Effect of direct voltage induction by low-frequency security systems on neurostimulator lead.

Low-frequency (LF) security systems, such as antitheft electronic article surveillance (EAS) gates emit strong magnetic fields that could potentially interfere with neurostimulator operation. Some patients reported pain and shocking sensations near EAS gates, even after they turned off their pulse generator. To investigate the direct voltage induction of EAS systems on neurostimulator leads, we evaluated voltages induced by two EAS systems (14 kHz continuous wave or 58 kHz pulsed) on a 40 cm sacral neurostimulator lead formed in a circular loop attached to a pulse generator that was turned off. The lead and neurostimulator were mounted in a saline-filled rectangular phantom placed within electromagnetic fields emitted by EAS systems. The measured voltage waveforms were applied to computational models of spinal nerve axons to predict whether these voltages may evoke action potentials. Additional in vitro testing was performed on the semicircular lead geometry, to study the effect of lead geometry on EAS induced voltages. While standard neurostimulator testing per ISO 14708-3:2017 recommends electromagnetic compatibility testing with LF magnetic fields for induction of malfunctions of the active electronic circuitry while generating intended stimulating pulses, our results show that close to the EAS antenna frames, the induced voltage on the lead could be strong enough to evoke action potentials, even with the pulse generator turned off. This work suggests that patient reports of pain and shocking sensations when near EAS systems could also be correlated with the direct EAS-induced voltage on neurostimulator lead.

Comparison of prone and upright, stereotactic, and tomosynthesis-guided biopsies with secondary analysis of ultrasound-occult architectural distortions.

OBJECTIVES: Compare prone and upright, stereotactic, and tomosynthesis-guided vacuum-assisted breast biopsies (prone DM-VABB, prone DBT-VABB, upright DM-VABB, and upright DBT-VABB) in a community-practice setting and review outcomes of ultrasound-occult architectural distortions (AD). METHODS: Consecutive biopsies performed at two community-based breast centers from 2016 to 2019 were retrospectively reviewed. Technical details of each procedure and patient outcomes were recorded. Separate analyses were performed for ultrasound-occult ADs. Two sample t-tests and Fisher's exact test facilitated comparisons. RESULTS: A total of 1133 patients underwent 369 prone DM-VABB, 324 prone DBT-VABB, 437 upright DM-VABB, and 123 upright DBT-VABB with 99.2%, 100%, 99.3%, and 99.2% success, respectively (p-values > 0.25). Mean lesion targeting times were greater for prone biopsy (minutes: 6.94 prone DM-VABB, 8.54 prone DBT-VABB, 5.52 upright DM-VABB, and 5.51 upright DBT-VABB; p-values < 0.001), yielding longer total prone procedure times for prone biopsy (p < 0.001). Compared to DM-VABB, DBT-VABB used fewer exposures (p < 0.001) and more commonly targeted AD, asymmetries, or masses (p < 0.001). Malignancy rates were similar between procedures: prone DM-VABB 22.4%, prone DBT-VABB 21.9%, upright DM-VABB 22.8%, and upright DBT-VABB 17.2% (p-values > 0.19). One hundred forty of the 1133 patients underwent 145 biopsies for ultrasound-occult AD (143 DBT-VABB and 2 DM-VABB). Biopsy yielded 27 malignancies and 47 high-risk lesions (74 of 145, 51%). Malignancy rate was 20.7% after surgical upgrade of one benign-discordant and two high-risk lesions. CONCLUSIONS: All biopsy procedure types were extremely successful. The 20.7% malignancy rate for ultrasound-occult AD confirms a management recommendation for tissue diagnosis. Upright biopsy was faster than prone biopsy, and DBT-VABB used fewer exposures than DM-VABB. CLINICAL RELEVANCE: Our results highlight important differences between prone DM-VABB, prone DBT-VABB, upright DM-VABB, and upright DBT-VABB. Moreover, the high likelihood of malignancy for ultrasound-occult AD will provide confidence in recommending tissue diagnosis in lieu of observation or clinical follow-up. KEY POINTS: • Upright and prone stereotactic and tomosynthesis-guided breast biopsies were safe and effective in the community-practice setting. • The malignancy rate for ultrasound-occult architectural distortion of 20.7% confirms the management recommendation for biopsy. • Upright procedures were faster than prone procedures, and tomosynthesis-guided biopsy used fewer exposures than stereotactic biopsy.

