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Three main patterns of T cell receptor (TCR) expression are identified in peripheral T cell lymphoma (PTCL): TCR-αβ type, TCR-γδ type, and TCR silent type. Cases of PTCL that express both αβ and γδ receptors are rare. Here, we report a case of PTCL-NOS (not otherwise specified) with dual αβ and γδ expression in a 61-year-old female 6 years after orthotopic cardiac transplant. The patient presented with fatigue, fever, worsening anemia, and thrombocytopenia. A chest CT showed multiple irregular lung nodules and diffuse lymphadenopathy. Cytology evaluation of the lymph nodes revealed large atypical lymphocytes with immunopositivity for CD3, CD8, CD56, TIA1, and granzyme B and immunonegativity for CD5 and CD30. Epstein-Barr virus (EBV) was not detected by EBV-encoded RNA (EBER) in situ hybridization study. The corresponding flow cytometry demonstrated abnormal T cells with TCR-αβ and TCR-γδ expression and loss of CD5 expression. A TCR gene rearrangement study demonstrated the presence of a clonal lymphoid population with TCRβ and TCRγ rearrangements. The patient was deceased within 2 months despite aggressive treatment. The findings were consistent with an EBV-negative, monomorphic T cell post-transplant lymphoproliferative disorder (PTLD) with features of PTCL-NOS. A literature review of T cell lymphoma with co-expression of TCR-αβ and TCR-γδ was performed. A case of aggressive PTCL with dual expression of TCR-αβ and TCR-γδ in a post-transplant setting has not been previously reported.

Keratoconus (KC) is classically considered a non-inflammatory condition caused by central corneal thinning that leads to astigmatism and reduced visual acuity. Previous studies have identified increased systemic levels of pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α, and matrix metalloproteinase-9, suggesting that KC may have an inflammatory component in at least a subset of patients. In this study, we evaluated the levels of different immunoglobulins (light and heavy chains) based on Ig α, Ig λ, Ig κ, Ig µ, and Ig heavy chain subunits in non-KC tears (n = 7 control individuals) and KC tears (n = 7 KC patients) using tandem-liquid chromatography mass spectrometry. The most abundant Ig heavy chains detected in both control individuals and KC patients were Ig α-1 and Ig α-2 likely correlating to the higher IgA levels reported in human tears. We identified significant differences in immunoglobulin κ-chain V-II levels in KC patients compared to control individuals with no significant difference in Ig κ/Ig λ ratios or heavy chain levels. Our study supports previous findings suggesting that KC possesses a systemic component that may contribute to the KC pathology. Further studies are required to define causality and establish a role for systemic immune system-dependent factors and pro-inflammatory processes in KC development or progression.

We previously demonstrated that β6 knockout mice showed impaired wound repair in corneal debridement and keratectomy wounds. In the current investigation, we continued our examination of integrin αvβ6 in order to determine if it was required for the initiation of wound healing in a corneal wound model that normally heals in a fibrotic manner. A full-thickness corneal incision was made in C57BL/6J wild type (WT) and C57BL/6-Itgb6 KO (β6(−/−)) mice. The mice were observed at 3, 7, 14, and 28 days post-incision. The morphology of corneal restoration was observed in tissue sections stained with hemotoxilin and eosin (H&E). In addition, indirect-immunofluorescence (IF) was performed on sections and/or whole mounts to evaluate the immunolocalization of α-smooth muscle actin (SMA) and thrombospondin-1 (TSP-1). H&E staining revealed that the corneas in β6(−/−) mice healed slower than those in WT mice, with an obvious delay in the restoration of the stromal matrix and epithelium. In sections at 3 and 7 days, SMA and TSP-1 were greatly reduced in the β6(−/−) mice as compared to WT, but peaked at 28 days after incision. Whole mount SMA IF results were consistent with those from sections. Therefore, the initiation of fibrosis was inhibited by the lack of αvβ6; however, there appeared to be an alternate mechanism that initiated fibrosis 7-14 days later. Localization of TSP-1 correlated with expression of SMA whether wound healing was delayed or initiated immediately after wounding.

[Figure][1] A 66-year-old man with follicular lymphoma after multiple therapies presented with a retroperitoneal mass (panel A: fine needle aspirate, Diff-Quik stain, 1000× oil immersion; panels B-C: needle biopsy, hematoxylin and eosin (H&E) and Ki-67 stains, 500× oil immersion)

The abscopal effect is the response to radiation at sites that are distant from the irradiated site of an organism, and it is thought to play a role in bone marrow (BM) recovery by initiating responses in the unirradiated bone marrow. Understanding the mechanism of this effect has applications in treating BM failure (BMF) and BM transplantation (BMT), and improving survival of nuclear disaster victims. Here, we investigated the use of multimodality imaging as a translational tool to longitudinally assess bone marrow recovery. We used positron emission tomography/computed tomography (PET/CT), magnetic resonance imaging (MRI) and optical imaging to quantify bone marrow activity, vascular response and marrow repopulation in fully and partially irradiated rodent models. We further measured the effects of radiation on serum cytokine levels, hematopoietic cell counts and histology. PET/CT imaging revealed a radiation-induced increase in proliferation in the shielded bone marrow (SBM) compared to exposed bone marrow (EBM) and sham controls. T2-weighted MRI showed radiation-induced hemorrhaging in the EBM and unirradiated SBM. In the EBM and SBM groups, we found alterations in serum cytokine and hormone levels and in hematopoietic cell population proportions, and histological evidence of osteoblast activation at the bone marrow interface. Importantly, we generated a BMT mouse model using fluorescent-labeled bone marrow donor cells and performed fluorescent imaging to reveal the migration of bone marrow cells from shielded to radioablated sites. Our study validates the use of multimodality imaging to monitor bone marrow recovery and provides evidence for the abscopal response in promoting bone marrow recovery after irradiation.

