Nunchaku-like Free Fibula Osteocutaneous Flap in Through-and-through Composite Oromandibular Defect Reconstruction.

The free fibula osteocutaneous flap (FFOCF) has been used for oromandibular reconstruction over several decades. However, when facing through-and-through composite oromandibular defects (COMDs), significant challenges still arise. The complexity of COMD necessitates the reconstruction of bone, intraoral mucosa, and extraoral skin. Additional flaps are often needed, which extend surgical durations and heighten associated risks. This report presents a 62-year-old man with squamous cell carcinoma of the left lower gingiva. After ablative surgery, successful reconstruction of a through-and-through COMD was achieved with a single FFOCF through innovative design. The flap was osteotomized into 2 segments with attached skin islands while preserving the vascular pedicle. Rotation of 1 segment created 2 skin islands on opposing sides, simultaneously repairing intraoral and extraoral defects. Postoperative outcomes at the 1-month follow-up were encouraging. Although technically challenging, the "Nunchaku-like FFOCF" offers a safe and effective approach for the comprehensive reconstruction of through-and-through COMD.

Clinical characteristics and overall survival among acute myeloid leukemia patients with TP53 gene mutation or chromosome 17p deletion.

Approximately 5% to 15% of acute myeloid leukemia (AML) patients have TP53 gene mutations (TP53m), which are associated with very poor outcomes. Adults (≥18 years) with a new AML diagnosis were included from a nationwide, de-identified, real-world database. Patients receiving first-line therapy were divided into three cohorts: venetoclax (VEN) + hypomethylating agents (HMAs; Cohort A), intensive chemotherapy (Cohort B), or HMA without VEN (Cohort C). A total of 370 newly diagnosed AML patients with TP53m (n = 124), chromosome 17p deletion (n = 166), or both (n = 80) were included. The median age was 72 years (range, 24-84); most were male (59%) and White (69%). Baseline bone marrow (BM) blasts were ≤30%, 31%-50%, and >50% in 41%, 24%, and 29% of patients in Cohorts A, B, and C, respectively. BM remission (<5% blasts) with first-line therapy was reported in 54% of patients (115/215) overall, and 67% (38/57), 62% (68/110), and 19% (9/48) for respective cohorts (median BM remission duration: 6.3, 6.9, and 5.4 months). Median overall survival (95% CI) was 7.4 months (6.0-8.8) for Cohort A, 9.4 months (7.2-10.4) for Cohort B, and 5.9 months (4.3-7.5) for Cohort C. There were no differences in survival by treatment type after adjusting for the effects of relevant covariates (Cohort A vs. C adjusted hazard ratio [aHR] = 0.9; 95% CI, 0.7-1.3; Cohort A vs. B aHR = 1.0; 95% CI, 0.7-1.5; and Cohort C vs. B aHR = 1.1; 95% CI, 0.8-1.6). Patients with TP53m AML have dismal outcomes with current therapies, demonstrating the high unmet need for improved treatments.

Characterizing spatiotemporal variability in airborne heavy metal concentration: Changes after 18 Years in Baltimore, MD.

INTRODUCTION: This study investigates the impact of changes in local industry, urban development, and proximity to suspected emission sources on airborne metal concentration in Baltimore, Maryland between 2001 and 2019 with particular focus on the urban industrial community of Curtis Bay in South Baltimore. METHODS: Integrated PM2.5 and PM10 Harvard Impactors were set up at six locations in the Baltimore City metropolitan area in weeklong sampling sessions from January-July 2019 to assess variation in airborne metal concentration by proximity to suspected metal emission sources. PM2.5 and PM10 were collected on Teflo filters and analyzed for a panel of 12 metals and metalloids (As, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb, Sb, and Zn) using inductively coupled plasma mass spectrometry. The findings were compared against airborne metal concentrations reported by the Baltimore Supersite in 2001 and 2003 to assess changes over the 18-year period. RESULTS: PM2.5 concentrations reported from this study ranged from 3.27 µg/m3 to 36.0 µg/m3 and PM10 concentrations ranged from 9.00 µg/m3 to 30.1 µg/m3 across all sampling sites. Metal concentrations ranged from 1.4 times (Cd) to 4.8 times (Cr) higher in PM10 compared to PM2.5. Compared to the study reference site, median PM2.5 concentrations of Co and Fe were roughly 1.8 times and 2.1 times higher, respectively, at near-road sampling sites indicating significant variability in airborne metal concentration by proximity to local traffic emissions. PM2.5 and PM10 Sb concentrations were 3.4 times and 6.7 times higher at a near incinerator site compared to the reference, consistent with existing evidence of Sb sourcing from municipal incinerators in Baltimore City. Decreases in Cr (-40%), Ni (-73%), Pb (-55%), and Zn (-36%) concentrations were observed over the 18-year period while concentrations of Cu, Fe, and Mn were not statistically significantly different. CONCLUSION: Declines in airborne Cr, Ni, Pb, and Zn concentration since 2001 appear to coincide with industrial decline highlighting the success of remediation and redevelopment efforts. Remaining spatial variability is related to vehicular traffic and proximity to a municipal incinerator which should be focal areas for future intervention to reduce metal exposure disparities in Baltimore City.

