Subdermal Plexus Density as It Relates to Obesity and Wound Complications in Patients Undergoing Reduction Mammaplasty.

Background: Reduction mammaplasty is one of the most common reconstructive procedures performed in plastic surgery. Multiple comorbidities play a role in postoperative wound healing complications; however, there are insufficient data on the subdermal plexus (SDP) as it relates to these comorbidities. The purpose of this study is to evaluate the relationship between body mass index (BMI) and SDP of the superficial breast tissues and examine the association between SDP and postoperative complications. Methods: After Institutional Review Board approval, screening, and informed consent, patients undergoing reduction mammaplasty were selected. Tissue to be discarded was sent to pathology for analysis of immunohistochemistry directed against endothelial cells to determine the density of the SDP. Patients with BMI <35 and ≥35 kg/m2 were compared. Statistical analysis, including 2-tailed t test and Pearson correlation, was conducted. Results: A significant difference in SDP density (standard deviation) was identified between patients with a BMI ≥35 versus <35 kg/m2 (2.65 capillaries/mm2 ± 1.8 vs 1.56 capillaries/mm2 ± 1.2; P = .033). Patients with no historical use of tobacco versus those who used tobacco showed a significantly increased SDP (2.11 capillaries/mm2 ± 1.6 vs 1.20 capillaries/mm2 ± 0.5; P = .009). A significant relationship between postoperative infection (1.00 capillaries/mm2 ± 1.1; P = .041) and hematoma/seroma (0.788 capillaries/mm2 ± 0.1; P = .003) was identified. No significant relationship was found between SDP and delayed wound healing, nipple-areolar complex complications, fat/flap necrosis, or symptomatic scar occurrence. Conclusions: There is a statistically significant increase in SDP seen with increasing BMI, which does not explain the higher rate of wound healing complications after reduction mammaplasty typically seen in the higher BMI patient population. The association between BMI and complications after reduction mammaplasty remains unclear.

Atorvastatin differentially regulates the interactions of cocaine and amphetamine with dopamine transporters.

The function of the dopamine transporter (DAT) is regulated by membrane cholesterol content. A direct, acute removal of membrane cholesterol by methyl-ß-cyclodextrin (MßCD) has been shown to reduce dopamine (DA) uptake and release mediated by the DAT. This is of particular interest because a few widely prescribed statins that lower peripheral cholesterol levels are blood-brain barrier (BBB) penetrants, and therefore could alter DAT function through brain cholesterol modulation. The goal of this study was to investigate the effects of prolonged atorvastatin treatment (24 h) on DAT function in neuroblastoma 2A cells stably expressing DAT. We found that atorvastatin treatment effectively lowered membrane cholesterol content in a concentration-dependent manner. Moreover, atorvastatin treatment markedly reduced DA uptake and abolished cocaine inhibition of DA uptake, independent of surface DAT levels. These deficits induced by atorvastatin treatment were reversed by cholesterol replenishment. However, atorvastatin treatment did not change amphetamine (AMPH)-induced DA efflux. This is in contrast to a small but significant reduction in DA efflux induced by acute depletion of membrane cholesterol using MßCD. This discrepancy may involve differential changes in membrane lipid composition resulting from chronic and acute cholesterol depletion. Our data suggest that the outward-facing conformation of DAT, which favors the binding of DAT blockers such as cocaine, is more sensitive to atorvastatin-induced cholesterol depletion than the inward-facing conformation, which favors the binding of DAT substrates such as AMPH. Our study on statin-DAT interactions may have clinical implications in our understanding of neurological side effects associated with chronic use of BBB penetrant statins.

The toll of transition: Caregiver perceptions of family adjustment during the transition off pediatric cancer therapy.