Systemic polyclonal immunoblastic proliferation (SPIP) is a very rare, atypical expansion of plasma cells and lymphoblasts associated with an aggressive clinical presentation. The pathogenesis of SPIP is unknown and it is unclear whether these proliferations represent a clinicopathologic entity or rather a pattern of cellular proliferation. Some evidence of infection as an initiating event has been proposed. SPIP is often difficult to differentiate from other disorders, particularly in the context of an obscuring inflammatory response. Untreated or even treated cases can be fatal. The morphologic features are characterized by a pronounced proliferation of B immunoblasts and plasma cells that typically involve the blood, bone marrow, lymph nodes, spleen, thymus, liver, kidneys, thyroid, adrenal glands, and lungs. A subset of reported cases has responded well to treatment with corticosteroids alone or in combination with cytotoxic agents, showing complete remission and resolution of lymphadenopathy and normalization of peripheral blood findings. Here, we present a case of SPIP in a 58-year-old male with polyclonal plasmacytosis, hypergammaglobulinemia, diffuse lymphadenopathy, splenomegaly, and a diffuse maculopapular rash; SPIP with skin involvement is very unusual. Fortunately, our patient showed a striking response to steroids. This article provides a brief overview of the clinicopathologic features associated with this atypical lymphoplasmacytic proliferation and a review of the literature highlighting the differential diagnosis of lymphoplasmacytic disorders.

Corneal wound healing studies have a long history and rich literature that describes the data obtained over the past 70 years using many different species of animals and methods of injury. These studies have lead to reduced suffering and provided clues to treatments that are now helping patients live more productive lives. In spite of the progress made, further research is required since blindness and reduced quality of life due to corneal scarring still happens. The purpose of this review is to summarize what is known about different types of wound and animal models used to study corneal wound healing. The subject of corneal wound healing is broad and includes chemical and mechanical wound models. This review focuses on mechanical injury models involving debridement and keratectomy wounds to reflect the authors’ expertise.

BACKGROUND: A well-known complication of peripheral nerve block is peripheral nerve injury, whether from the needle or toxicity of the medication used. In this study, we sought to determine the extent of damage that results from intrafascicular injection of various commonly used local anesthetics (LAs). METHODS: Sixteen Lewis rats received an intrafascicular injection of saline (control) or 1 of 3 LAs (bupivacaine, lidocaine, or ropivacaine) into the sciatic nerve (n = 4). At a 2-week end point, the sciatic nerves were harvested for histomorphometric and electron microscopic analysis. RESULTS: Animals that received intrafascicular LA injections showed increased severity of injury as compared with control. In particular, there was a significant loss of large-diameter fibers as indicated by decreased counts (P < 0.01 for all LAs) and area (P < 0.01 for all LAs) of remaining fibers in severely injured versus noninjured areas of the nerve. There was a layering of severity of injury with most severely injured areas closest to and noninjured areas furthest from the injection site. Bupivacaine caused more damage to large fibers than the other 2 LAs. In all groups, fascicular transection injury from the needle was observed. Electron microscopy confirmed nerve injury. CONCLUSIONS: Frequently used LAs at traditional concentrations are toxic to and can injure the peripheral nerve. Any combination of motor and/or sensory sequelae may result due to the varying fascicular topography of a nerve. (Anesth Analg 2013;117:00–00)

Purpose To evaluate intraoperative findings and outcomes of revision carpal tunnel release (CTR) and to identify predictors of pain outcomes. Methods We performed a retrospective cohort study of all adult patients undergoing revision CTR between 2001 and 2012. Patients were classified according to whether they presented with persistent, recurrent, or new symptoms. We compared study groups by baseline characteristics, intraoperative findings, and outcomes (strength and pain). Within each group, we analyzed changes in postoperative pinch strength, grip strength, and pain from baseline. Predictors of postoperative average pain were examined using both multivariable linear regression analyses and univariable logistic regression to calculate odds ratios of worsened or no change in pain. Results We performed revision CTR in 97 extremities (87 patients). Symptoms were classified as persistent in 42 hands, recurrent in 19, and new in 36. The recurrent group demonstrated more diabetes and a longer interval from primary CTR, and was less likely to present with pain. Incomplete release of the flexor retinaculum and scarring of the median nerve were common intraoperative findings over all. Nerve injury was more common in the new group. Postoperative pinch strength, grip strength, and pain significantly improved from baseline in all groups, apart from strength measures in the recurrent group. Persistent symptoms and more than 1 prior CTR had higher odds of not changing or worsening postoperative pain. Higher preoperative pain, use of pain medication, and workers' compensation were significant predictors of higher postoperative average pain. Conclusions Carpal tunnel release may not always be entirely successful. Most patients improve after revision CTR, but a methodical approach to diagnosis and adherence to safe surgical principles are likely to improve outcomes. Symptom classification, number of prior CTRs, baseline pain, pain medications, and workers' compensation status are important predictors of pain outcomes in this population. Type of study/level of evidence Therapeutic III.

