Prenatal exposure to consumer product chemical mixtures and size for gestational age at delivery.

BACKGROUND: While fetal growth is a tightly regulated process, it is sensitive to environmental exposures that occur during pregnancy. Many commonly used consumer products contain chemicals that can disturb processes underlying fetal growth. However, mixtures of these chemicals have been minimally examined. We investigated associations between prenatal exposure to 33 consumer product chemicals (nine organophosphate ester flame retardant [OPE] metabolites, 12 phthalate metabolites, and 12 phenols) and the odds of small- or large-for-gestational age (SGA and LGA) births. METHODS: This case-control study was comprised of SGA (N = 31), LGA (N = 28), and appropriate for gestational age control (N = 31) births selected from the larger LIFECODES cohort. Biomarkers of exposure to consumer product chemicals were quantified in maternal urine collected from up to three study visits during pregnancy. In a single-pollutant approach, odds ratios (OR) and 95% confidence intervals (CI) of SGA and LGA associated with an interquartile range (IQR)-increase in exposure biomarkers were estimated using multinomial logistic regression. In a multi-pollutant approach, quantile g-computation was used to jointly estimate the OR (95% CI) of SGA and LGA per simultaneous one quartile-change in all biomarkers belonging to each chemical class. RESULTS: Among the 33 biomarkers analyzed, 20 were detected in at least 50% of the participants. After adjusting for potential confounders, we observed reduced odds of LGA in association with higher urinary concentrations of several exposure biomarkers. For example, an IQR-increase in the OPE metabolite, diphenyl phosphate, was associated with lower odds of LGA (OR: 0.40 [95% CI: 0.18, 0.87]). Using quantile g-computation, we estimated lower odds of an LGA birth for higher OPE metabolite concentrations (OR: 0.49 [95% CI: 0.27, 0.89]) and phthalate metabolite concentrations (OR: 0.23 [95% CI: 0.07, 0.73]). Associations between consumer product chemicals and SGA were largely null. CONCLUSIONS: Joint exposure to OPEs and phthalates was associated with lower odds of delivering LGA. Associations with LGA could indicate a specific impact of these exposures on the high end of the birth weight spectrum. Future work to understand this nuance in the associations between consumer product chemical mixtures and fetal growth is warranted.

The current status of thermal ablation in the management of T1b renal masses.

The role of thermal ablation in the management of T1b renal masses is not well defined. The purpose of this review is to examine current evidence for cryoablation, radiofrequency ablation, and microwave ablation of T1b renal masses as well as review current AUA and EAU guidelines for thermal ablation of T1b masses. Given the size of these tumors, adjunctive maneuvers are often necessary to ensure patient safety and protect vital adjacent structures.

A multicentre randomized trial of the treatment of patients with pemphigus vulgaris with infliximab and prednisone compared with prednisone alone.

BACKGROUND: Pemphigus vulgaris (PV) is a blistering disease and tumour necrosis factor-α has a role in its pathogenesis. OBJECTIVES: To evaluate the safety of infliximab (IFX) with prednisone compared with prednisone alone in the treatment of PV. In addition, treatment response was assessed and mechanistic studies were performed. METHODS: Subjects with PV who had ongoing disease activity while being maintained on prednisone were randomized to receive either IFX or placebo in addition to prednisone. Response status and immunoglobulin (Ig) G anti-desmoglein (Dsg)1 and Dsg3 antibodies were assessed at 18 and 26 weeks. RESULTS: Ten subjects were randomized to each group. There were no safety signals during the course of the study. At week 18, one subject in each group had responded. At week 26, three IFX-treated subjects vs. none in the placebo group had responded (P = 0·21). At weeks 18 and 26, the median IgG anti-Dsg1 and anti-Dsg3 levels were lower in the IFX-treated patients [IgG anti-Dsg-1 (week 18, P = 0·035; week 26, P = 0·022); IgG anti-Dsg3 (week 18, P = 0·035; week, 26 P = 0·05)]. CONCLUSIONS: This study is limited by the relatively small sample size. There was no significant difference between study arms in the proportion of subjects with treatment-related adverse events > grade 3. IFX therapy was not shown to be effective for the treatment of patients with PV in this randomized, placebo-controlled trial, although IFX treatment may be associated with a decrease in anti-Dsg1 and Dsg3 antibodies.

Temporal trends and predictors of phthalate, phthalate replacement, and phenol biomarkers in the LIFECODES Fetal Growth Study.