OBJECTIVE: The role of transition-focused psychology appointments in managing the transition off therapy is unclear. The objective of this research was to explore caregiver perceived familial distress and the role of psychology in preparing families for transition. METHODS: Fifty-seven caregivers of youth, who finished treatment, completed an online questionnaire through a quality improvement project on experiences of families at transition. Twenty-two percent of caregivers had children who completed a transition-focused psychology consult and 63% completed a cognitive assessment at transition. Retrospective analyses were conducted assessing the association of psychology visits on caregiver perceptions of being informed of and prepared to manage transition-related challenges. RESULTS: Most caregivers reported experiencing adjustment concerns for family members. Caregivers of children completing a transition-focused psychology consult or cognitive assessment reported feeling more informed and greater preparedness to manage difficulties. Although decreased distress was not associated with the visit, those who felt more informed and prepared reported lower distress. CONCLUSIONS: Caregivers perceive transitioning off therapy as stressful for their family, though they experience decreased familial distress when informed of and prepared to manage transition-related challenges. These findings highlight the importance of psychosocial support at transition.

Family and parent-child relationship correlates of pediatric cancer survivors' substance use.

OBJECTIVE: The primary aims of this research were to examine substance use among adolescent and young adult survivors of pediatric cancer (AYA survivors) and AYA without a history of chronic or life threatening illness (AYA comparisons) and to explore links between demographic, medical, caregiver-AYA, and family system factors with AYA substance use patterns. METHODS: Participants included 289 AYA (survivors, n = 171; comparisons = 118; 51% female; Mage = 17.15, SDage = 2.86) and their caregivers (Mage = 46.54, SDage = 6.81; 88% mothers). AYA and caregivers completed the family environment scale, and caregivers completed the parenting relationship questionnaire at the initial assessment. Two years later, AYA completed an assessment of substance use. Chi-square and frequency analyses were used to compare differences in substance use among AYA survivors and comparisons. Multivariate analysis of variance was used to examine links between AYA substance use patterns with family and caregiver-AYA system level factors. RESULTS: Patterns of substance use did not differ between AYA survivors and comparisons. AYA survivors were more likely to report polysubstance use if caregivers endorsed problematic caregiver-AYA relationship patterns. Family functioning and caregiver relationship patterns did not predict AYA comparison substance use. CONCLUSION: AYA survivors were just as likely as AYA comparisons to engage in substance use, increasing their vulnerability to problematic health outcomes. Findings indicate that the role caregiver-AYA relationship patterns may have on youth at risk for substance use and potential mechanisms for future intervention.

Prolonged ethanol exposure modulates constitutive internalization and recycling of 5-HT1A receptors.

Alcohol exposure alters the signaling of the serotoninergic system, which is involved in alcohol consumption, reward, and dependence. In particular, dysregulation of serotonin receptor type 1A (5-HT1AR) is associated with alcohol intake and withdrawal-induced anxiety-like behavior in rodents. However, how ethanol regulates 5-HT1AR activity and cell surface availability remains elusive. Using neuroblastoma 2a cells stably expressing human 5-HT1ARs tagged with hemagglutinin at the N-terminus, we found that prolonged ethanol exposure (18 h) reduced the basal surface levels of 5-HT1ARs in a concentration-dependent manner. This reduction is attributed to both enhanced receptor internalization and attenuated receptor recycling. Moreover, constitutive 5-HT1AR internalization in ethanol naïve cells was blocked by concanavalin A (ConA) but not nystatin, suggesting clathrin-dependent 5-HT1AR internalization. In contrast, constitutive 5-HT1AR internalization in ethanol-treated cells was blocked by nystatin but not by ConA, indicating that constitutive 5-HT1AR internalization switched from a clathrin- to a caveolin-dependent pathway. Dynasore, an inhibitor of dynamin, blocked 5-HT1AR internalization in both vehicle- and ethanol-treated cells. Furthermore, ethanol exposure enhanced the activity of dynamin I via dephosphorylation and reduced myosin Va levels, which may contribute to increased internalization and reduced recycling of 5-HT1ARs, respectively. Our findings suggest that prolonged ethanol exposure not only alters the endocytic trafficking of 5-HT1ARs but also the mechanism by which constitutive 5-HT1AR internalization occurs.

Incomplete resection of necrotic bowel may increase mortality in infants with necrotizing enterocolitis.