Corneal scarring is an obligatory consequence of stroma corneal injury and is a major cause of decreased visual quality and vision loss worldwide. There are currently no satisfactory intervention therapies for corneal fibrosis. In this chapter, we describe well-established in vivo corneal wound models to allow researchers to investigate epithelial and stromal responses to corneal injury.

Background: Baxter received reports of visible precipitate, identified as calcium carbonate, forming during hemofiltration with Accusol 35 solution. Aim: To evaluate the potential for acute cardiopulmonary adverse effects of Accusol 35 containing exaggerated calcium carbonate particles. Methods: Anesthetized dogs underwent continuous veno-venous hemofiltration (CVVH) with Accusol 35 containing visible and subvisible particles (≥10 µm) 36 times higher than the maximum concentration specified in the European Pharmacopoeia (P-Accusol), or Accusol 35 conforming to specification (Accusol). Select cardiovascular and blood gas parameters were evaluated during CVVH. Lung tissue samples were collected following CVVH. Results: No differences were observed in cardiovascular and blood gas parameters or lung histology between P-Accusol and Accusol. Conclusion: Accusol 35 containing visible and subvisible particles (≥10 µm) 36 times higher than the maximum concentration specified in the European Pharmacopoeia resulted in no acute cardiopulmonary adverse effects compared with Accusol 35 containing no visible particles and subvisible particles within European Pharmacopoeia specification.

The purpose of this study was to investigate which histological changes associated with risk factors could contribute to the progression from the initial atherosclerotic lesions including fatty streaks to the advanced lesions.We examined the associations of histomorphometric findings in the determined anatomical sites of mid-thoracic aortas (TAs) and left anterior descending coronary arteries (LADs) with major risk factors for atherosclerosis, using a young autopsied series from the the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. The histological classification by the American Heart Association was graded for 1013 TAs and 1009 LADs. Histometric study, including immunohistochemistry, was performed in type 2 lesions (fatty streaks) of TAs from 59 subjects and LADs from 45 ones.For the progression from the initial lesions into the advanced atherosclerotic lesions, the most effective lipid profiles were low plasma HDL-C in TA and elevated serum non-HDL-C in LAD. This lipid profile of each artery correlated with number or density of intimal smooth muscle cell-derived foam cells, respectively. The serum concentration of non-HDL-C correlated with macrophage foam cells in TAs. Hypertension and hyperglycemia were associated with increase of intimal area and/or collagen content in both arteries, but not with either types of foam cell proliferation. Smoking correlated with increased collagen content in TAs.There were histologically different ways of progressing from fatty streaks to advanced atherosclerotic lesions depending on the risk factors. For the atherosclerosis progression from type 2 lesions to advanced lesions, increase in number of smooth muscle cell-derived foam cells could be an important indicator.

Emergency physicians (EPs) are asked to evaluate and treat a growing population of hospice patients who present to the emergency department (ED) for a number of important reasons. Hospice patients pose unique ethical challenges, and "best practices" for these patients can differ from the life-preserving interventions of usual ED care. Having a solid understanding of professional responsibilities and ethical principles is useful for guiding EP management of these patients. In end-of-life care, EPs need to recognize that there are barriers and complexities to the best management of hospice patients, but they need to commit to strategies that optimize their care. This article describes the case of a hospice patient who presented with sepsis and end-stage cancer to the ED. Patient, system, and physician factors made management decisions in the ED difficult. The goal in the ED should be to determine the best way to address terminally ill patient needs while respecting wishes to limit interventions that will only increase suffering near the end of life.

To test the hypothesis that uvulopalatopharyngoplasty (UPPP) improves sleep apnea-related quality of life (measured on the Functional Outcomes of Sleep Questionnaire [FOSQ]) at 3-month follow-up. Secondary objectives were to test (1) the stability of the outcomes at 6 months, (2) the effect on global sleep apnea quality-of-life change, and (3) the effect on sleep apnea symptoms.Multicenter, prospective, longitudinal case series.Diverse university- and community-based otolaryngology practices.The cohort included 68 patients from 17 practices, with a mean ± standard deviation age of 44 ± 12 years and mean apnea-hypopnea index of 35 ± 32 events/hour. All patients underwent UPPP, defined as an open procedure modifying the shape and size of the palate, pharynx, and uvula, with or without tonsillectomy. Baseline data were collected on site before surgery, and outcome data were collected by mail 3 and 6 months after surgery, with follow-up rates of 51% and 50%, respectively.FOSQ scores improved from 14.3 ± 3.4 (scale 5-20, normal ≥17.9) at baseline to 17.2 ± 2.7 at 3 months (mean improvement 2.9; 95% confidence interval, 1.8-4.0; P.001) and 17.5 ± 2.5 at 6 months (mean improvement 3.1; 95% confidence interval, 2.0-4.2; P.001). All quality-of-life and symptom measures improved significantly at 3 and 6 months (all P.05).This prospective, multicenter, university- and community-based study provides evidence that UPPP significantly improves disease-specific quality of life and sleep apnea symptoms in patients with sleep apnea. Validity may be limited by significant loss to follow-up and absence of an unoperated control group.

