A Case of Stress Cardiomyopathy With Nab-Paclitaxel Infusion.

Stress cardiomyopathy is a transient left ventricular dysfunction caused by physiologic or pathologic stressors. Anaphylaxis is a hypersensitivity disorder that can lead to a rapid life-threatening respiratory collapse. It happens due to exposure to allergens including medications. During anaphylaxis, there is a compensatory release of catecholamines that can lead to stress cardiomyopathy. In this case, nab-paclitaxel infusion led to anaphylaxis with respiratory failure. Echocardiogram showed features of diffuse hypokinesis with preserved basal segment contractility, and cardiac catheterization did not show any evidence of obstructive coronary artery disease. The overall clinical picture suggested stress cardiomyopathy. The patient was treated with guideline-directed medical therapy which resulted in normalization of the ejection fraction with no symptoms of congestive heart failure at any point. The patient was thereafter resumed on a reduced dose of nab-paclitaxel. This case report adds to the spectrum of infusion-related reactions associated with paclitaxel and demonstrates the course of events in the management of anaphylaxis and stress cardiomyopathy in this scenario.

Platelet number and function in response to a single intravenous dose of vincristine.

BACKGROUND: Vincristine might increase circulating platelet numbers but the functional capacity of these newly released platelets is unknown. OBJECTIVE: To evaluate and compare the functionality of mature and immature (reticulated) platelets after a single intravenous dose of vincristine in dogs. ANIMALS: Ten healthy purpose-bred dogs. METHODS: Dogs prospectively received a single IV injection of 0.02 mg/kg vincristine or 0.9% saline. Before and after treatment on days 3, 5, and 7, platelets (resting and after thrombin stimulation) were assessed by flow cytometric determination of P-selectin (CD62P) expression. Reticulated platelets were distinguished using thiazole orange (TO) staining. RESULTS: Relative to saline, vincristine administration increased platelet count from day 0 to day 7 (225 ± 58 to 273 ± 65 × 103 /µL, vs 299 ± 76.4 to 214 ± 20 × 103 /µL, P = .01) and increased percentage of reticulated platelets from day 0 to day 5 (3.9 ± 1.5% to 6.1 ± 1.6%, P = .02). On all days, reticulated platelets had greater resting expression of CD62P than did mature platelets (49.6 ± 4% vs 10.2 ± 1%, P ≤ .001). Across all days, CD62P expression by reticulated platelets in the vincristine and saline-treated groups was not different when unstimulated (P = .7) or after thrombin stimulation (P = .33). CONCLUSIONS AND CLINICAL IMPORTANCE: Reticulated platelets released in response to vincristine administration function similarly to mature platelets.

Differential short-term memorisation for vocal and instrumental rhythms.

This study explores differential processing of vocal and instrumental rhythms in short-term memory with three decision (same/different judgments) and one reproduction experiment. In the first experiment, memory performance declined for delayed versus immediate recall, with accuracy for the two rhythms being affected differently: Musicians performed better than non-musicians on clapstick but not on vocal rhythms, and musicians were better on vocal rhythms in the same than in the different condition. Results for the second experiment showed that concurrent sub-vocal articulation and finger-tapping differentially affected the two rhythms and same/different decisions, but produced no evidence for articulatory loop involvement in delayed decision tasks. In a third experiment, which tested rhythm reproduction, concurrent sub-vocal articulation decreased memory performance, with a stronger deleterious effect on the reproduction of vocal than of clapstick rhythms. This suggests that the articulatory loop may only be involved in delayed reproduction not in decision tasks. The fourth experiment tested whether differences between filled and empty rhythms (continuous vs. discontinuous sounds) can explain the different memorisation of vocal and clapstick rhythms. Though significant differences were found for empty and filled instrumental rhythms, the differences between vocal and clapstick can only be explained by considering additional voice specific features.

Time-dependence in mixture toxicity prediction.