The conduction velocity-potassium relationship in the heart is modulated by sodium and calcium.

The relationship between cardiac conduction velocity (CV) and extracellular potassium (K+) is biphasic, with modest hyperkalemia increasing CV and severe hyperkalemia slowing CV. Recent studies from our group suggest that elevating extracellular sodium (Na+) and calcium (Ca2+) can enhance CV by an extracellular pathway parallel to gap junctional coupling (GJC) called ephaptic coupling that can occur in the gap junction adjacent perinexus. However, it remains unknown whether these same interventions modulate CV as a function of K+. We hypothesize that Na+, Ca2+, and GJC can attenuate conduction slowing consequent to severe hyperkalemia. Elevating Ca2+ from 1.25 to 2.00 mM significantly narrowed perinexal width measured by transmission electron microscopy. Optically mapped, Langendorff-perfused guinea pig hearts perfused with increasing K+ revealed the expected biphasic CV-K+ relationship during perfusion with different Na+ and Ca2+ concentrations. Neither elevating Na+ nor Ca2+ alone consistently modulated the positive slope of CV-K+ or conduction slowing at 10-mM K+; however, combined Na+ and Ca2+ elevation significantly mitigated conduction slowing at 10-mM K+. Pharmacologic GJC inhibition with 30-µM carbenoxolone slowed CV without changing the shape of CV-K+ curves. A computational model of CV predicted that elevating Na+ and narrowing clefts between myocytes, as occur with perinexal narrowing, reduces the positive and negative slopes of the CV-K+ relationship but do not support a primary role of GJC or sodium channel conductance. These data demonstrate that combinatorial effects of Na+ and Ca2+ differentially modulate conduction during hyperkalemia, and enhancing determinants of ephaptic coupling may attenuate conduction changes in a variety of physiologic conditions.

HNF4α pathway mapping identifies wild-type IDH1 as a targetable metabolic node in gastric cancer.

OBJECTIVE: Gastric cancer (GC) is a leading cause of cancer mortality. Previous studies have shown that hepatocyte nuclear factor-4α (HNF4α) is specifically overexpressed in GC and functionally required for GC development. In this study, we investigated, on a genome-wide scale, target genes of HNF4α and oncogenic pathways driven by HNF4α and HNF4α target genes. DESIGN: We performed HNF4α chromatin immunoprecipitation followed by sequencing across multiple GC cell lines, integrating HNF4α occupancy data with (epi)genomic and transcriptome data of primary GCs to define HNF4α target genes of in vitro and in vivo relevance. To investigate mechanistic roles of HNF4α and HNF4α targets, we performed cancer metabolic measurements, drug treatments and functional assays including murine xenograft experiments. RESULTS: Gene expression analysis across 19 tumour types revealed HNF4α to be specifically upregulated in GCs. Unbiased pathway analysis revealed organic acid metabolism as the top HNF4α-regulated pathway, orthogonally supported by metabolomic analysis. Isocitrate dehydrogenase 1 (IDH1) emerged as a convergent HNF4α direct target gene regulating GC metabolism. We show that wild-type IDH1 is essential for GC cell survival, and that certain GC cells can be targeted by IDH1 inhibitors. CONCLUSIONS: Our results highlight a role for HNF4α in sustaining GC oncogenic metabolism, through the regulation of IDH1. Drugs targeting wild-type IDH1 may thus have clinical utility in GCs exhibiting HNF4α overexpression, expanding the role of IDH1 in cancer beyond IDH1/2 mutated malignancies.