To evaluate the effect of age and other risk factors for atherosclerosis on arterial blood velocity, carotid arteries in 179 healthy individuals ranging from 21 to 102 years old were examined using color Doppler ultrasonography. Velocity in common and internal carotid arteries decreased consecutively from young adults to very elderly people except for peak internal carotid artery velocity. Peak common carotid artery velocity in the elderly (≥ 65 years old) people was inversely associated with age and diastolic blood pressure and directly associated with pulse pressure. Minimum velocity of common carotid artery was inversely correlated with age and diastolic blood pressure in the elderly people. In elderly group, peak internal carotid artery velocity correlated only with serum high-density lipoprotein cholesterol. Minimum internal carotid artery velocity correlated inversely with systolic blood pressure in adults and diastolic blood pressure in elderly people. Blood velocity in the very elderly population approaches the critical level for thrombogenesis.

Objective The literature supports a negative D-dimer (−DD) excluding venous thromboembolic disease (VTE) in low-risk patients. We determined the radiologic diagnoses in patients where imaging was ordered despite a −DD. Methods This is a retrospective chart review of patients with a −DD (Tinaquant; Roche Diagnostics, Mannheim, Germany) and a radiologic study within 48 hours, sought to determine radiologic diagnosis (primary outcome), treatment of VTE, and consensus diagnosis of acute VTE. Results Among 3462 DD tests, 1678 met the inclusion criteria. Of 1362 patients with DD values of 350 ng/mL or less, 166 (12.2%) had radiologic studies: 93.4% of the final radiologic diagnoses were negative for VTE, 3.6% were indeterminate, and 3.0% (1.0%-6.9%) were positive; 1.8% ultimately had a consensus diagnosis of acute VTE. In 316 patients with DD values between 351 and 500 ng/mL, 88 (27.8%) had radiologic studies: 95.5% were negative, 1.1% were indeterminate, and 3.4% (0.7%-9.6%) were positive. Conclusions Of patients who receive radiologic studies despite −DD tests, 3.0% have positive radiologic diagnoses for acute VTE; only 1.8% had acute VTE after the review of their hospital course.

Background A 73-year-old woman presented with acute lower back pain, fever, chills and arthralgias. She had previously had a positive protein derivative test with a negative chest X-ray; her medical history was also remarkable for a mitral valve prolapse. Initial symptoms resolved spontaneously without therapy, but fever recurred with associated arthralgias, myalgias, diffuse and worsening lymphadenopathy, splenomegaly, and bilateral pulmonary infiltrates. Investigations Physical examination, blood and urine cultures, MRI of the spine, echocardiogram, extensive serologies, serum and urine protein electrophoresis, immunofixation electrophoresis, bone-marrow aspiration and biopsy with flow cytometry, cytogenetics, and gene rearrangement studies, CT scan of the chest, abdomen and pelvis, whole-body PET, and lymph-node biopsy for histological examination, immunohistochemistry, and gene rearrangement studies. Diagnosis Angioimmunoblastic T-cell lymphoma. Management Steroids (prednisone, methylprednisolone), levofloxacin, isoniazid with pyridoxine, ciclosporin A, methotrexate, alemtuzumab, broad-spectrum antibiotics, Pneumocystis carinii prophylaxis, vancomycin, and clindamycin.

Smoking is linked to atherosclerosis and coronary heart disease (CHD) in older adults. However, evidence that smoking affects coronary atherosclerosis in young people is incomplete. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study collected arteries, blood, and other tissues from persons 15 to 34 years of age dying of external causes and autopsied in forensic laboratories. Lesions in the proximal left anterior descending coronary arteries (LAD) from 1127 subjects were graded microscopically according to the American Heart Association criteria. Among individuals with advanced lesions (Grade 4 or 5), smokers had a greater prevalence of Grade 5 lesions than non-smokers (odds ratio 9.61, 95% confidence interval 2.34-39.57), a difference suggesting that smoking accelerates the transition from Grade 4 to Grade 5 lesions. This association occurred among both men and women, and among persons with and without other CHD risk factors. The difference in qualities of advanced lesions suggests that smoking possibly accelerates the transition from Grade 4 to Grade 5 lesions by promoting thrombosis and accretion on the intimal surface of the plaque.

We report on the results of a large autopsy study focusing upon the hypothesis that deletion of the Alu insert in the angiotensin converting enzyme (ACE) gene is associated with: (a) greater prevalence or extent of atherosclerosis in the aorta and coronary arteries; and (b) microscopic qualities of established atherosclerotic plaques in the coronary arteries. This study was conducted in young US black ( n =290) and white ( n =379) males using available materials and data from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, a multi-center cooperative autopsy study organized in 1985 to explore the relationships of known cardiovascular risk factors to atherosclerosis in victims of accidents, homicides, or suicides in the age range of 15–34 years. The results provide strong evidence that ACE genotype may not be a predictor of either the prevalence or the extent of the lesions of atherosclerosis in the right coronary artery or the aorta of young adults, an observation that confirms previous studies that estimated the prevalence and extent of atherosclerosis using coronary angiography. In addition, the results suggest that ACE genotype does not contribute to the formation of atherosclerotic lesions that have the characteristics of vulnerable plaques in the left anterior descending coronary artery of young adults.