The value of time-dependent toxicity (TDT) data in predicting mixture toxicity was examined. Single chemical (A and B) and mixture (A+B) toxicity tests using Microtox(®) were conducted with inhibition of bioluminescence (Vibrio fischeri) being quantified after 15, 30 and 45-min of exposure. Single chemical and mixture tests for 25 sham (A1:A2) and 125 true (A:B) combinations had a minimum of seven duplicated concentrations with a duplicated control treatment for each test. Concentration/response (x/y) data were fitted to sigmoid curves using the five-parameter logistic minus one parameter (5PL-1P) function, from which slope, EC25, EC50, EC75, asymmetry, maximum effect, and r(2) values were obtained for each chemical and mixture at each exposure duration. Toxicity data were used to calculate percentage-based TDT values for each individual chemical and mixture of each combination. Predicted TDT values for each mixture were calculated by averaging the TDT values of the individual components and regressed against the observed TDT values obtained in testing, resulting in strong correlations for both sham (r(2)=0.989, n=25) and true mixtures (r(2)=0.944, n=125). Additionally, regression analyses confirmed that observed mixture TDT values calculated for the 50% effect level were somewhat better correlated with predicted mixture TDT values than at the 25 and 75% effect levels. Single chemical and mixture TDT values were classified into five levels in order to discern trends. The results suggested that the ability to predict mixture TDT by averaging the TDT of the single agents was modestly reduced when one agent of the combination had a positive TDT value and the other had a minimal or negative TDT value.

Baylor Pediatric SBIRT Medical Residency Training Program: model description and evaluation.

BACKGROUND: The Baylor College of Medicine SBIRT Medical Residency Training Program is a multilevel project that trains residents and faculty in evidenced-based screening, brief intervention, and referral to treatment methods for alcohol and substance use problems. METHODS: This paper describes the training program created for pediatric residents and provides an evaluation of the program. Ninety-five first-year pediatric residents participated in the training program. They were assessed on satisfaction with the program, self-rated skills, observed competency, and implementation into clinical practice. RESULTS: The program was successfully incorporated into the residency curricula in two pediatric residencies. Evaluations indicate a high degree of satisfaction with the program, self-reported improvement in SBIRT skills, observed proficiency in SBIRT skills, and utilization of SBIRT skills in clinical practice. CONCLUSIONS: SBIRT skills training can be incorporated into pediatric residency training, and residents are able to learn and implement the skills in clinical practice.

Cellular localization of dieldrin and structure-activity relationship of dieldrin analogues in dopaminergic cells.

The incidence of Parkinson's disease (PD) correlates with environmental exposure to pesticides, such as the organochlorine insecticide, dieldrin. Previous studies found an increased concentration of the pesticide in the striatal region of the brains of PD patients and also that dieldrin adversely affects cellular processes associated with PD. These processes include mitochondrial function and reactive oxygen species production. However, the mechanism and specific cellular targets responsible for dieldrin-mediated cellular dysfunction and the structural components of dieldrin contributing to its toxicity (toxicophore) have not been fully defined. In order to identify the toxicophore of dieldrin, a structure-activity approach was used, with the toxicity profiles of numerous analogues of dieldrin (including aldrin, endrin, and cis-aldrin diol) assessed in PC6-3 cells. The MTT and lactate dehydrogenase (LDH) assays were used to monitor cell viability and membrane permeability after treatment with each compound. Cellular assays monitoring ROS production and extracellular dopamine metabolite levels were also used. Structure and stereochemistry for dieldrin were found to be very important for toxicity and other end points measured. Small changes in structure for dieldrin (e.g., comparison to the stereoisomer endrin) yielded significant differences in toxicity. Interestingly, the cis-diol metabolite of dieldrin was found to be significantly more toxic than the parent compound. Disruption of dopamine catabolism yielded elevated levels of the neurotoxin, 3,4-dihydroxyphenylacetaldehyde, for many organochlorines. Comparisons of the toxicity profiles for each dieldrin analogue indicated a structure-specific effect important for elucidating the mechanisms of dieldrin neurotoxicity.