BACKGROUND: Infants with advanced necrotizing enterocolitis (NEC) often need surgical resection of necrotic bowel. We hypothesized that incomplete resection of NEC lesions, signified by the detection of necrotic patches in margins of resected bowel loops, results in inferior clinical outcomes. METHODS: We reviewed the medical records of infants with surgical NEC in the past 15 years for demographic, clinical, and histopathological data. We also developed statistical models to predict mortality and hospital stay. RESULTS: Ninety infants with surgical NEC had a mean (±standard error) gestational age of 27.3 ± 0.4 weeks, birth weight 1008 ± 48 g, NEC onset at 25.2 ± 2.4 days, and resected bowel length of 29.2 ± 3.2 cm. Seventeen (18.9%) infants who had complete resection of the necrosed bowel had fewer (4; 23.5%) deaths and shorter lengths of hospital stay. In contrast, a group of 73 infants with some necrosis within the margins of resected bowel had significantly more (34; 46.6%) deaths and longer hospital stay. The combination of clinical and histopathological data gave better regression models for mortality and hospital stay. CONCLUSION: In surgical NEC, incomplete resection of necrotic bowel increased mortality and the duration of hospitalization. Regression models combining clinical and histopathological data were more accurate for mortality and the length of hospital stay. IMPACT: In infants with surgical NEC, complete resection of necrotic bowel reduced mortality and hospital stay. Regression models combining clinical and histopathological information were superior at predicting mortality and hospital stay than simpler models focusing on either of these two sets of data alone. Prediction of mortality improved with the combination of antenatal steroids, chorioamnionitis, and duration of post-operative ileus, with severity of inflammation and hemorrhages in resected intestine. Length of hospital stay was shorter in infants with higher gestational ages, but longer in those with greater depth of necrosis or needing prolonged parenteral nutrition or supervised feedings.

Umbilical Cord Teratomas Associated With Congenital Malformations.

CONTEXT.­: Congenital mature teratomas of the umbilical cord are extremely rare and pose a challenge in prenatal diagnosis. Mature teratomas are defined as tumors composed of mature tissues derived from more than 1 germ cell layer. The tumor often shows solid and cystic components, which adds to the difficulty of prenatal diagnosis. Although benign, mature teratomas of the umbilical cord are commonly associated with congenital malformations of the fetus with variable severity and rarely, with chromosomal abnormalities. OBJECTIVE.­: To review the clinical, radiologic, gross, and histologic features of umbilical cord teratoma; its differential diagnosis; and to emphasize the increased risk of associated congenital malformations. DATA SOURCES.­: Umbilical cord teratoma cases published in the literature. CONCLUSIONS.­: Umbilical cord teratomas are difficult to diagnose by imaging studies alone and require histopathologic examination for diagnosis. Given the increased risk of associated anomalies and malformations, the finding of umbilical cord teratoma should trigger a detailed and comprehensive evaluation of the neonate for additional abnormalities.

Stromal cell extracellular vesicular cargo mediated regulation of breast cancer cell metastasis via ubiquitin conjugating enzyme E2 N pathway.

Mesenchymal stromal cells (hMSCs) have been used to understand the stromal cell properties in solid tumors because of their ablity to differentiate into most cell types. We investigated the role of EVs from hMSCs (hMSC-EVs) in breast cancer metastasis using MDA-MB-231 parental cell line and organotropic sub-lines. We demonstrated that hMSC-EVs significantly suppressed the metastatic potential of the parental cell line when compared to their organotropic sublines. hMSC-EVs induce dormancy in the parental cell line but not in their organotropic sub-lines and miR-205 and miR-31 from EV cargo played a role. Further, Ubiquitin Conjugating Enzyme E2 N (UBE2N/Ubc13) - metastasis-regulating gene, is a target of these miRNAs and silencing of UBE2N/Ubc13 expression significantly suppressed migration, invasion, and proliferation of breast cancer cells. To summarize, hMSC-EVs support primary breast tumor progression but suppress the metastasis of breast cancer cells that are not organ-committed through the UBE2N/Ubc13 pathway and play a role in premetastic niche formation.

Fibrolamellar hepatocellular carcinoma in ascitic fluid: A case report with cytohistological correlation.