Neonatal Hyperoxia Activates Activating Transcription Factor 4 to Stimulate Folate Metabolism and Alveolar Epithelial Type 2 Cell Proliferation.

Oxygen supplementation in preterm infants disrupts alveolar epithelial type 2 (AT2) cell proliferation through poorly understood mechanisms. Here, newborn mice are used to understand how hyperoxia stimulates an early aberrant wave of AT2 cell proliferation that occurs between Postnatal Days (PNDs) 0 and 4. RNA-sequencing analysis of AT2 cells isolated from PND4 mice revealed hyperoxia stimulates expression of mitochondrial-specific methylenetetrahydrofolate dehydrogenase 2 and other genes involved in mitochondrial one-carbon coupled folate metabolism and serine synthesis. The same genes are induced when AT2 cells normally proliferate on PND7 and when they proliferate in response to the mitogen fibroblast growth factor 7. However, hyperoxia selectively stimulated their expression via the stress-responsive activating transcription factor 4 (ATF4). Administration of the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia suppressed ATF4 and thus early AT2 cell proliferation, but it had no effect on normative AT2 cell proliferation seen on PND7. Because ATF4 and methylenetetrahydrofolate dehydrogenase are detected in hyperplastic AT2 cells of preterm infant humans and baboons with bronchopulmonary dysplasia, dampening mitochondrial oxidative stress and ATF4 activation may provide new opportunities for controlling excess AT2 cell proliferation in neonatal lung disease.

Breast cancer screening in women with and without implants: retrospective study comparing digital mammography to digital mammography combined with digital breast tomosynthesis.

OBJECTIVES: Compare four groups being screened: women without breast implants undergoing digital mammography (DM), women without breast implants undergoing DM with digital breast tomosynthesis (DM/DBT), women with implants undergoing DM, and women with implants undergoing DM/DBT. METHODS: Mammograms from February 2011 to March 2017 were retrospectively reviewed after 13,201 were excluded for a unilateral implant or prior breast cancer. Patients had been allowed to choose between DM and DM/DBT screening. Mammography performance metrics were compared using chi-square tests. RESULTS: Six thousand forty-one women with implants and 91,550 women without implants were included. In mammograms without implants, DM (n = 113,973) and DM/DBT (n = 61,896) yielded recall rates (RRs) of 8.53% and 6.79% (9726/113,973 and 4204/61,896, respectively, p < .001), cancer detection rates per 1000 exams (CDRs) of 3.96 and 5.12 (451/113,973 and 317/61,896, respectively, p = .003), and positive predictive values for recall (PPV1s) of 4.64% and 7.54% (451/9726 and 317/4204, respectively, p < .001), respectively. In mammograms with implants, DM (n = 6815) and DM/DBT (n = 5138) yielded RRs of 5.81% and 4.87% (396/6815 and 250/5138, respectively, p = .158), CDRs of 2.49 and 2.92 (17/6815 and 15/5138, respectively, p > 0.999), and PPV1s of 4.29% and 6.0% (17/396 and 15/250, respectively, p > 0.999), respectively. CONCLUSIONS: DM/DBT significantly improved recall rates, cancer detection rates, and positive predictive values for recall compared to DM alone in women without implants. DM/DBT performance in women with implants trended towards similar improvements, though no metric was statistically significant. KEY POINTS: • Digital mammography with tomosynthesis improved recall rates, cancer detection rates, and positive predictive values for recall compared to digital mammography alone for women without implants. • Digital mammography with tomosynthesis trended towards improving recall rates, cancer detection rates, and positive predictive values for recall compared to digital mammography alone for women with implants, but these trends were not statistically significant - likely related to sample size.

Multiple Bilateral Circumscribed Breast Masses Detected at Imaging: Review of Evidence for Management Recommendations.

OBJECTIVE. Historically, management recommendations for multiple bilateral circumscribed breast masses encountered with breast imaging have varied. This article reviews the evidence and provides best-practice recommendations for managing these masses. CONCLUSION. Meticulous imaging technique and interpretation are required to correctly diagnose multiple bilateral circumscribed breast masses. Radiologists should classify such masses identified at mammography, digital breast tomosynthesis, or bilateral whole-breast sonography as benign and recommend annual follow-up. Elucidating the significance of these masses on MRI, contrast-enhanced mammography, or nuclear breast imaging requires further study.