BACKGROUND: Exposure to many phthalates and phenols is declining as replacements are introduced. There is little information on temporal trends or predictors of exposure to these newer compounds, such as phthalate replacements, especially among pregnant populations. OBJECTIVE: Examine temporal trends and predictors of exposure to phthalates, phthalate replacements, and phenols using single- and multi-pollutant approaches. METHODS: We analyzed data from 900 singleton pregnancies in the LIFECODES Fetal Growth Study, a nested case-cohort with recruitment from 2007 to 2018. We measured and averaged concentrations of 12 phthalate metabolites, four phthalate replacement metabolites, and 12 phenols in urine at three timepoints during pregnancy. We visualized and analyzed temporal trends and predictors of biomarker concentrations. To examine chemical mixtures, we derived clusters of individuals with shared exposure profiles using a finite mixture model and examined temporal trends and predictors of cluster assignment. RESULTS: Exposure to phthalates and most phenols declined across the study period, while exposure to phthalate replacements (i.e., di(isononyl) cyclohexane-1,2-dicarboxylic acid, diisononyl ester [DINCH] and di-2-ethylhexyl terephthalate [DEHTP]) and bisphenol S (BPS) increased. For example, the sum of DEHTP biomarkers increased multiple orders of magnitude, with an average concentration of 0.92 ng/mL from 2007 to 2008 and 61.9 ng/mL in 2017-2018. Biomarkers of most chemical exposures varied across sociodemographic characteristics, with the highest concentrations observed in non-Hispanic Black or Hispanic participants relative to non-Hispanic White participants. We identified five clusters with shared exposure profiles and observed temporal trends in cluster membership. For example, at the end of the study period, a cluster characterized by high exposure to phthalate replacements was the most prevalent. SIGNIFICANCE: In a large and well-characterized pregnancy cohort, we observed exposure to phthalate replacements and BPS increased over time while exposure to phthalates and other phenols decreased. Our results highlight the changing nature of exposure to consumer product chemical mixtures.

Temporal trends and predictors of gestational exposure to organophosphate ester flame retardants and plasticizers.

BACKGROUND: Organophosphate esters (OPEs), used as flame retardants and plasticizers, are chemicals of concern for maternal and infant health. Prior studies examining temporal trends and predictors of OPE exposure are primarily limited by small sample sizes. OBJECTIVES: Characterize temporal trends and predictors of OPE exposure biomarkers. METHODS: We determined urinary concentrations of eight biomarkers of OPE exposure at three timepoints during pregnancy for participants in the LIFECODES Fetal Growth Study (n = 900), a nested case-cohort recruited between 2007 and 2018. We examined biomarker concentrations, their variability during pregnancy, and temporal trends over the study period. In addition, we identified sociodemographic and pregnancy characteristics associated with biomarker concentrations. Analyses were conducted using both the within-subject pregnancy geometric means and biomarker concentrations measured at individual study visits. RESULTS: Five OPE biomarkers were detected in at least 60% of the study participants. Biomarkers were not strongly correlated with one another and intraclass correlation coefficients, measuring within-subject variability during pregnancy, ranged from 0.27 to 0.51. Biomarkers exhibited varying temporal trends across study years. For example, bis(1-chloro-2-propyl) phosphate (BCIPP) increased monotonically, whereas bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP), displayed non-monotonic trends with concentrations that peaked between 2011 and 2014. We observed associations between sociodemographic characteristics and OPE biomarkers. In general, concentrations of most OPE biomarkers were higher among participants from racial and ethnic minority populations, participants who were younger, had higher pre-pregnancy body mass index (BMI), and less than a college degree. We observed consistent results using either averaged or visit-specific biomarker concentrations. SIGNIFICANCE: We observed widespread exposure to several OPEs and OPE biomarkers displayed varying temporal trends in pregnant people from 2007 to 2018. Concentrations of most OPE biomarkers varied according to sociodemographic factors, suggesting higher burdens of exposure among participants with higher pre-pregnancy BMI, those belonging to racial and ethnic minority populations, and lower educational attainment.

Evaluate the safety and efficacy of dura sealant patch in reducing cerebrospinal fluid leakage following elective cranial surgery (ENCASE II): study protocol for a randomized, two-arm, multicenter trial.

