zinc transporter 1 action as an endogenous inhibitor of L-type calcium channels.

The L-type calcium channel (LTCC) has a variety of physiological roles that are critical for the proper function of many cell types and organs. Recently, a member of the zinc-regulating family of proteins, ZnT-1, was recognized as an endogenous inhibitor of the LTCC, but its mechanism of action has not been elucidated. In the present study, using two-electrode voltage clamp recordings in Xenopus oocytes, we demonstrate that ZnT-1-mediated inhibition of the LTCC critically depends on the presence of the LTCC regulatory beta-subunit. Moreover, the ZnT-1-induced inhibition of the LTCC current is also abolished by excess levels of the beta-subunit. An interaction between ZnT-1 and the beta-subunit, as demonstrated by co-immunoprecipitation and by fluorescence resonance energy transfer, is consistent with this result. Using surface biotinylation and total internal reflection fluorescence microscopy in HEK293 cells, we show a ZnT-1-dependent decrease in the surface expression of the pore-forming alpha(1)-subunit of the LTCC. Similarly, a decrease in the surface expression of the alpha(1)-subunit is observed following up-regulation of the expression of endogenous ZnT-1 in rapidly paced cultured cardiomyocytes. We conclude that ZnT-1-mediated inhibition of the LTCC is mediated through a functional interaction of ZnT-1 with the LTCC beta-subunit and that it involves a decrease in the trafficking of the LTCC alpha(1)-subunit to the surface membrane.