Neonatal hyperoxia depletes pulmonary vein cardiomyocytes in adult mice via mitochondrial oxidation.

Supplemental oxygen given to preterm infants has been associated with permanently altering postnatal lung development. Now that these individuals are reaching adulthood, there is growing concern that early life oxygen exposure may also promote cardiovascular disease through poorly understood mechanisms. We previously reported that adult mice exposed to 100% oxygen between postnatal days 0 and 4 develop pulmonary hypertension, defined pathologically by capillary rarefaction, dilation of arterioles and veins, cardiac failure, and a reduced lifespan. Here, Affymetrix Gene Arrays are used to identify early transcriptional changes that take place in the lung before pulmonary capillary rarefaction. We discovered neonatal hyperoxia reduced expression of cardiac muscle genes, including those involved in contraction, calcium signaling, mitochondrial respiration, and vasodilation. Quantitative RT-PCR, immunohistochemistry, and genetic lineage mapping using Myh6CreER; Rosa26RmT/mG mice revealed this reflected loss of pulmonary vein cardiomyocytes. The greatest loss of cadiomyocytes was seen within the lung followed by a graded loss beginning at the hilum and extending into the left atrium. Loss of these cells was seen by 2 wk of age in mice exposed to ≥80% oxygen and was attributed, in part, to reduced proliferation. Administering mitoTEMPO, a scavenger of mitochondrial superoxide during neonatal hyperoxia prevented loss of these cells. Since pulmonary vein cardiomyocytes help pump oxygen-rich blood out of the lung, their early loss following neonatal hyperoxia may contribute to cardiovascular disease seen in these mice, and perhaps in people who were born preterm.

Screening Mammography Findings From One Standard Projection Only in the Era of Full-Field Digital Mammography and Digital Breast Tomosynthesis.

OBJECTIVE: The purpose of this article is to compare outcomes of findings seen on one view only from screening full-field digital mammography (FFDM) and FFDM plus digital breast tomosynthesis (DBT). MATERIALS AND METHODS: A retrospective review was performed of 103,070 consecutive screening mammograms obtained from February 2011 through June 2014 at two community-based breast centers. Recalled findings prospectively seen on one view only were analyzed. Pearson chi-square test and Fisher exact test were performed, and 95% CIs were determined. RESULTS: Mammograms were acquired using FFDM (n = 71,656) and FFDM-DBT (n = 31,414) during the study period, and 2213 FFDM (3.1%) and 433 FFDM-DBT (1.4%) mammograms were recalled for one-view-only findings (p < 0.0001). The final study population (1592 FFDM and 354 FFDM-DBT) was defined after 689 of these recalled FFDM and 92 of these recalled FFDM-DBT examinations were excluded for insufficient mammographic follow-up (< 24 months). Summation artifacts accounted for more one-view-only findings from FFDM (1067/1592; 67.0%) than FFDM-DBT (190/354; 53.7%) (p < 0.0001). In the FFDM cohort, 28 one-view-only findings proved malignant (24 invasive ductal carcinoma [IDC], one invasive lobular carcinoma [ILC], and three ductal carcinoma in situ [DCIS]). In the FFDM-DBT cohort, 14 one-view-only findings proved malignant (11 IDC, one ILC, and two DCIS). The positive predictive value (PPV) of a one-view-only finding was significantly lower for FFDM (1.8%) than for FFDM-DBT (4.0%) (p = 0.010). CONCLUSION: One-view-only findings occur with both FFDM and FFDM-DBT and remain an important but uncommon sign of malignancy. They are more frequent, are more likely to represent summation artifacts, and have a lower PPV with FFDM than with FFDM-DBT.

Wnt ligand/Frizzled 2 receptor signaling regulates tube shape and branch-point formation in the lung through control of epithelial cell shape.