Introduction— Modest elevations of total homocysteine have been associated with increased risk for coronary atherosclerosis but correlation between elevated homocysteine and plaque morphology has not been described in humans. Methods— We determined serum homocysteine at postmortem from 87 men with coronary thrombus (62 of whom were diagnosed as acute), from 35 men with severe coronary disease without thrombus, and from 46 controls. In coronary deaths, atherosclerotic plaques at the sites of maximal luminal narrowing of the four epicardial coronary arteries were classified as fibrous plaques, fibrous cap atheromas, thin-cap atheromas, and healed ruptures, and macrophage infiltration was assessed semiquantitatively. Results— Median serum homocysteine postmortem as a result of acute thrombus was 10.4 μmol/L ( P =0.4 versus controls), 12.1 μmol/L in men with organized thrombi ( P =0.1 versus controls), 15.6 μmol/L in men without thrombus ( P =0.007 versus controls), and 9.8 μmol/L in controls. The median homocysteine was 12.1 μmol/L in 65 men with healed infarcts ( P =0.03 versus controls). The number of fibrous plaques was associated with log-normalized homocysteine ( P =0.004), independent of age, albumin, smoking, hypertension, and serum cholesterol. Homocysteine levels in the upper tertile (>15 μmol/L) were associated with sudden death without acute or organized thrombus (odds ratio 3.8, P =0.03) independent of age and other risk factors; the coexistence of diabetes increased the association (odds ratio 25.1, P =0.009, versus lowest tertile ≤8.5 μmol/L). Conclusions— Increased serum homocysteine is associated with sudden death in the absence of acute coronary thrombosis, especially with concomitant diabetes, and with the presence of lipid-poor, fibrous plaques.

Background — Blacks have a high rate of sudden coronary death (SCD). We determined the rate of SCD in men and women 30 to 69 years of age in a 6-year period recorded at a state Medical Examiner’s Office. Methods and Results — In a subset of 327 whites and 130 blacks, hearts were systematically studied to determine the extent of coronary disease, presence and type of thrombus (acute rupture, acute erosion, stable plaque), and heart weight. These parameters were correlated with the presence of conventional risk factors. The estimated rate of SCD in blacks was similar to that in whites under the age of 40 years but increased compared with whites with advancing age, becoming 1.5 times the rate for whites in the 7th decade (95% of the increase in the 6th decade was due to sudden death with stable plaque). Among the autopsied group with severe coronary atherosclerosis, HDL cholesterol was higher and hypertension more prevalent in blacks, but there was no difference in the prevalence of healed infarcts, plaque burden, heart weight, acute thrombi, or rates of diabetes, cigarette smoking, and total cholesterol. Conclusions — When compared with a control autopsy group of 568 deaths, multivariate analysis showed a significant association in blacks between stable plaque and left ventricular hypertrophy (risk ratio, 7.6), type 1 diabetes (risk ratio, 3.6), hypertension (risk ratio, 3.5), elevated total cholesterol (risk ratio, 3.1) and type 2 diabetes (risk ratio, 2.9). Because these risk factors are associated with SCD in blacks, they may be important targets for reducing the disparately high rate of SCD in blacks as compared with whites.

PURPOSE To characterize extracellular matrix (ECM) and nine matrix metalloproteinase (MMP) changes in two corneas that underwent a complicated laser-assisted in situ keratomileusis (LASIK) procedure. METHODS The first patient underwent bilateral LASIK. The flap on the left eye was transected in several locations and placed back. This cornea later developed edema, and the removed flap was analyzed after lamellar keratoplasty. The second patient had a LASIK flap lifted, replaced twice, and then completely removed. The epithelium grew over the stroma, but haze and severe ectasia occurred. After penetrating keratoplasty, the recipient cornea was analyzed. An autopsy cornea from a person who underwent uneventful LASIK and ten normal autopsy corneas served as controls. Corneas were analyzed by immunohistochemistry. RESULTS Both flap regions in the treated corneas had marked alterations of ECM components and MMPs. Stromal deposits of various ECM proteins, including those normally absent in the central cornea (tenascin-C, fibrillin-1, type XIV collagen), were found. Rare myofibroblasts and inflammatory cells were present. The epithelial basement membrane (BM) was altered in both cases. The most dramatic change was poor or no staining for alpha3-alpha6 type IV collagen chains and thrombospondin. The limbal alpha1-alpha2 type IV collagen and laminin-2 (alpha2beta1gamma1) appeared in the central epithelial BM. Other components were altered to a lesser extent. The anterior stroma was positive for MMP-1 and MMP-2, and some MMP-7 was seen in the epithelium. These ECM and MMP patterns were not seen in uneventful LASIK or normal corneas. CONCLUSIONS In the flaps of LASIK-treated corneas, fibrosed areas of anterior stroma had increased levels of MMP-1 and MMP-2 that may have caused loss of specific type IV collagen isoforms in the epithelial BM. These changes may reflect an ongoing wound healing process and contribute to the development of ectasia.

Atherosclerotic plaque-like lesions are prevalent in synthetic arteriovenous shunts created to provide vascular access for hemodialysis. Similarities to atherosclerotic plaques in native arteries include eccentric location, immunoreactivity for smooth muscle actin, dystrophic calcifications, superimposed thrombi, and foam cells. Fatty streaks were not grossly identified on Sudan IV staining. Because of the similarities to atherosclerosis in native vessels, these findings may have several implications for atherogenesis. The development of raised, fibrous lesions does not require decades. The presence of smooth muscle in atherosclerotic plaque-like lesions does not require a source from tunica media. A precursor fatty streak may not be required for the development of raised, fibrous lesions. Finally, development of atherosclerotic plaque-like lesions does not require putative inflammatory effects from cholesterol or LDL accumulation, or even a native vessel that can respond to injury. The atherosclerotic plaque-like lesions in this study probably developed from organization of mural thrombi.