Positive feelings during pregnancy, early feeding practices, and infant health.

BACKGROUND: Early parenting practices, such as infant feeding, can affect children's physical health. Additionally, negative prenatal maternal affect can influence feeding choices, such as breast-feeding, and can have a detrimental effect on children's health. Little is known, however, about the contribution of positive maternal affect during pregnancy on feeding practices and children's health. METHODS: This study explored whether positive prenatal feelings influenced children's health during the first 18 months, and whether early feeding practices mediated the relationship between these two variables. Low-income, ethnically diverse, primiparous women (n = 114) reported their feelings of pregnancy uplifts and hassles during their third trimester. These women were interviewed again at 2, 4, 6, 9, 12, and 18 months post-partum about their feeding practices. A retrospective audit of their infants' medical charts was completed from birth to 18 months. RESULTS: Using structural equation modeling, having more uplifts than hassles during pregnancy was associated with longer breast-feeding duration and greater adherence to recommended schedules for introducing fruits and vegetables, solids, and baby cereal. These feeding practices were linked to better child health outcomes, including reduced risk of upper respiratory tract infections, conjunctivitis, otitis media, and thrush. CONCLUSIONS: Positive maternal feelings during pregnancy were associated with better feeding practices, and these better feeding practices were associated with fewer common childhood illnesses. Helping expectant women focus on the positive aspects of their pregnancy may lead to postnatal care methods that are fiscally advantageous, preventive of detrimental postnatal choices, and medically beneficial for children.

Potassium channels in the Cx43 gap junction perinexus modulate ephaptic coupling: an experimental and modeling study.

It was recently demonstrated that cardiac sodium channels (Nav1.5) localized at the perinexus, an intercalated disc (ID) nanodomain associated with gap junctions (GJ), may contribute to electrical coupling between cardiac myocytes via an ephaptic mechanism. Impairment of ephaptic coupling by acute interstitial edema (AIE)-induced swelling of the perinexus was associated with arrhythmogenic, anisotropic conduction slowing. Given that Kir2.1 has also recently been reported to localize at intercalated discs, we hypothesized that Kir2.1 channels may reside within the perinexus and that inhibiting them may mitigate arrhythmogenic conduction slowing observed during AIE. Using gated stimulated emission depletion (gSTED) and stochastic optical reconstruction microscopy (STORM) super-resolution microscopy, we indeed find that a significant proportion of Kir2.1 channels resides within the perinexus. Moreover, whereas Nav1.5 inhibition during AIE exacerbated arrhythmogenic conduction slowing, inhibiting Kir2.1 channels during AIE preferentially increased transverse conduction velocity-decreasing anisotropy and ameliorating arrhythmia risk compared to AIE alone. Comparison of our results with a nanodomain computer model identified enrichment of both Nav1.5 and Kir2.1 at intercalated discs as key factors underlying the experimental observations. We demonstrate that Kir2.1 channels are localized within the perinexus alongside Nav1.5 channels. Further, targeting Kir2.1 modulates intercellular coupling between cardiac myocytes, anisotropy of conduction, and arrhythmia propensity in a manner consistent with a role for ephaptic coupling in cardiac conduction. For over half a century, electrical excitation in the heart has been thought to occur exclusively via gap junction-mediated ionic current flow between cells. Further, excitation was thought to depend almost exclusively on sodium channels with potassium channels being involved mainly in returning the cell to rest. Here, we demonstrate that sodium and potassium channels co-reside within nanoscale domains at cell-to-cell contact sites. Experimental and computer modeling results suggest a role for these channels in electrical coupling between cardiac muscle cells via an ephaptic mechanism working in tandem with gap junctions. This new insight into the mechanism of cardiac electrical excitation could pave the way for novel therapies against cardiac rhythm disturbances.

Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS-NO-nitrite signaling.

Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by severe intestinal necrosis and for which breast milk represents the most effective protective strategy. Previous studies have revealed a critical role for the lipopolysaccharide receptor toll-like receptor 4 (TLR4) in NEC development through its induction of mucosal injury, yet the reasons for which intestinal ischemia in NEC occurs in the first place remain unknown. We hypothesize that TLR4 signaling within the endothelium plays an essential role in NEC development by regulating perfusion to the small intestine via the vasodilatory molecule endothelial nitric oxide synthase (eNOS). Using a unique mouse system in which we selectively deleted TLR4 from the endothelium, we now show that endothelial TLR4 activation is required for NEC development and that endothelial TLR4 activation impairs intestinal perfusion without effects on other organs and reduces eNOS expression via activation of myeloid differentiation primary response gene 88. NEC severity was significantly increased in eNOS(-/-) mice and decreased upon administration of the phosphodiesterase inhibitor sildenafil, which augments eNOS function. Strikingly, compared with formula, human and mouse breast milk were enriched in sodium nitrate--a precursor for enteral generation of nitrite and nitric oxide--and repletion of formula with sodium nitrate/nitrite restored intestinal perfusion, reversed the deleterious effects of endothelial TLR4 signaling, and reduced NEC severity. These data identify that endothelial TLR4 critically regulates intestinal perfusion leading to NEC and reveal that the protective properties of breast milk involve enhanced intestinal microcirculatory integrity via augmentation of nitrate-nitrite-NO signaling.

Toll-like receptor 4-mediated endoplasmic reticulum stress in intestinal crypts induces necrotizing enterocolitis.

The cellular cues that regulate the apoptosis of intestinal stem cells (ISCs) remain incompletely understood, yet may play a role in diseases characterized by ISC loss including necrotizing enterocolitis (NEC). Toll-like receptor-4 (TLR4) was recently found to be expressed on ISCs, where its activation leads to ISC apoptosis through mechanisms that remain incompletely explained. We now hypothesize that TLR4 induces endoplasmic reticulum (ER) stress within ISCs, leading to their apoptosis in NEC pathogenesis, and that high ER stress within the premature intestine predisposes to NEC development. Using transgenic mice and cultured enteroids, we now demonstrate that TLR4 induces ER stress within Lgr5 (leucine-rich repeat-containing G-protein-coupled receptor 5)-positive ISCs, resulting in crypt apoptosis. TLR4 signaling within crypts was required, because crypt ER stress and apoptosis occurred in TLR4(ΔIEC-OVER) mice expressing TLR4 only within intestinal crypts and epithelium, but not TLR4(ΔIEC) mice lacking intestinal TLR4. TLR4-mediated ER stress and apoptosis of ISCs required PERK (protein kinase-related PKR-like ER kinase), CHOP (C/EBP homologous protein), and MyD88 (myeloid differentiation primary response gene 88), but not ATF6 (activating transcription factor 6) or XBP1 (X-box-binding protein 1). Human and mouse NEC showed high crypt ER stress and apoptosis, whereas genetic inhibition of PERK or CHOP attenuated ER stress, crypt apoptosis, and NEC severity. Strikingly, using intragastric delivery into fetal mouse intestine, prevention of ER stress reduced TLR4-mediated ISC apoptosis and mucosal disruption. These findings identify a novel link between TLR4-induced ER stress and ISC apoptosis in NEC pathogenesis and suggest that increased ER stress within the premature bowel predisposes to NEC development.

Sodium channels in the Cx43 gap junction perinexus may constitute a cardiac ephapse: an experimental and modeling study.

It has long been held that electrical excitation spreads from cell-to-cell in the heart via low resistance gap junctions (GJ). However, it has also been proposed that myocytes could interact by non-GJ-mediated "ephaptic" mechanisms, facilitating propagation of action potentials in tandem with direct GJ-mediated coupling. We sought evidence that such mechanisms contribute to cardiac conduction. Using super-resolution microscopy, we demonstrate that Nav1.5 is localized within 200 nm of the GJ plaque (a region termed the perinexus). Electron microscopy revealed close apposition of adjacent cell membranes within perinexi suggesting that perinexal sodium channels could function as an ephapse, enabling ephaptic cell-to-cell transfer of electrical excitation. Acute interstitial edema (AIE) increased intermembrane distance at the perinexus and was associated with preferential transverse conduction slowing and increased spontaneous arrhythmia incidence. Inhibiting sodium channels with 0.5 µM flecainide uniformly slowed conduction, but sodium channel inhibition during AIE slowed conduction anisotropically and increased arrhythmia incidence more than AIE alone. Sodium channel inhibition during GJ uncoupling with 25 µM carbenoxolone slowed conduction anisotropically and was also highly proarrhythmic. A computational model of discretized extracellular microdomains (including ephaptic coupling) revealed that conduction trends associated with altered perinexal width, sodium channel conductance, and GJ coupling can be predicted when sodium channel density in the intercalated disk is relatively high. We provide evidence that cardiac conduction depends on a mathematically predicted ephaptic mode of coupling as well as GJ coupling. These data suggest opportunities for novel anti-arrhythmic therapies targeting noncanonical conduction pathways in the heart.