The fibrolamellar variant of hepatocellular carcinoma (FL-HCC) is distinguished from other hepatocellular carcinoma's (HCC) by its unique clinical and pathological features. Cytological features of this tumor on fine needle aspiration have been described earlier. We report a rare case of a 17-year-old African American male with metastatic FL-HCC, diagnosed by body fluid cytology. The patient presented with ascites and computed tomography (CT) scan revealed multiple omental masses and liver lesions. The fluid sample was obtained along with the omental biopsy and was found positive for metastatic fibrolamellar hepatocellular carcinoma. The fluid cytology showed atypical polygonal cells with enlarged nuclei, prominent nucleoli, and abundant granular cytoplasm. Cytomorphologic features of FL-HCC presenting in body fluids have been rarely described before. This case enriches the cytopathology literature by providing awareness of this tumor presenting as metastasis in body fluids, especially in young individuals with liver lesions. Presence of a concurrent biopsy specimen provided cytohistological correlation, as it remains the gold standard for the accuracy and reliability of cytological diagnoses. Diagn. Cytopathol. 2016;44:757-760. © 2016 Wiley Periodicals, Inc.

Xanthogranulomatous Adrenalitis: A Case Report of a Diabetic, 55-Year-Old Male.

We report a rare case of xanthogranulomatous adrenalitis in a 55-year-old man. The patient presented to the hospital with fever, nausea, and right flank pain. His medical history was significant for diabetes and an adrenal mass that was detected 6 years prior to presentation during a computed tomography (CT) scan for trauma secondary to a motor vehicle collision. The mass was thought to be a myelolipoma. Magnetic resonance imaging (MRI) revealed a 12-cm right adrenal mass that was considered suspicious for carcinoma, which was surgically excised and cultured intraoperatively. The cultures subsequently grew methicillin-resistant Staphylococcus aureus (MRSA). Grossly, the adrenal mass was an encapsulated, necrotic lesion with surrounding areas of fat necrosis. On histologic examination, the tissue showed sheets of histiocytes, lymphocytes, and plasma cells diffusely involving the adrenal gland along with bright yellow lipofuscin crystals in a background of necrosis and fibrosis.

Pleural-based neuroblastoma-like schwannoma: a case report with cytologic findings and review of literature.

We report a rare case of a 45-year-old African American woman with Neuroblastoma-like Schwannoma (Neurilemmoma) occurring in the posterior mediastinum as a pleural-based mass noted on computed tomography (CT) scan. A CT-guided core biopsy of the mass was performed and core biopsy imprints were prepared during the procedure. A Diff-Quik stain was performed for on-site evaluation of specimen adequacy. The hematoxylin and eosin (H&E) staining was evaluated subsequently. Immunohistochemistry panels were applied to the same specimen. The cytologic findings of the core biopsy imprints showed hypercellular smears with a predominance of small cells with atypical features including hyperchromatic, round nuclei and occasional nucleoli. Neurocytic rosettes were particularly appreciated on H&E stain. The immunohistochemical results exhibited strong and diffuse immunoreactivity for S-100 and vimentin. This case enriches the cytopathology literature by providing awareness of this tumor presenting as a posterior mediastinal mass.

Extracellular vesicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA, proteins, and metabolites.

Human mesenchymal stem/stromal cells (hMSCs) have been shown to support breast cancer cell proliferation and metastasis, partly through their secretome. hMSCs have a remarkable ability to survive for long periods under stress, and their secretome is tumor supportive. In this study, we have characterized the cargo of extracellular vesicular (EV) fraction (that is in the size range of 40-150nm) of serum deprived hMSCs (SD-MSCs). Next Generation Sequencing assays were used to identify small RNA secreted in the EVs, which indicated presence of tumor supportive miRNA. Further assays demonstrated the role of miRNA-21 and 34a as tumor supportive miRNAs. Next, proteomic assays revealed the presence of ≈150 different proteins, most of which are known tumor supportive factors such as PDGFR-ß, TIMP-1, and TIMP-2. Lipidomic assays verified presence of bioactive lipids such as sphingomyelin. Furthermore, metabolite assays identified the presence of lactic acid and glutamic acid in EVs. The co-injection xenograft assays using MCF-7 breast cancer cells demonstrated the tumor supportive function of these EVs. To our knowledge this is the first comprehensive -omics based study that characterized the complex cargo of extracellular vesicles secreted by hMSCs and their role in supporting breast cancers.

Current status of the epidemiologic evidence linking polychlorinated biphenyls and non-hodgkin lymphoma, and the role of immune dysregulation.