BACKGROUND: Cerebrospinal fluid (CSF) leakage is a frequent and challenging complication in neurosurgery, especially in the posterior fossa, with a prevalence of 8%. It is associated with substantial morbidity and increased healthcare costs. A novel dural sealant patch (LIQOSEAL) was developed for watertight dural closure. The objective of this study is to clinically assess the safety and effectiveness of LIQOSEAL as a means of reducing intra- as well as postoperative CSF leakage in patients undergoing elective posterior fossa intradural surgery with a dural closure procedure compared to the best currently available dural sealants. METHODS: We will conduct a two-arm, randomized controlled, multicenter study with a 90-day follow-up. A total of 228 patients will be enrolled in 19 sites, of which 114 will receive LIQOSEAL and 114 an FDA-approved PEG sealant. The composite primary endpoint is defined as intraoperative CSF leakage at PEEP 20 cm H2O, percutaneous CSF leakage within 90 days of, wound infection within 90 days of or pseudomeningocele of more than 20cc on MRI or requiring intervention. We hypothesize that the primary endpoint will not be reached by more than 10 patients (9%) in the investigational arm, which will demonstrate non-inferiority of LIQOSEAL compared to control. DISCUSSION: This trial will evaluate whether LIQOSEAL is non-inferior to control as a means of reducing CSF leakage and safety TRIAL REGISTRATION: ClinicalTrials.gov NCT04086550 . Registered on 11 September 2019.

Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.

One hallmark of Alzheimer disease is the accumulation of amyloid beta-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy. Active immunization of PDAPP mice with human amyloid beta-peptide reduces plaque burden and its associated pathologies. Several hypotheses have been proposed regarding the mechanism of this response. Here we report that peripheral administration of antibodies against amyloid beta-peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid beta-peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood-brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.

Adaptation of the adrenal medulla: sustained increase in choline acetyltransferase by psychosocial stimulation.

Sustained increases were produced in adrenal choline acetyltransferase of individually caged mice by placing them into groups for 10 or 15 minutes daily for 7 to 10 days. They were left undisturbed in their individual cages for the remainder of each day. As in previous experiments of similar design, adrenal catecholamines and adrenal weight were also increased, although body weight was not affected.

Catecholamine uptake in cerebral cortex: adaptive change induced by fighting.

Kinetics of the catecholainine uptake process in brain were altered by fighting. Significant increases in the apparent Michaelis constant (Km) for the uptake of norepinephrine into cerebral cortical homnogenates and significant increases in the inhibition constant (Ki) for d-amphetamnine inhibition of this uptake occurred in group-caged mice living under chronic attack from aggressive cage mates. Also, significant increases in the apparent Km and maximum velocity (Vmax) for norepinephrine uptake were observed 18 to 20 hours after the last of a series of short intense daily fights between male mice previously made aggressive by long-term individual caging. These results suggest that the natural stress of fighting leads to (i) lowered affinity for reuptake of norepinephrine into nerve endings of the cerebral cortex, (ii) an increase in the number of uptake sites, and (iii) lowered affinity for d-amphetamine.

Catecholamine uptake in cerebral cortex: adaptive change induced by fighting.

The name of the senior author of "Catecholamine uptake in cerebral cortex: an adaptive change induced by fighting" (8 June 1973, page 1050) was misspelled. It should be Edith D. Hendley and not Edith D. Henley.

Norepinephrine uptake into cerebral cortical synaptosomes after one fight or electroconvulsive shock.

Membrane affinity for the neurotransmitter norepinephrine is rapidly but reversibly decreased in nerve terminals of the cerebral cortex by intense nervous stimulation. This should adaptively facilitate alerting during acute emergency and stress. The Michaelis constant (K(m)) for the high-affinity active uptake of norepinephrine into crude synaptosome-rich homogenates of the cerebral cortices of mice was increased 68 percent after 15 minutes of intense fighting and 110 percent 5 minutes after a single electroconvulsive shock. These changes were no longer evident 18 to 20 hours later.

Contribution of whole platelet aggregometry to the endovascular management of unruptured aneurysms: an institutional experience.