Extracellular sodium and potassium levels modulate cardiac conduction in mice heterozygous null for the Connexin43 gene.

UNLABELLED: Several studies have disagreed on measurements of cardiac conduction velocity (CV) in mice with a heterozygous knockout of the connexin gene Gja1--a mutation that reduces the gap junction (GJ) protein, Connexin43 (Cx43), by 50 %. We noted that perfusate ionic composition varied between studies and hypothesized that extracellular ionic concentration modulates CV dependence on GJs. CV was measured by optically mapping wild-type (WT) and heterozygous null (HZ) hearts serially perfused with solutions previously associated with no change (Solution 1) or CV slowing (Solution 2). In WT hearts, CV was similar for Solutions 1 and 2. However, consistent with the hypothesis, Solution 2 in HZ hearts slowed transverse CV (CVT) relative to Solution 1. Previously, we showed CV slowing in a manner consistent with ephaptic conduction correlated with increased perinexal inter-membrane width (W P) at GJ edges. Thus, W P was measured following perfusion with systematically adjusted [Na(+)]o and [K(+)]o in Solutions 1 and 2. A wider W P was associated with reduced CVT in WT and HZ hearts, with the greatest effect in HZ hearts. Increasing [Na(+)]o increased CVT only in HZ hearts. Increasing [K(+)]o slowed CVT in both WT and HZ hearts with large W P but only in HZ hearts with narrow W P. CONCLUSION: When perinexi are wide, decreasing excitability by modulating [Na(+)]o and [K(+)]o increases CV sensitivity to reduced Cx43. By contrast, CV is less sensitive to Cx43 and ion composition when perinexi are narrow. These results are consistent with cardiac conduction dependence on both GJ and non-GJ (ephaptic) mechanisms.

Efficacy and safety of argatroban and bivalirudine in patients with suspected heparin-induced thrombocytopenia.

BACKGROUND: Argatroban is the only commercially available Food and Drug Administration (FDA)-approved anticoagulant for managing heparin-induced thrombocytopenia (HIT). However, bivalirudin may be an attractive alternative. OBJECTIVE: To assess the efficacy and safety of argatroban and bivalirudin in patients with suspected HIT. METHODS: This single-center, retrospective analysis included patients who received argatroban or bivalirudin for at least 24 hours between January 1, 2000, and June 30, 2012. The primary end point assessed anticoagulation goals, specifically time to therapeutic activated partial thromboplastin time (aPTT) goal and percentage of aPTT values within therapeutic range. Secondary end points included new thromboembolic events, bleeding, and mortality. RESULTS: Of the 68 patients who met the inclusion criteria, 48 received argatroban and 20 received bivalirudin. Baseline characteristics were similar between the 2 groups except for age, percentage of patients with liver dysfunction, aPTT immediately prior to drug initiation, and the serotonin release assay results. The mean ± SD times to reach therapeutic aPTT goal for argatroban and bivalirudin were 14 ± 15 and 7 ± 8 hours, respectively (P = 0.024). The mean ± SD percentage of aPTT values within therapeutic aPTT goal was 69% ± 23% for argatroban and 84% ± 18% for bivalirudin (P = 0.005). Rates of thromboembolic events were similar between the 2 groups, as were the rates of bleeding and all-cause mortality. CONCLUSIONS: Bivalirudin appears to reach therapeutic aPTT goal faster with more aPTT values within therapeutic aPTT goal while achieving similar clinical outcomes. Although not approved by the FDA for managing HIT, bivalirudin may be an attractive alternative anticoagulant.

Amniotic fluid inhibits Toll-like receptor 4 signaling in the fetal and neonatal intestinal epithelium.