Changing the morphology of a simple epithelial tube to form a highly ramified branching network requires changes in cell behavior that lead to tissue-wide changes in organ shape. How epithelial cells in branched organs modulate their shape and behavior to promote bending and sculpting of the epithelial sheet is not well understood, and the mechanisms underlying this process remain obscure. We show that the Wnt receptor Frizzled 2 (Fzd2) is required for domain branch formation during the initial establishment of the respiratory tree. Live imaging and transcriptome analysis of lung-branching morphogenesis demonstrate that Fzd2 promotes changes in epithelial cell length and shape. These changes in cell morphology deform the developing epithelial tube to generate and maintain new domain branches. Fzd2 controls branch formation and the shape of the epithelial tube by regulating Rho signaling and by the localization of phospho-myosin light chain 2, in turn controlling the changes in the shape of epithelial cells during morphogenesis. This study demonstrates the importance of Wnt/Fzd2 signaling in promoting and maintaining changes in epithelial cell shape that affect development of a branching network.

Wnt5a and Wnt11 inhibit the canonical Wnt pathway and promote cardiac progenitor development via the Caspase-dependent degradation of AKT.

Wnt proteins regulate cell behavior via a canonical signaling pathway that induces ß-catenin dependent transcription. It is now appreciated that Wnt/ß-catenin signaling promotes the expansion of the second heart field (SHF) progenitor cells that ultimately give-rise to the majority of cardiomyocytes. However, activating ß-catenin can also cause the loss of SHF progenitors, highlighting the necessity of precise control over ß-catenin signaling during heart development. We recently reported that two non-canonical Wnt ligands, Wnt5a and Wnt11, act cooperatively to attenuate canonical Wnt signaling that would otherwise disrupt the SHF. While these data reveal the essential role of this anti-canonical Wnt5a/Wnt11 signaling in SHF development, the mechanisms by which these ligands inhibit the canonical Wnt pathway are unclear. Wnt11 was previously shown to inhibit ß-catenin and promote cardiomyocyte maturation by activating a novel apoptosis-independent function of Caspases. Consistent with these data, we now show that Wnt5a and Wnt11 are capable of inducing Caspase activity in differentiating embryonic stem (ES) cells and that hearts from Wnt5a(-/-); Wnt11(-/-) embryos have diminished Caspase 3 (Casp3) activity. Furthermore, SHF markers are reduced in Casp3 mutant ES cells while the treatment of wild type ES cells with Caspase inhibitors blocked the ability of Wnt5a and Wnt11 to promote SHF gene expression. This finding was in agreement with our in vivo studies in which injecting pregnant mice with Caspase inhibitors reduced SHF marker expression in their gestating embryos. Caspase inhibition also blocked other Wnt5a/Wnt11 induced effects, including the suppression of ß-catenin protein expression and activity. Interestingly, Wnt5a/Wnt11 treatment of differentiating ES cells reduced both phosphorylated and total Akt through a Caspase-dependent mechanism and phosphorylated Akt levels were increased in the hearts Caspase inhibitor treated. Surprisingly, inhibition of either Akt or PI3K in ES cells was an equally effective means of increasing SHF markers compared to treatment with Wnt5a/Wnt11. Moreover, Akt inhibition restored SHF gene expression in Casp3 mutant ES cells. Taken together, these findings suggest that Wnt5a/Wnt11 inhibit ß-catenin to promote SHF development through Caspase-dependent Akt degradation.

DAAM1 and DAAM2 are co-required for myocardial maturation and sarcomere assembly.

Wnt ligands regulate heart morphogenesis but the underlying mechanisms remain unclear. Two Formin-related proteins, DAAM1 and 2, were previously found to bind the Wnt effector Disheveled. Here, since DAAM1 and 2 nucleate actin and mediate Wnt-induced cytoskeletal changes, a floxed-allele of Daam1 was used to disrupt its function specifically in the myocardium and investigate Wnt-associated pathways. Homozygous Daam1 conditional knockout (CKO) mice were viable but had misshapen hearts and poor cardiac function. The defects in Daam1 CKO mice were observed by mid-gestation and were associated with a loss of protrusions from cardiomyocytes invading the outflow tract. Further, these mice exhibited noncompaction cardiomyopathy (NCM) and deranged cardiomyocyte polarity. Interestingly, Daam1 CKO mice that were also homozygous for an insertion disrupting Daam2 (DKO) had stronger NCM, severely reduced cardiac function, disrupted sarcomere structure, and increased myocardial proliferation, suggesting that DAAM1 and DAAM2 have redundant functions. While RhoA was unaffected in the hearts of Daam1/2 DKO mice, AKT activity was lower than in controls, raising the issue of whether DAAM1/2 are only mediating Wnt signaling. Daam1-floxed mice were thus bred to Wnt5a null mice to identify genetic interactions. The hearts of Daam1 CKO mice that were also heterozygous for the null allele of Wnt5a had stronger NCM and more severe loss of cardiac function than Daam1 CKO mice, consistent with DAAM1 and Wnt5a acting in a common pathway. However, deleting Daam1 further disrupted Wnt5a homozygous-null hearts, suggesting that DAAM1 also has Wnt5a-independent roles in cardiac development.