Introduction Amyloid β-protein oligomers play a key role in Alzheimer’s disease (AD), but well-validated assays that routinely detect them in cerebrospinal fluid (CSF) are just emerging. We sought to confirm and extend a recent study using the Singulex Erenna platform that reported increased mean CSF oligomer levels in AD. Methods We tested four antibody pairs and chose one pair that was particularly sensitive, using 1C22, our new oligomer-selective monoclonal antibody, for capture. We applied this new assay to extracts of human brain and CSF. Results A combination of 1C22 for capture and 3D6 for detection yielded an Erenna immunoassay with a lower limit of quantification of approximately 0.15 pg/ml that was highly selective for oligomers over monomers and detected a wide size-range of oligomers. Most CSFs we tested had detectable oligomer levels but with a large overlap between AD and controls and a trend for higher mean levels in mild cognitive impairment (MCI) than controls. Conclusion Aβ oligomers are detectable in most human CSFs, but AD and controls overlap. MCI CSFs may have a modest elevation in mean value by this assay. Electronic supplementary material The online version of this article (doi:10.1186/s13195-015-0100-y) contains supplementary material, which is available to authorized users.

Context.—Body fluids submitted to the hematology laboratory for cell counts may also be examined for the presence of malignancy. Previous studies evaluating the hematology laboratory's performance at detecting malignancy in body fluids have reached conflicting conclusions. Objective.—To investigate the hematology laboratory's ability to detect malignancy in body fluids by comparison with cytology. Design.—Retrospective analysis of 414 body fluid samples during an 18-month period, with introduction of new quality assurance measures after the first 210 cases. If no concurrent cytology was ordered, results were compared with recent previous and/or subsequent cytologic, histologic, or flow cytometric diagnoses. Results.—Of the initial 210 cases, the hematology laboratory detected 3 of 13 malignancies diagnosed by concurrent cytology (23% sensitivity), with no false-positives (100% specificity). Malignancy was not identified on retrospective review of the hematology slides in the 10 discrepant cases. After the initial study, educational sessions on morphology for the medical technologists and a more thorough hematology-cytology correlation policy were implemented. The subsequent 204 hematology laboratory cases had increased sensitivity for the detection of malignancy (60%; 6 of 10). Definitive features of malignancy were seen in only one discrepant hematology laboratory slide on retrospective review. This case had not been flagged for hematopathologist review. None of the discrepancies before or after implementation of the additional quality assurance measures impacted patient care. Conclusions.—Body fluid processing by the hematology laboratory is not optimized for the detection of malignancy. Concurrent cytologic examination is critical for the detection of malignancy, and needs to be considered as cost-saving measures are increasingly implemented.

Over the years, most researchers have approached corneal epithelial and stromal wound healing as separate events. However, it is becoming increasingly clear that even the simplest epithelial debridement wound results in keratocyte death and a subsequent stromal response to regenerate the affected area. Thus, the interaction between stromal and epithelial healing must be considered to fully understand corneal wound healing. Although wound healing has been an active area of research for many years, the advent of refractive surgery has stimulated research into the regulation of wound repair and provided important insights into the molecular components involved in repair. Epithelial and stromal wound healing are influenced by extracellular matrix components. The purpose of the current article is to review progress in the year 2000 toward understanding mechanisms involved in corneal wound healing and how extracellular matrix affects the healing processes.

Background: Midsubstance tears of the anterior cruciate ligament in skeletally immature patients are increasingly common and are a challenging problem. The results of nonoperative treatment are no better in children than they are in adults. Physeal-sparing reconstructive procedures have yielded poor results. Reconstructive procedures that are utilized in adults violate the physis, potentially resulting in growth abnormalities. The objective of this study was to provide a model for reconstruction of the anterior cruciate ligament in skeletally immature patients by evaluating the effects of a tensioned connective-tissue graft placed across the canine physis. Methods: Twelve ten-week-old beagles underwent reconstruction of the anterior cruciate ligament consisting of placement of fascia lata autograft through drill-holes across the femoral and tibial physes, tensioning of the graft to 80 N, and fixing it with screws and washers. The contralateral limb served as a control. One dog was eliminated from the study secondary to a postoperative infection. Four months postoperatively, the dogs were killed and were inspected grossly, radiographically, and histologically for any evidence of growth disturbance. Results: Significant valgus deformity of the distal part of the femur (p < 0.001) and significant varus deformity of the proximal part of the tibia (p = 0.03) developed in the treated limbs. Neither radiographic nor histologic examination demonstrated any evidence of physeal bar formation. Conclusions: Significant growth disturbances occur with excessively tensioned transphyseal reconstruction of the anterior cruciate ligament in the canine model. These growth disturbances occur without radiographic or histologic evidence of physeal bar formation. Clinical Relevance: This study illustrates the risk to the physis associated with transphyseal reconstruction of the anterior cruciate ligament with the use of a tensioned connective-tissue graft in skeletally immature patients. We do not recommend transphyseal reconstruction of the anterior cruciate ligament in this patient population.