The fetal intestinal mucosa is characterized by elevated Toll-like receptor 4 (TLR4) expression, which can lead to the development of necrotizing enterocolitis (NEC)--a devastating inflammatory disease of the premature intestine--upon exposure to microbes. To define endogenous strategies that could reduce TLR4 signaling, we hypothesized that amniotic fluid can inhibit TLR4 signaling within the fetal intestine and attenuate experimental NEC, and we sought to determine the mechanisms involved. We show here that microinjection of amniotic fluid into the fetal (embryonic day 18.5) gastrointestinal tract reduced LPS-mediated signaling within the fetal intestinal mucosa. Amniotic fluid is abundant in EGF, which we show is required for its inhibitory effects on TLR4 signaling via peroxisome proliferator-activated receptor, because inhibition of EGF receptor (EGFR) with cetuximab or EGF-depleted amniotic fluid blocked the inhibitory effects of amniotic fluid on TLR4, whereas amniotic fluid did not prevent TLR4 signaling in EGFR- or peroxisome proliferator-activated receptor γ-deficient enterocytes or in mice deficient in intestinal epithelial EGFR, and purified EGF attenuated the exaggerated intestinal mucosal TLR4 signaling in wild-type mice. Moreover, amniotic fluid-mediated TLR4 inhibition reduced the severity of NEC in mice through EGFR activation. Strikingly, NEC development in both mice and humans was associated with reduced EGFR expression that was restored upon the administration of amniotic fluid in mice or recovery from NEC in humans, suggesting that a lack of amniotic fluid-mediated EGFR signaling could predispose to NEC. These findings may explain the unique susceptibility of premature infants to the development of NEC and offer therapeutic approaches to this devastating disease.

Microdomain effects on transverse cardiac propagation.

The effect of gap junctional coupling, sodium ion channel distribution, and extracellular conductivity on transverse conduction in cardiac tissue is explored using a microdomain model that incorporates aspects of the inhomogeneous cellular structure. The propagation velocities found in our model are compared to those in the classic bidomain model and indicate a strong ephaptic microdomain contribution to conduction depending on the parameter regime. We show that ephaptic effects can be quite significant in the junctional spaces between cells, and that the cell activation sequence is modified substantially by these effects. Further, we find that transverse propagation can be maintained by ephaptic effects, even in the absence of gap junctional coupling. The mechanism by which this occurs is found to be cablelike in that the junctional regions act like inverted cables. Our results provide insight into several recent experimental studies that indirectly indicate a mode of action potential propagation that does not rely exclusively on gap junctions.

Pitch Variation Skills in Cantonese Speakers With Apraxia of Speech After Stroke: Preliminary Findings of Acoustic Analyses.

PURPOSE: Literature on apraxia of speech (AOS) in Chinese speakers is sparse compared to the English literature. This study aims to examine the pitch variation skills of Cantonese adults with AOS poststroke in terms of perceptual tone accuracy, acoustic fundamental frequency (fo) changes, and repetition durations on items with different syllable structures, lexical status, and tone syllables in various positions in a sequencing context. METHOD: Six Cantonese adults with AOS poststroke (AOS group), six adults without AOS poststroke (nAOS group), and six healthy controls (HC group) performed the tone sequencing task (TST), which was adapted from oral diadochokinetic tasks, with three different tone syllables. Tone accuracy, fo values across 10 time points, and acoustic repetition durations were compared within and between the groups. RESULTS: The AOS group produced significantly lower tone accuracy and different fo changes on the three Cantonese tone syllables compared with the control groups and significantly longer repetition durations than the HC group. The AOS group showed more difficulty with the tone syllables with the consonant-vowel structure, while a priming effect was observed on the T2 (high-rising) syllables with lexical meanings. A unique lowering of fo in the final syllable of the trisyllabic items was observed only in the AOS group. CONCLUSIONS: The AOS group showed degraded pitch variation skills. The effects of the three linguistic elements were discussed. Future investigations are called for to adapt the TST in other tonal languages to determine if degraded pitch variation skills are present in other tonal language speakers with AOS.

Associations of a toenail metal mixture with attention and memory in the Gulf long-term follow-up (GuLF) study.