Wnt5a and Wnt11 are essential for second heart field progenitor development.

Wnt/ß-catenin has a biphasic effect on cardiogenesis, promoting the induction of cardiac progenitors but later inhibiting their differentiation. Second heart field progenitors and expression of the second heart field transcription factor Islet1 are inhibited by the loss of ß-catenin, indicating that Wnt/ß-catenin signaling is necessary for second heart field development. However, expressing a constitutively active ß-catenin with Islet1-Cre also inhibits endogenous Islet1 expression, reflecting the inhibitory effect of prolonged Wnt/ß-catenin signaling on second heart field development. We show that two non-canonical Wnt ligands, Wnt5a and Wnt11, are co-required to regulate second heart field development in mice. Loss of Wnt5a and Wnt11 leads to a dramatic loss of second heart field progenitors in the developing heart. Importantly, this loss of Wnt5a and Wnt11 is accompanied by an increase in Wnt/ß-catenin signaling, and ectopic Wnt5a/Wnt11 inhibits ß-catenin signaling and promotes cardiac progenitor development in differentiating embryonic stem cells. These data show that Wnt5a and Wnt11 are essential regulators of the response of second heart field progenitors to Wnt/ß-catenin signaling and that they act by restraining Wnt/ß-catenin signaling during cardiac development.

Wnt ligands signal in a cooperative manner to promote foregut organogenesis.

Endoderm-mesenchyme cross-talk is a central process in the development of foregut-derived organs. How signaling pathways integrate the activity of multiple ligands to guide organ development is poorly understood. We show that two Wnt ligands, Wnt2 and Wnt7b, cooperatively induce Wnt signaling without affecting the stabilization of the Wnt canonical effector ß-catenin despite it being necessary for Wnt2-Wnt7b cooperativity. Wnt2-Wnt7b cooperation is specific for mesenchymal cell lineages and the combined loss of Wnt2 and Wnt7b leads to more severe developmental defects in the lung than loss of Wnt2 or Wnt7b alone. High-throughput small-molecule screens and biochemical assays reveal that the Pdgf pathway is required for cooperative Wnt2-Wnt7b signaling. Inhibition of Pdgf signaling in cell culture reduces Wnt2-Wnt7b cooperative signaling. Moreover, inhibition of Pdgf signaling in lung explant cultures results in decreased Wnt signaling and lung smooth-muscle development. These data suggest a model in which Pdgf signaling potentiates Wnt2-Wnt7b signaling to promote high levels of Wnt activity in mesenchymal progenitors that is required for proper development of endoderm-derived organs, such as the lung.

Effect of epiretinal electrical stimulation on the glial cells in a rabbit retinal eyecup model.

Introduction: We examined how pulse train electrical stimulation of the inner surface of the rabbit retina effected the resident glial cells. We used a rabbit retinal eyecup preparation model, transparent stimulus electrodes, and optical coherence tomography (OCT). The endfeet of Müller glia processes line the inner limiting membrane (ILM). Methods: To examine how epiretinal electrode stimulation affected the Müller glia, we labeled them post stimulation using antibodies against soluble glutamine synthetase (GS). After 5 min 50 Hz pulse train stimulation 30 µm from the surface, the retina was fixed, immunostained for Müller glia, and examined using confocal microscopic reconstruction. Stimulus pulse charge densities between 133-749 µC/cm2/ph were examined. Results: High charge density stimulation (442-749 µC/cm2/ph) caused significant losses in the GS immunofluorescence of the Müller glia endfeet under the electrode. This loss of immunofluorescence was correlated with stimuli causing ILM detachment when measured using OCT. Müller cells show potassium conductances at rest that are blocked by barium ions. Using 30 msec 20 µA stimulus current pulses across the eyecup, the change in transretinal resistance was examined by adding barium to the Ringer. Barium caused little change in the transretinal resistance, suggesting under low charge density stimulus pulse conditions, the Müller cell radial conductance pathway for these stimulus currents was small. To examine how epiretinal electrode stimulation affected the microglia, we used lectin staining 0-4 h post stimulation. After stimulation at high charge densities 749 µC/cm2/ph, the microglia under the electrode appeared rounded, while the local microglia outside the electrode responded to the stimulated retina by process orientation inwards in a ring by 30 min post stimulation. Discussion: Our study of glial cells in a rabbit eyecup model using transparent electrode imaging suggests that epiretinal electrical stimulation at high pulse charge densities, can injure the Müller and microglia cells lining the inner retinal surface in addition to ganglion cells.