BACKGROUND: Although case-control studies conducted to date have largely affirmed the relationship between polychlorinated biphenyls (PCBs) and non-Hodgkin lymphoma (NHL), occupational cohort studies of PCB-exposed workers have been generally interpreted as negative, thereby raising doubts about a potential causal association. A common theme of immune dysregulation unifies many of NHL's strongest risk factors, and several authors have posited that subclinical immune dysregulation may increase NHL risk by decreasing host resistance, reducing control of cellular proliferation and differentiation, and diminishing tumor surveillance mechanisms. OBJECTIVES: The goals of this review were a) to evaluate the epidemiological research examining the association between PCB exposure and NHL and discuss the contribution to the weight of evidence of case-control studies and occupational cohort studies; and b) to summarize the evidence for immune dysregulation as a means by which PCBs may cause NHL. METHODS: We performed a literature search using PubMed and seven additional online biomedical and toxicological referencing libraries to identify literature published through August 2011. DISCUSSION AND CONCLUSIONS: Overall, we conclude that the weight of evidence supports a causal role of PCBs in lymphomagenesis. The strongest epidemiological evidence for the relationship between PCBs and NHL comes from case-control studies conducted among the general population. Epidemiological and toxicological data demonstrating immunosuppressive and inflammatory effects of PCBs further contribute to the weight of evidence by providing a plausible explanation for how PCBs can cause NHL through immune dysregulation.

Real-time dynamic imaging of virus distribution in vivo.

The distribution of viruses and gene therapy vectors is difficult to assess in a living organism. For instance, trafficking in murine models can usually only be assessed after sacrificing the animal for tissue sectioning or extraction. These assays are laborious requiring whole animal sectioning to ascertain tissue localization. They also obviate the ability to perform longitudinal or kinetic studies in one animal. To track viruses after systemic infection, we have labeled adenoviruses with a near-infrared (NIR) fluorophore and imaged these after intravenous injection in mice. Imaging was able to track and quantitate virus particles entering the jugular vein simultaneous with injection, appearing in the heart within 500 milliseconds, distributing in the bloodstream and throughout the animal within 7 seconds, and that the bulk of virus distribution was essentially complete within 3 minutes. These data provide the first in vivo real-time tracking of the rapid initial events of systemic virus infection.

Human Lymphatic Architecture and Dynamic Transport Imaged Using Near-infrared Fluorescence.

BACKGROUND: Although the importance of lymphatic function is well recognized, the lack of real-time imaging modalities limits our understanding of its role in many diseases. In a phase 0 exploratory study, we used dynamic, near-infrared (NIR) fluorescence imaging to assess the extremes of lymphatic architecture and transport in healthy human subjects and in subjects clinically diagnosed with unilateral lymphedema (LE), a disease that can be prevalent in cancer survivors. METHODS AND RESULTS: Active lymphatic propulsion was imaged after intradermal injections of 25 µg of indocyanine green (total maximum dose ≤400 µg) bilaterally in the arms or legs of control and subjects. Images show well-defined lymphatic structures with propulsive dye transport in limbs of healthy subjects. In LE subjects, we observed extravascular dye accumulation, networks of fluorescent lymphatic capillaries, and/or tortuous lymphatic vessels in all symptomatic and some asymptomatic limbs. Statistical models indicate that disease status and/or limb significantly affect parameters of apparent lymph propagation velocity and contractile frequency. CONCLUSIONS: These clinical research studies demonstrate the potential of NIR fluorescence imaging as a diagnostic measure of functional lymphatics and as a new tool in translational research studies to decipher the role of the lymphatic system in cancer and other diseases.

Direct evidence of lymphatic function improvement after advanced pneumatic compression device treatment of lymphedema.

Lymphedema affects up to 50% of all breast cancer survivors. Management with pneumatic compression devices (PCDs) is controversial, owing to the lack of methods to directly assess benefit. This pilot study employed an investigational, near-infrared (NIR) fluorescence imaging technique to evaluate lymphatic response to PCD therapy in normal control and breast cancer-related lymphedema (BCRL) subjects. Lymphatic propulsion rate, apparent lymph velocity, and lymphatic vessel recruitment were measured before, during, and after advanced PCD therapy. Lymphatic function improved in all control subjects and all asymptomatic arms of BCRL subjects. Lymphatic function improved in 4 of 6 BCRL affected arms, improvement defined as proximal movement of dye after therapy. NIR fluorescence lymphatic imaging may be useful to directly evaluate lymphatic response to therapy. These results suggest that PCDs can stimulate lymphatic function and may be an effective method to manage BCRL, warranting future clinical trials.