BACKGROUND: Research on metal-associated neurodegeneration has largely focused on single metals. Since metal exposures typically co-occur as combinations of both toxic and essential elements, a mixtures framework is important for identifying risk and protective factors. This study examined associations between toenail levels of an eight-metal mixture and attention and memory in men living in US Gulf states. METHODS: We measured toenail concentrations of toxic (arsenic, chromium, lead, and mercury) and essential (copper, manganese, selenium, and zinc) metals in 413 non-smoking men (23-69 years, 46 % Black) from the Gulf Long-Term Follow-Up (GuLF) Study. Sustained attention and working memory were assessed at the time of toenail sample collection using the continuous performance test (CPT) and digit span test (DST), respectively. Associations between toenail metal concentrations and performance on neurobehavioral tests were characterized using co-pollutant adjusted general linear models and Bayesian Kernel Machine Regression. RESULTS: Adjusting for other metals, one interquartile range (IQR) increase in toenail chromium was associated with a 0.19 (95 % CI: -0.31, -0.07) point reduction in CPT D Prime score (poorer ability to discriminate test signals from noise). One IQR increase in toenail manganese was associated with a 0.20 (95 % CI, -0.41, 0.01) point reduction on the DST Reverse Count (fewer numbers recalled). Attention deficits were greater among Black participants compared to White participants for the same increase in toenail chromium concentrations. No evidence of synergistic interaction between metals or adverse effect of the overall metal mixture was observed for either outcome. CONCLUSIONS: Our findings support existing studies of manganese-related memory deficits and are some of the first to show chromium related attention deficits in adults. Longitudinal study of cognitive decline is needed to verify chromium findings. Research into social and chemical co-exposures is also needed to explain racial differences in metal-associated neurobehavioral deficits observed in this study.

A graded neonatal mouse model of necrotizing enterocolitis demonstrates that mild enterocolitis is sufficient to activate microglia and increase cerebral cytokine expression.

Background: Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal process that afflicts approximately 10% of preterm infants born in the United States each year, with a mortality rate of 30%. NEC severity is graded using Bell's classification system, from stage I mild NEC to stage III severe NEC. Over half of NEC survivors present with neurodevelopmental impairment during adolescence, a long-term complication that is poorly understood but can occur even after mild NEC. Although multiple animal models exist, none allow the experimenter to control nor represent the gradient of symptom severities seen in NEC patients. We bridge this knowledge gap by developing a graded murine model of NEC and studying its relationship with neuroinflammation across a range of NEC severities. Methods: Postnatal day 3 (P3) C57BL/6 mice were fed a formula containing different concentrations (0% control, 0.25%, 1%, 2%, and 3%) of dextran sodium sulfate (DSS). P3 mice were fed every 3 hours for 72-hours. We collected data on weight gain and behavior (activity, response, body color) during feeding. At the end of the experiment, we collected tissues (intestine, liver, plasma, brain) for immunohistochemistry, immunofluorescence, and cytokine and chemokine analysis. Results: Throughout NEC induction, mice fed higher concentrations of DSS died sooner, lost weight faster, and became sick or lethargic earlier. Intestinal characteristics (dilation, color, friability) were worse in mice fed with higher DSS concentrations. Histology revealed small intestinal disarray among mice fed all DSS concentrations, while higher DSS concentrations resulted in reduced small intestinal cellular proliferation and increased hepatic and systemic inflammation. In the brain, IL-2, G-CSF, and CXCL1 concentrations increased with higher DSS concentrations. Although the number of neurons and microglia in the CA1 hippocampal region did not differ, microglial branching was significantly reduced in DSS-fed mice. Conclusion: We characterize a novel graded model of NEC that recapitulates the full range of NEC severities. We show that mild NEC is sufficient to initiate neuroinflammation and microglia activation. This model will facilitate studies on the neurodevelopmental effects of NEC.

Modeling electrical activity of myocardial cells incorporating the effects of ephaptic coupling.

Existing models of electrical activity in myocardial tissue are unable to easily capture the effects of ephaptic coupling. Homogenized models do not account for cellular geometry, while detailed spatial models are too complicated to simulate in three dimensions. Here we propose a unique model that accurately captures the geometric effects while being computationally efficient. We use this model to provide an initial study of the effects of changes in extracellular geometry, gap junctional coupling, and sodium ion channel distribution on propagation velocity in a single 1D strand of cells. In agreement with previous studies, we find that ephaptic coupling increases propagation velocity at low gap junctional conductivity while it decreases propagation at higher conductivities. We also find that conduction velocity is relatively insensitive to gap junctional coupling when sodium ion channels are located entirely on the cell ends and cleft space is small. The numerical efficiency of this model, verified by comparison with more detailed simulations, allows a thorough study in parameter variation and shows that cellular structure and geometry has a nontrivial impact on propagation velocity. This model can be relatively easily extended to higher dimensions while maintaining numerical efficiency and incorporating ephaptic effects through modeling of complex, irregular cellular geometry.