Playground safety and quality in chicago.

OBJECTIVES: To assess playground safety and quality in Chicago, Illinois, identify disparities in access, and use the data to inform collaborative improvement. METHODS: A cross-sectional survey of public park playgrounds in Chicago, Illinois, was conducted in 2009, 2010, and 2011 by using the National Program for Playground Safety Standardized Survey. All playgrounds were surveyed in 2009 and 2010; those that failed in 2010 were resurveyed in 2011. Playgrounds were assessed in 4 main categories: age-appropriate design, fall surfacing, equipment maintenance, and physical environment. Safety scores were generated from the assessment. Geographic information system mapping provided a visual description of the playground pass/fail rate based on neighborhood, child population, race/ethnicity, and poverty level. RESULTS: Of the ∼500 playgrounds, 467 were assessed in 2009, and 459 were assessed in 2010. In 2009, half of all playgrounds (55%) and in 2010, nearly two-thirds (61%) earned scores consistent with safe playgrounds (P < .001). Playgrounds scored poorest in fall surfacing and equipment maintenance. Geographic information system mapping showed neighborhoods with a higher percentage of children and impoverished families had fewer playgrounds and more failing playgrounds. In 2011, 154 (85%) of the playgrounds that failed in 2010 were surveyed. The mean playground score among failing playgrounds improved significantly between 2010 (61%) and 2011 (67%, P < .001). CONCLUSIONS: Since the playground improvement initiative began in 2009, considerable progress has been made in the safety scores, although access to high-quality playgrounds varies by neighborhood. Many failing playgrounds can be brought up to standard with improvement in fall surfacing and equipment maintenance.

Protein-thiol oxidation and cell death: regulatory role of glutaredoxins.

SIGNIFICANCE: Glutaredoxin (Grx) is the primary enzyme responsible for catalysis of deglutathionylation of protein-mixed disulfides with glutathione (GSH) (protein-SSG). This reversible post-translational modification alters the activity and function of many proteins important in regulation of critical cellular processes. Aberrant regulation of protein glutathionylation/deglutathionylation reactions due to changes in Grx activity can disrupt both apoptotic and survival signaling pathways. RECENT ADVANCES: Grx is known to regulate the activity of many proteins through reversible glutathionylation, such as Ras, Fas, ASK1, NFκB, and procaspase-3, all of which play important roles in control of apoptosis. Reactive oxygen species and/or reactive nitrogen species mediate oxidative modifications of critical Cys residues on these apoptotic mediators, facilitating protein-SSG formation and thereby altering protein function and apoptotic signaling. CRITICAL ISSUES: Much of what is known about the regulation of apoptotic mediators by Grx and reversible glutathionylation has been gleaned from in vitro studies of discrete apoptotic pathways. To relate these results to events in vivo it is important to examine changes in protein-SSG status in situ under natural cellular conditions, maintaining relevant GSH:GSSG ratios and using appropriate inducers of apoptosis. FUTURE DIRECTIONS: Apoptosis is a highly complex, tightly regulated process involving many different checks and balances. The influence of Grx activity on the interconnectivity among these various pathways remains unknown. Knowledge of the effects of Grx is essential for developing novel therapeutic approaches for treating diseases involving dysregulated apoptosis, such as cancer, heart disease, diabetes, and neurodegenerative diseases, where alterations in redox homeostasis are hallmarks for pathogenesis.

Mohs frozen tissue sections in comparison to similar paraffin-embedded tissue sections in identifying perineural tumor invasion in cutaneous squamous cell carcinoma.