Near-Infrared Fluorescence Imaging in Humans with Indocyanine Green: A Review and Update.

Near-infrared (NIR) fluorescence imaging clinical studies have been reported in the literature with six different devices that employ various doses of indocyanine green (ICG) as a non-specific contrast agent. To date, clinical applications range from (i) angiography, intraoperative assessment of vessel patency, and tumor/metastasis delineation following intravenous administration of ICG, and (ii) imaging lymphatic architecture and function following subcutaneous and intradermal ICG administration. In the latter case, NIR fluorescence imaging may enable new discoveries associated with lymphatic function due to (i) a unique niche that is not met by any other conventional imaging technology and (ii) its exquisite sensitivity enabling high spatial and temporal resolution. Herein, we (i) review the basics of clinical NIR fluorescence imaging, (ii) survey the literature on clinical application of investigational devices using ICG fluorescent contrast, (iii) provide an update of non-invasive dynamic lymphatic imaging conducted with our FDPM device, and finally, (iv) comment on the future NIR fluorescence imaging for non-invasive and intraoperative use given recent demonstrations showing capabilities for imaging following microdose administration of contrast agent.

New horizons for imaging lymphatic function.

In this review, we provide a comprehensive summary of noninvasive imaging modalities used clinically for the diagnosis of lymphatic diseases, new imaging agents for assessing lymphatic architecture and cancer status of lymph nodes, and emerging near-infrared (NIR) fluorescent optical imaging technologies and agents for functional lymphatic imaging. Given the promise of NIR optical imaging, we provide example results of functional lymphatic imaging in mice, swine, and humans, showing the ability of this technology to quantify lymph velocity and frequencies of propulsion resulting from the contractility of lymphatic structures.

Imaging of lymph flow in breast cancer patients after microdose administration of a near-infrared fluorophore: feasibility study.

PURPOSE: To prospectively demonstrate the feasibility of using indocyanine green, a near-infrared (NIR) fluorophore at the minimum dose needed for noninvasive optical imaging of lymph nodes (LNs) in breast cancer patients undergoing sentinel lymph node mapping (SLNM). MATERIALS AND METHODS: Informed consent was obtained from 24 women (age range, 30-85 years) who received intradermal subcutaneous injections of 0.31-100 microg indocyanine green in the breast in this IRB-approved, HIPAA-compliant, dose escalation study to find the minimum microdose for imaging. The breast, axilla, and sternum were illuminated with NIR light and the fluorescence generated in the tissue was collected with an NIR-sensitive intensified charged-coupled device. Lymphoscintigraphy was also performed. Resected LNs were evaluated for the presence of radioactivity, blue dye accumulation, and fluorescence. The associations between the resected LNs that were fluorescent and (a) the time elapsed between NIR fluorophore administration and resection and (b) the dosage of NIR fluorophores were tested with the Spearman rank and Pearson product moment correlation tests, respectively. RESULTS: Lymph imaging consistently failed with indocyanine green microdosages between 0.31 and 0.77 microg. When indocyanine green dosages were 10 microg or higher, lymph drainage pathways from the injection site to LNs were imaged in eight of nine women; lymph propulsion was observed in seven of those eight. When propulsion in the breast and axilla regions was present, the mean apparent velocities ranged from 0.08 to 0.32 cm/sec, the time elapsed between "packets" of propelled fluid varied from 14 to 92 seconds. In patients who received 10 microg of indocyanine green or more, a weak negative correlation between the fluorescence status of resected LNs and the time between NIR fluorophore administration and LN resection was found. No statistical association was found between the fluorescence status of resected LNs and the dose of NIR fluorophore. CONCLUSION: NIR fluorescence imaging of lymph function and LNs is feasible in humans at microdoses that would be needed for future molecular imaging of cancer-positive LNs.