Background —The strong association between coronary heart disease and dyslipoproteinemia has often overshadowed the effects of the nonlipid risk factors–smoking, hypertension, obesity, and diabetes and impaired glucose tolerance–and even led to questioning the importance of these risk factors in the presence of a favorable lipoprotein profile. Methods and Results —A cooperative multicenter study, the Pathobiological Determinants of Atherosclerosis in Youth (PDAY), examined the relation of the nonlipid risk factors to atherosclerosis in 629 men and 227 women 15 to 34 years of age who died of external causes and who had a favorable lipoprotein profile (non-HDL cholesterol 2 ) had more extensive fatty streaks and raised lesions than nonobese men, and individuals with impaired glucose intolerance had more extensive fatty streaks. Obese men had more severe lesions (American Heart Association grade 2 through 5) of the left anterior descending coronary artery. Conclusions —These substantial effects of the nonlipid risk factors on the extent and severity of coronary and aortic atherosclerosis, even in the presence of a favorable lipoprotein profile, support the need to control all cardiovascular risk factors.

Objective: This study was designed to investigate the histologic changes to the knee joints of rabbits after insertion of a metal implant in retrograde fashion. Design: Eighteen rabbits had a modified stainless steel screw implanted in one knee, with the other knee serving as a sham-operated control. The animals were killed after two, six, or twelve months. Outcome Measures: The histologic status of the cartilage and synovium were graded by the Modified Mankin and Mirra criteria, respectively. Results: At the time of killing, every insertion site was covered by fibrous tissue. Statistical analysis showed no significant differences in histologic scores between implanted and control knees. Conclusions: Insertion of a stable, well-fixed implant results in no deleterious effect to the knee joint.

Abstract —The raised fatty streak (fatty plaque) is the gross term for the lesion intermediate between the juvenile (flat) fatty streak and the raised lesion of atherosclerosis. We measured the percentage of intimal surface involved with flat fatty streaks, raised fatty streaks, and raised lesions in the aortas and right coronary arteries of 2876 autopsied persons aged 15 through 34 years who died of external causes. Raised fatty streaks were present in the abdominal aortas of ≈20% of 15- to 19-year-old subjects, and this percentage increased to ≈40% for 30- to 34-year-old subjects. Raised fatty streaks were present in the right coronary arteries of ≈10% of 15- to 19-year-old subjects, and this percentage increased to ≈30% for 30- to 34-year-old subjects. The percent intimal surface involved with raised fatty streaks increased with age in both arteries and was associated with high non–high density lipoprotein (HDL) and low HDL cholesterol concentrations in the abdominal aorta and right coronary artery, with hypertension in the abdominal aorta, with obesity in the right coronary artery of men, and with impaired glucose tolerance in the right coronary artery. Associations of risk factors with raised fatty streaks became evident in subjects in their late teens, whereas associations of risk factors with raised lesions became evident in subjects aged >25 years. These results are consistent with the putative transitional role of raised fatty streaks and show that coronary heart disease risk factors accelerate atherogenesis in the second decade of life. Thus, long-range prevention of atherosclerosis should begin in childhood or adolescence.

Background —This study examined whether atherosclerosis in young people is associated with the risk factors for clinical coronary heart disease (CHD). Methods and Results —Histological sections of left anterior descending coronary arteries (LADs) from 760 autopsied 15- to 34-year-old victims of accidents, homicides, and suicides were graded according to the American Heart Association (AHA) system and computerized morphometry. Risk factors (dyslipoproteinemia, smoking, hypertension, obesity, impaired glucose tolerance) were assessed by postmortem measurements. Approximately 2% of 15- to 19-year-old men and 20% of 30- to 34-year-old men had AHA grade 4 or 5 (advanced) lesions. No 15- to 19-year-old women had grade 4 or 5 lesions; 8% of 30- to 34-year-old women had such lesions. Approximately 19% of 30- to 34-year-old men and 8% of 30- to 34-year-old women had atherosclerotic stenosis ≥40% in the LAD. AHA grade 2 or 3 lesions (fatty streaks), grade 4 or 5 lesions, and stenosis ≥40% were associated with non-HDL cholesterol ≥4.14 mmol/L (160 mg/dL). AHA grade 2 or 3 lesions were associated with HDL cholesterol 2 ) and hypertension (mean arterial pressure ≥110 mm Hg). Conclusions —Young Americans have a high prevalence of advanced atherosclerotic coronary artery plaques with qualities indicating vulnerability to rupture. Early atherosclerosis is influenced by the risk factors for clinical CHD. Long-range prevention of CHD must begin in adolescence or young adulthood.