BACKGROUND: Stent-assisted coiling of intracranial aneurysms is an efficient alternative treatment to surgical clipping but requires prolonged antiplatelet therapy. Some patients are non-responsive to aspirin and/or clopidogrel. OBJECTIVE: To analyze the implications of this assessment using the 'whole blood aggregometry (WBA) by impedance' technique. MATERIALS AND METHODS: The Southwestern Tertiary Aneurysm Registry was reviewed between 2002 and 2012 for patients with unruptured aneurysms treated with stent-assisted coiling. The study population was divided into patients who were tested preoperatively for platelet responsiveness to aspirin and clopidogrel ('tested' patients) and those who were not ('non-tested'). Where necessary, tested patients received additional doses of antiplatelet drugs to achieve adequate platelet inhibition. Endpoints included the incidence of non-responsiveness, the rates of thrombotic and hemorrhagic complications, and the rates of permanent morbidity and mortality. RESULTS: A total of 266 patients fulfilled our selection criteria: 114 non-tested patients who underwent 121 procedures, and 152 tested patients who underwent 171 procedures. The two groups did not vary significantly in patient age, gender, and aneurysms location. Aspirin non-responsiveness was detected in 3 patients (1.75%) and clopidogrel non-responsiveness in 21 patients (12.3%). Non-tested patients had an 11.6% rate of thrombotic complications with a 4.1% permanent morbidity or mortality rate versus 2.3% and 0.6% in tested patients (p=0.0013). The incidence of hemorrhagic complications was similar between the two groups. CONCLUSIONS: Preoperative platelet inhibition testing using WBA can be useful to assess and correct antiaggregant non-responsiveness, and may reduce postoperative mortality and permanent morbidity.

A Single-Institution Experience in Percutaneous Image-Guided Biopsy of Malignant Pleural Mesothelioma.

PURPOSE: Mesothelioma has been considered a difficult pathologic diagnosis to achieve via image-guided core needle biopsy. The purpose of this study was to assess the diagnostic sensitivity of percutaneous image-guided biopsy for diagnosis of pleural mesothelioma. MATERIALS AND METHODS: Retrospective review was performed to identify patients with a confirmed diagnosis of pleural mesothelioma and who underwent image-guided needle biopsy between January 1, 2002, and January 1, 2016. Thirty-two patients with pleural mesothelioma were identified and included for analysis in 33 image-guided biopsy procedures. Patient, procedural, and pathologic characteristics were recorded. Complications were characterized via standardized nomenclature [Common Terminology for Clinically Adverse Events (CTCAE)]. RESULTS: Percutaneous image-guided biopsy was associated with an overall sensitivity of 81%. No CTCAE clinically significant complications were observed. No image-guided procedures were complicated by pneumothorax or necessitated chest tube placement. No patients had tumor seeding of the biopsy tract. CONCLUSION: Percutaneous image-guided biopsy can achieve high sensitivity for pathologic diagnosis of pleural mesothelioma with a low procedural complication rate, potentially obviating need for surgical biopsy.

Evaluation of infectious complications following percutaneous liver ablation in patients with bilioenteric anastomoses.

PURPOSE: Prior bilioenteric anastomosis (BEA) has been associated with elevated risk of abscess formation after thermal ablation of hepatic tumors. We assessed the incidence of hepatic abscess after thermal ablation in a BEA cohort treated with extended antibiotic regimens following ablation. MATERIALS AND METHODS: Retrospective review was performed to identify patients with BEA who underwent percutaneous hepatic thermal ablation between January 1, 2003-September 1, 2016. Fifteen patients with BEA underwent 18 percutaneous thermal ablation procedures. Patient and procedural characteristics were reviewed, as well as the antibiotic regiment utilized post ablation. Complications were characterized via standardized nomenclature [Common Terminology for Clinically Adverse Events (CTCAE) v4.03]. RESULTS: Fifteen patients with BEA underwent treatment of 49 liver lesions during 18 ablation sessions. Mean follow-up in these patients was 39 months (range 3-138 months). Two patients (11%) developed hepatic abscesses, both of which occurred within 45 days of the ablation procedure while the patients were still on extended prophylactic antibiotic therapy. No additional CTCAE clinically significant complications were observed. CONCLUSION: Thermal ablation of hepatic tumors can be accomplished safely in patients with BEA. Long-term post-procedural antibiotics may mitigate the risk of hepatic abscess formation. Due to the high number of patients who are deemed surgically unresectable, patients with BEA may have limited alternate treatment modalities and percutaneous hepatic thermal ablative treatments warrant consideration.

Phantom evaluations of a dedicated dual-head scintimammography system.