Breast Imaging Patient Demographics at a Major Comprehensive Cancer Center Before and During the COVID-19 Pandemic.

OBJECTIVE: The coronavirus disease of 2019 (COVID-19) pandemic disproportionately affected certain vulnerable communities. The purpose of our study was to determine how COVID-19 affected the socioeconomic demographics of breast imaging patients at a major comprehensive cancer center. METHODS: This retrospective cohort study compared female patients who underwent screening mammograms, diagnostic mammograms, breast ultrasound, or breast MRI during the following time periods: prepandemic (February 1, 2018, through February 29, 2020), acute pandemic (March 1, 2020, through June 30, 2020), subacute pandemic (August 1, 2020, through December 31, 2020), and chronic pandemic (January 1, 2021, through June 30, 2022). Statistics were performed using the generalized estimating equations approach. RESULTS: A total of 74,398 female patients (mean age, 55.6 ± 12.4 years) underwent 238,776 total breast imaging examinations. For screening mammograms, Hispanics represented 27.1% (9,197 of 33,960) of patients in the prepandemic time period compared with 16.7% (604 of 3,621) in the acute pandemic time period, 18.7% (1,835 of 9,830) in the subacute pandemic time period, and 24.3% (7,492 of 30,869) in the chronic pandemic time period (all P < .0001). Self-pay patients saw similar declines for screening mammograms during the same time periods: 21.7% (7,375 of 33,960), 7.9% (286 of 3,621), 9.5% (933 of 9,830), and 17.4% (5,357 of 30,869), respectively (all P < .0001, compared with the prepandemic time period). Similarly dramatic trends were not observed for race or other imaging examinations. DISCUSSION: At our cancer center, Hispanics and self-pay patients were disproportionately affected by the COVID-19 pandemic. Strategies to improve health inequities are needed.

Endoscopic closure of a recto-pelvic fistula with a cardiac septal occluder device.

Video 1Endoscopic closure of a recto-pelvic fistula with a cardiac septal occluder device in a patient for whom other surgical and endoscopic interventions had failed.

Identification of novel NRF2-dependent genes as regulators of lead and arsenic toxicity in neural progenitor cells.

Lead (Pb) and arsenic (As) are prevalent metal contaminants in the environment. Exposures to these metals are associated with impaired neuronal functions and adverse effects on neurodevelopment in children. However, the molecular mechanisms by which Pb and As impair neuronal functions remain poorly understood. Here, we identified F2RL2, TRIM16L, and PANX2 as novel targets of Nuclear factor erythroid 2-related factor 2 (NRF2)-the master transcriptional factor for the oxidative stress response-that are commonly upregulated with both Pb and As in human neural progenitor cells (NPCs). Using a ChIP (Chromatin immunoprecipitation)-qPCR assay, we showed that NRF2 directly binds to the promoter region of F2RL2, TRIM16L, and PANX2 to regulate expression of these genes. We demonstrated that F2RL2, PANX2, and TRIM16L have differential effects on cell death, proliferation, and differentiation of NPCs in both the presence and absence of metal exposures, highlighting their roles in regulating NPC function. Furthermore, the analyses of the transcriptomic data on NPCs derived from autism spectrum disorder (ASD) patients revealed that dysregulation of F2RL2, TRIM16L, and PANX2 was associated with ASD genetic backgrounds and ASD risk genes. Our findings revealed that Pb and As induce a shared NRF2-dependent transcriptional response in NPCs and identified novel genes regulating NPC function. While further in vivo studies are warranted, this study provides a novel mechanism linking metal exposures to NPC function and identifies potential genes of interest in the context of neurodevelopment.