BACKGROUND: Perineural invasion (PNInv) in cutaneous squamous cell carcinoma (cSCC) increases the risk of recurrence, possibly because of suboptimal identification on frozen or paraffin-embedded tissue sections. Perineural inflammation (PNInf) may portend PNInv. OBJECTIVE: We sought to correlate identification of PNInv and PNInf in hematoxylin-eosin-stained Mohs frozen sections with PNInv and PNInf identified in similarly oriented paraffin-embedded sections obtained in cases of cSCC. METHODS: We reviewed same patient Mohs frozen and paraffin-embedded tissue sections for all patients presenting within a 2-year period to our Mohs micrographic surgical unit for removal of cSCC with PNInv or PNInf identified on either type of tissue section. RESULTS: Of 537 patients undergoing surgical resection of cSCC, 21 (3.9%) had either PNInv (n = 11) or PNInf (n = 10) on frozen sections. PNInv on Mohs frozen sections was identified in 11 cases and confirmed on paraffin-embedded sections in 9 cases (82%). Paraffin-embedded sections failed to identify PNInv present in Mohs frozen sections in two (2/11), or 18% of cases. PNInf on Mohs frozen sections was confirmed on paraffin-embedded sections in 3 cases (30%), but PNInv was identified in 5 cases (50%). LIMITATIONS: Our results are a retrospective case review from a specific time period by one institution. Furthermore, it is impossible to compare identical tissue specimens using two sequential tissue processing techniques. CONCLUSION: PNInv can be accurately identified with Mohs frozen sections. PNInf on Mohs frozen sections suggests the presence of PNInv and requires further histologic investigation.

Dopamine-derived biological reactive intermediates and protein modifications: Implications for Parkinson's disease.

Dopamine (DA) undergoes monoamine oxidase catalyzed oxidative deamination to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is metabolized primarily to 3,4-dihydroxyphenylacetic acid (DOPAC) via aldehyde dehydrogenase (ALDH). Previous studies demonstrated DOPAL to be neurotoxic, more so than DA and other metabolites, and implicated the aldehyde intermediate as a factor in the pathogenesis of Parkinson's disease (PD). However, the mechanism for generation of DOPAL at aberrant levels and the pathways for toxicity are not conclusively known. Various models for DA catabolism revealed the susceptibility of DOPAL biotransformation (e.g., ALDH) to products of oxidative stress, e.g., 4-hydroxy-2-nonenal, at physiologic/pathologic levels and agents that induce oxidative stress. An elevated concentration of DOPAL correlated with increased protein modification with subsequent work demonstrating significant reactivity of the DA-derived electrophile toward protein nucleophiles compared to DA and other metabolites, e.g., DOPAC. The addition of DOPAL to proteins proceeds via reaction of the aldehyde with Lys residues, yielding a Schiff base; however, post-adduction chemistry occurs for the DOPAL-modification resulting in protein cross-linking. Preliminary work indicates enzymes in DA synthesis and catabolism to be cellular targets for DOPAL. Functional consequences for elevated levels of the DA-derived aldehyde and protein modification may include adverse cellular effects. These data implicate DOPAL as a toxic and reactive intermediate potentially serving as a "chemical trigger" for some stage of PD pathogenesis.

Keloid formation occurring in the distribution of a congenital vascular malformation.