Development of a gastrocutaneous fistula from a marginal ulcer after repair of duodenal injury with pyloric exclusion.

Introduction: Duodenal trauma is rare but can be associated with significant morbidity and mortality (Pandey et al., 2011). Adjunct procedures, such as pyloric exclusion, can be performed to assist in surgical repair of these injuries. However, pyloric exclusion can lead to severe long-term complications associated with significant morbidity that can be difficult to repair. Case: A 35-year-old man with a history of duodenal trauma from a gunshot wound (GSW) status post pyloric exclusion and Roux-en-Y gastrojejunostomy presented to the Emergency Department (ED) with complaints of abdominal pain and leakage of food particles and fluid from an open wound around his surgical scar. Computed tomography (CT) scan on admission showed a tract extending from the gastrojejunostomy anastomosis to the skin representing a fistula. Esophago-gastro-duodenoscopy (EGD) reconfirmed a large marginal ulcer that had fistulized to the skin. After nutritional repletion, the patient was taken to the operating room (OR) for takedown of the enterocutaneous fistula and Roux-en-Y gastrojejunostomy, closure of gastrostomy and enterotomy, pyloroplasty and feeding jejunostomy tube placement. The patient was re-admitted after discharge with abdominal pain, vomiting and early satiety. EGD showed gastric outlet obstruction and severe pyloric stenosis which was managed with endoscopic balloon dilation. Conclusion: This case represents the severe and potentially life-threatening complications that may occur after pyloric exclusion with Roux-en-Y gastrojejunostomy. Gastrojejunostomies are prone to marginal ulceration which can perforate if not adequately treated. Free perforations cause peritonitis, but if the perforation is contained it can erode through the abdominal wall creating the rare complication of a gastrocutaneous fistula. Even after restoration of normal anatomy with a pyloroplasty, patients may suffer additional complications such as pyloric stenosis requiring continued intervention.

Laboratory and field evaluation of a low-cost methane sensor and key environmental factors for sensor calibration.

Low-cost sensors enable finer-scale spatiotemporal measurements within the existing methane (CH4) monitoring infrastructure and could help cities mitigate CH4 emissions to meet their climate goals. While initial studies of low-cost CH4 sensors have shown potential for effective CH4 measurement at ambient concentrations, sensor deployment remains limited due to questions about interferences and calibration across environments and seasons. This study evaluates sensor performance across seasons with specific attention paid to the sensor's understudied carbon monoxide (CO) interferences and environmental dependencies through long-term ambient co-location in an urban environment. The sensor was first evaluated in a laboratory using chamber calibration and co-location experiments, and then in the field through two 8 week co-locations with a reference CH4 instrument. In the laboratory, the sensor was sensitive to CH4 concentrations below ambient background concentrations. Different sensor units responded similarly to changing CH4, CO, temperature, and humidity conditions but required individual calibrations to account for differences in sensor response factors. When deployed in-field, co-located with a reference instrument near Baltimore, MD, the sensor captured diurnal trends in hourly CH4 concentration after corrections for temperature, absolute humidity, CO concentration, and hour of day. Variable performance was observed across seasons with the sensor performing well (R 2 = 0.65; percent bias 3.12%; RMSE 0.10 ppm) in the winter validation period and less accurately (R 2 = 0.12; percent bias 3.01%; RMSE 0.08 ppm) in the summer validation period where there was less dynamic range in CH4 concentrations. The results highlight the utility of sensor deployment in more variable ambient CH4 conditions and demonstrate the importance of accounting for temperature and humidity dependencies as well as co-located CO concentrations with low-cost CH4 measurements. We show this can be addressed via Multiple Linear Regression (MLR) models accounting for key covariates to enable urban measurements in areas with CH4 enhancement. Together with individualized calibration prior to deployment, the sensor shows promise for use in low-cost sensor networks and represents a valuable supplement to existing monitoring strategies to identify CH4 hotspots.