Coordinated metabolic responses to cyclophilin D deletion in the developing heart.

In the embryonic heart, the activation of the mitochondrial electron transport chain (ETC) coincides with the closure of the cyclophilin D (CypD) regulated mitochondrial permeability transition pore (mPTP). However, it remains to be established whether the absence of CypD has a regulatory effect on mitochondria during cardiac development. Using a variety of assays to analyze cardiac tissue from wildtype and CypD knockout mice from embryonic day (E)9.5 to adult, we found that mitochondrial structure, function, and metabolism show distinct transitions. Deletion of CypD altered the timing of these transitions as the mPTP was closed at all ages, leading to coupled ETC activity in the early embryo, decreased citrate synthase activity, and an altered metabolome particularly after birth. Our results suggest that manipulating CypD activity may control myocyte proliferation and differentiation and could be a tool to increase ATP production and cardiac function in immature hearts.

Suspicious Ultrasound-Occult Non-Calcified Mammographic Masses, Asymmetries, and Architectural Distortions Are Moderate Probability for Malignancy.

Suspicious non-calcified mammographic findings have not been evaluated with modern mammographic technique, and the purpose of this work is to compare the likelihood of malignancy for those findings. To do this, 5018 consecutive mammographically guided biopsies performed during 2016-2019 at a large metropolitan, community-based hospital system were retrospectively reviewed. In total, 4396 were excluded for targeting calcifications, insufficient follow-up, or missing data. Thirty-seven of 126 masses (29.4%) were malignant, 44 of 194 asymmetries (22.7%) were malignant, and 77 of 302 architectural distortions (AD, 25.5%) were malignant. The combined likelihood of malignancy was 25.4%. Older age was associated with a higher likelihood of malignancy for each imaging finding type (all p ≤ 0.006), and a possible ultrasound correlation was associated with a higher likelihood of malignancy when all findings were considered together (p = 0.012). Two-view asymmetries were more frequently malignant than one-view asymmetries (p = 0.03). There were two false-negative biopsies (98.7% sensitivity and 100% specificity). In conclusion, the 25.4% likelihood of malignancy confirms the recommendation for biopsy of suspicious, ultrasound-occult, mammographic findings. Mammographically guided biopsies were highly sensitive and specific in this study. Older patient age and a possible ultrasound correlation should raise concern given the increased likelihood of malignancy in those scenarios.

Aortic aneurysm generation in mice with targeted deletion of integrin-linked kinase in vascular smooth muscle cells.

RATIONALE: Integrin-linked kinase (ILK) is located at focal adhesions and links the extracellular matrix (ECM) to the actin cytoskeleton via ß1- and ß3-integrins. ILK plays a role in the activation of kinases including protein kinase B/Akt and glycogen synthase kinase 3ß and regulates cell proliferation, motility, and survival. OBJECTIVE: To determine the function of ILK in vascular smooth muscle cells (SMCs) in vivo. METHODS AND RESULTS: SM22Cre(+)Ilk(Fl/Fl) conditional mutant mice were generated in which the Ilk gene was selectively ablated in SMCs. SM22Cre(+)Ilk(Fl/Fl) conditional mutant mice survive to birth but die in the perinatal period exhibiting multiple vascular pathologies including aneurysmal dilatation of the aorta and patent ductus arteriosus (PDA). Defects in morphogenetic development of the aorta were observed as early as E12.5 in SM22Cre(+)Ilk(Fl/Fl) mutant embryos. By late gestation (E16.5 to 18.5), striking expansion of the thoracic aorta was observed in ILK mutant embryos. Histological analyses revealed that the structural organization of the arterial tunica media is severely disrupted with profound derangements in SMC morphology, cell-cell, and cell-matrix relationships, including disruption of the elastic lamellae. ILK deletion in primary aortic SMCs results in alterations of RhoA/cytoskeletal signaling transduced through aberrant localization of myocardin-related transcription factor (MRTF)-A repressing the transcription and expression of SMC genes, which are required for the maintenance of the contractile SMC phenotype. CONCLUSIONS: These data identify a molecular pathway linking ILK signaling to the contractile SMC gene program. Activation of this pathway is required for morphogenetic development of the aorta and ductus arteriosus during embryonic and postnatal survival.