A 35-year-old African American man presented with complaints of malodorous drainage from hypertrophic lesions on his occipital scalp (Figure 1, inset). The patient had no family history of keloid formation and no other keloids on his body. The hypertrophic mass on his scalp had been present for 10 years and had not been a result of any type of mechanical, surgical, or laser treatment. It corresponded to the distribution of a large vascular malformation over the occiput (Figure 1). The vascular malformation extended from the occipital scalp to the right parietal scalp, the right side of the face, neck, upper chest, and right arm, with varicosities and hypertrophy of the right upper extremity (Figure 2). The vascular malformation over the right parietal scalp and ear was characterized by bleb formation and hypertrophy of the right ear. The patient reported that no manipulation, including laser treatment, of the vascular malformation had been previously performed. He did state that a previous dermatologist had attempted serial surgical excision of the cerebriform nodules but retired during the course of treatment. He stated that the appearance of his keloid formation and port-wine stain had not changed during the past 10 years. A previous biopsy of a hypertrophic lesion showed histologic findings consistent with folliculitis keloidalis nuchae. Cephalexin 500 mg 4 times daily for 14 days was prescribed for the purulent drainage. A Doppler ultrasound was ordered of the right upper extremity to evaluate for an arteriovenous malformation and showed no evidence of venous thrombosis or arteriovenous malformation. On a second visit 2 weeks later, the hypertrophic lesions continued to show drainage. Clindamycin gel to be applied twice daily to the scalp was added. The patient also had magnetic resonance imaging with and without gadolinium contrast (Figure 3) ordered, which showed a large hypertrophic giant scalp keloid overlying the occipital and suboccipital region measuring 12x 19 cm. There was soft tissue thickening involving the right external ear, extending inferior to the right ear, overlying an intact parotid gland. There was no evidence of muscular or skull invasion.

Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2: implications for the mechanism of enzyme inhibition.

Molinate is a thiocarbamate herbicide used as a pre-emergent in rice patty fields. It has two predominant sulfoxidation metabolites, molinate sulfoxide and molinate sulfone. Previous work demonstrated an in vivo decrease in liver aldehyde dehydrogenase (ALDH) activity in rats treated with molinate and motor function deficits in dogs dosed chronically with this compound. ALDH is an enzyme important in the catabolism of many neurotransmitters, such as dopamine. Inhibition of this enzyme may lead to the accumulation of endogenous neurotoxic metabolites such as 3,4-dihydroxyphenylacetaldehyde, a dopamine metabolite, which may account for the observed neurotoxicity. In this study, the relative reactivity of molinate and both of its sulfoxidation metabolites toward ALDH was investigated, as well as the mechanism of inhibition. The ALDH activity was monitored in two different model systems, human recombinant ALDH (hALDH2) and mouse striatal synaptosomes. Molinate sulfone was found to be the most potent ALDH inhibitor, as compared to molinate and molinate sulfoxide. The reactivity of these three compounds was also assessed, using N-acetyl Cys, model peptides, and hALDH2. It was determined that molinate sulfone is capable of covalently modifying Cys residues, including catalytic Cys302 of ALDH, accounting for the observed enzyme inhibition.

Nitrative and oxidative stress in toxicology and disease.

Persistent inflammation and the generation of reactive oxygen and nitrogen species play pivotal roles in tissue injury during disease pathogenesis and as a reaction to toxicant exposures. The associated oxidative and nitrative stress promote diverse pathologic reactions including neurodegenerative disorders, atherosclerosis, chronic inflammation, cancer, and premature labor and stillbirth. These effects occur via sustained inflammation, cellular proliferation and cytotoxicity and via induction of a proangiogenic environment. For example, exposure to the ubiquitous air pollutant ozone leads to generation of reactive oxygen and nitrogen species in lung macrophages that play a key role in subsequent tissue damage. Similarly, studies indicate that genes involved in regulating oxidative stress are altered by anesthetic treatment resulting in brain injury, most notable during development. In addition to a role in tissue injury in the brain, inflammation, and oxidative stress are implicated in Parkinson's disease, a neurodegenerative disease characterized by the loss of dopamine neurons. Recent data suggest a mechanistic link between oxidative stress and elevated levels of 3,4-dihydroxyphenylacetaldehyde, a neurotoxin endogenous to dopamine neurons. These findings have significant implications for development of therapeutics and identification of novel biomarkers for Parkinson's disease pathogenesis. Oxidative and nitrative stress is also thought to play a role in creating the proinflammatory microenvironment associated with the aggressive phenotype of inflammatory breast cancer. An understanding of fundamental concepts of oxidative and nitrative stress can underpin a rational plan of treatment for diseases and toxicities associated with excessive production of reactive oxygen and nitrogen species.