Results of aboratory evaluations are presented of the dual-head scintimammography system using two opposed and co-registered compact gamma heads. The system is intended for clinical studies imaging suspicious lesions in a compressed breast. The studies were performed using 5 cm and 6 cm compressed breast phantoms with lesion sizes from 6 to 10 mm and lesion to breast tissue activity ratios from 6 to 10. Two imagers with a field-of-view (FOV) of 15 cmx20 cm were placed on the opposite sides of the breast phartoms. In some studies anthropomorphic torso phantom was used to simulate realistic scatter gamma radiation field. Two types of parallel-hole lead collimators were employed. Combining the co-registered images from both detector heads resulted in an over two-fold increase in lesioin contrast in the central plane of the phantom and substantially increased detection sensitivity over the whole breast volume, especially of asymmetrically placed small lesions. The results confirm the important advantage of a co-registoed two-head scintimammography system over a single head system in lesion detection and localization.

Auto-brewery Syndrome in the Setting of Long-standing Crohn's Disease: A Case Report and Review of the Literature.

CLINICAL BACKGROUND: A 71-year-old male with 50-year history of Crohn's disease was evaluated for acute onset of dizziness and slurred speech. Blood ethanol levels were elevated despite abstinence from alcohol for over 30 years. CT enterography demonstrated massive dilation of the small bowel with anastomotic stricture. DISCUSSION: Auto-brewery syndrome may be considered in a patient with chronic obstruction or hypomotility presenting with elevated serum ethanol levels in the setting of high carbohydrate intake. Although treatment algorithms lack validation, judicious use of antibiotic therapy, carbohydrate control, and short courses of antifungal therapy have all been reported in the literature. Importantly, clinical consideration of 'auto-brewery' should be undertaken with substantial caution, given the lack of validated mechanisms linking endogenous ethanol production to peripheral blood ethanol.

Studies of renin activation and regulation of aldosterone and 18-hydroxycorticosterone biosynthesis in hyporeninemic hypoaldosteronism.

In an attempt to evaluate deficiencies of renin activation and adrenal zona glomerulosa biosynthesis in hyporeninemic hypoaldosteronism (HH), we studied active and inactive renin (AR and IR, respectively) responses to the dopamine antagonist metoclopramide, furosemide, and graded dose infusion of ACTH in 10 HH patients and 6 normal subjects. In HH patients, AR levels, but not IR levels, were decreased relative to normal values. While normal subjects had an AR response to metoclopramide, the HH patients did not. The AR response to furosemide in HH patients was markedly diminished compared to that in normal subjects. Plasma cortisol and corticosterone levels were in the normal range, but the zona glomerulosa products 18-hydroxycorticosterone (18-OHB) and aldosterone (Aldo) were low in HH patients. Plasma 18-OHB and Aldo responses to metoclopramide and furosemide were diminished, but cortisol and 18-OHB responses to ACTH were normal in the HH patients. Our observation that 18-OHB and Aldo responses to metoclopramide were diminished refutes the possibility that excessive adrenal zona glomerulosa dopaminergic activity could account for reduced biosynthesis of 18-OHB and Aldo in HH patients. Our results appear most consistent with the concept that the primary etiological factor in the HH syndrome is impairment of renal activation of renin.

Effects of diltiazem on hormonal and hemodynamic responses to lower body negative pressure and tilt in patients with mild to moderate systemic hypertension.

Mean arterial blood pressure, forearm vascular resistance, plasma norepinephrine, plasma renin activity and aldosterone responses to graded lower body negative pressure and tilt at 80 degrees were examined in 10 men with mild to moderate essential hypertension before and after 12 weeks of diltiazem (240 to 360 mg/day) therapy. Diltiazem therapy lowered basal supine systolic and diastolic blood pressures without affecting basal heart rate. Mean arterial blood pressure and forearm vascular resistance were decreased from 114 +/- 1.5 to 105 +/- 1 mm Hg, p less than 0.01 and from 29.3 +/- 3.5 to 18.9 +/- 2.1 units, p less than 0.01, respectively. Diltiazem therapy had no effect on basal supine levels of norepinephrine, plasma renin activity or aldosterone, nor on the responses of these hormones to lower body negative pressure. Diltiazem did decrease the forearm vascular resistance responses to lower body negative pressure and tilt. Diltiazem abolished an orthostatic increase (10 +/- 0.3 mm Hg) in mean arterial blood pressure and this was associated with a greater plasma norepinephrine response to tilt. These results suggest that diltiazem decreases vascular resistance through a reduction in the postjunctional effects of norepinephrine on vascular smooth muscle.