Abstract —We examined topographic distributions of atherosclerosis and their relation to risk factors for adult coronary heart disease in right coronary arteries and abdominal aortas of more than 2000 autopsied persons 15 through 34 years of age. We digitized images of Sudan IV–stained fatty streaks and of manually outlined raised lesions and computed the percent surface area involved by each lesion in each of 6 regions of each artery. In abdominal aortas of 15- to 24-year-old persons, fatty streaks involve an elongated oval area on the dorsolateral intimal surface and another oval area in the middle third of the ventral surface. Raised lesions in 25- to 34-year-old persons involve an oval area in the distal third of the dorsolateral intimal surface. In other areas of the abdominal aortas of older persons, fatty streaks occur but raised lesions are rare. In the right coronary arteries of 15- to 24-year-old persons, fatty streaks are most frequent on the myocardial aspect of the first 2 cm. Raised lesions follow a similar pattern in 25- to 34-year-old persons. High non-HDL cholesterol and low HDL cholesterol concentrations are associated with more extensive fatty streaks and raised lesions in all regions of both arteries. Smoking is associated with more extensive fatty streaks and raised lesions of the abdominal aorta, particularly in the dorsolateral region of the distal third of the abdominal aorta. Hypertension is not associated with fatty streaks in whites or blacks but is associated with more extensive raised lesions in blacks. Risk factor effects on arterial regions that are vulnerable to lesions are ≈25% greater than risk factor effects assessed over entire arterial segments. These risk factor effects on vulnerable sites emphasize the need for risk factor control during adolescence and young adulthood to prevent or delay the progression of atherosclerosis.

BACKGROUND The role of the immune system in the surveillance of the body for cancer cells is well established. Human tumor cells do not survive in mice with intact immune systems, but they propagate in athymic nude mice. Presumably, the lack of a thymus gland and consequent loss of T lymphocytes results in a seriously compromised immune system without adequate cell-mediated immunity and tumor surveillance. In patients infected with the human immunodeficiency virus (HIV), a progressive loss of cell-mediated immunity is associated with the development of malignancies and opportunistic infections. This effect may be exacerbated in patients who chronically consume alcohol. METHODS Normal and alcoholic BALB/c mice were treated with a monoclonal antibody to deplete CD4+ lymphocytes before orthotopic implantation of human lung adenocarcinoma xenografts. Tumor volume and weight were measured and compared between groups. RESULTS The authors' data show that a single treatment of anti-CD4 antibody causes almost complete depletion of CD4+ lymphocytes and permits the formation of large intrapulmonary human nonsmall lung carcinoma xenografts in 100% of treated mice. All control animals injected with heat-denatured antibody failed to produce tumors. Chronic alcohol consumption by CD4-depleted mice resulted in larger tumors, compared with mice that did not receive ethanol in their diet (P = 0.05). CONCLUSIONS Depletion of CD4+ lymphocytes allows for the orthotopic growth of human lung adenocarcinoma xenografts in BALB/c mice. Furthermore, the consumption of alcohol reduces the ability of the impaired immune system to reject tumors. Cancer 2000;88:468–79. © 2000 American Cancer Society.

Coronary heart disease is the most common cause of death in the US. Studies have demonstrated that smoking is a major risk factor for coronary heart disease and that a positive relationship occurs between smoking and aortic and coronary atherosclerosis in adults. In 1985, a multicenter cooperative study, Pathobiological Determinants of Atherosclerosis in Youth (PDAY), was organized to study atherosclerosis in trauma victims 15-34 years of age. Reports from this study have demonstrated that smoking is strongly associated with the prevalence and extent of grossly visible raised lesions in the abdominal aorta but only weakly associated with similar lesions in the right coronary artery. Coronary arteries from 50 smokers and 50 non-smokers were classified microscopically using a system developed by the American Heart Association in order to determine the stage at which smoking affects atherosclerosis. Smokers had over twice as many advanced lesions, types IV and V, as non-smokers (32 vs 14%) and fewer early lesions, types I, II, III, as non-smokers (38 vs 62%). The prevalence of advanced or types IV and V lesions (32%) was over twice that of intermediate or type III lesions (14%) in smokers. The opposite relationship was observed in non-smokers (14 vs 26%). This observation suggest that intermediate lesions progress rapidly into advanced lesions in smokers and that intima formerly having early lesions is replaced by intima with raised lesions.

Purpose: Prostate cancer is the most common malignancy of males in the United States. Although the overall survival rate for early stage prostate cancer is good, if cancer recurs following curative therapies there is no adequate salvage therapy. Systemic chemotherapy has never been associated with any meaningful improvement in overall survival or overall objective benefit. There is a need to develop novel therapies for prostate cancer.Materials and Methods: Two prostatic cancer cell lines, DU-145 and PC-3, were grown as subcutaneous xenografts in athymic nude mice. The recombinant oncotoxin AR209, formerly OLX-209 [e23(Fv)PE38KDEL]), has the specificity of an anti-p185erbB-2 antibody contained within a single-chain antibody domain (e23Fv) coupled to a portion of the Pseudomonas exotoxin A (PE38KDEL). Using Western blot analysis, the cell lines were shown to express p185erbB-2. The mice received either 3 i.v. injections, one every 2 days, of the recombinant oncotoxin AR209 or PBS, or were implanted...

Lung cancer remains a significant public health problem in the U.S.A. and will result in an estimated 160,400 deaths in 1997. This appalling number is due in large part to the lack of adequate treatment for tumours that are refractory to surgery with curable intent, or of an adequate salvage therapy for those patients who recur after surgical resection. Because non-small cell lung cancer is refractory to traditional chemotherapy, non-traditional therapies have been developed to treat patients with this disease. Recombinant oncotoxins have been designed to target cells that express certain proteins as part of their cellular membrane. One such oncotoxin, AR209 (formerly OLX-209 [e23(Fv)PE38KDEL]), has the specificity of an anti-ErbB-2 antibody contained within a single-chain antibody domain (e23v) coupled to a portion of the Pseudomonas exotoxin A (PE38KDEL). Previous studies demonstrate that this drug is capable of significantly reducing the size of orthotopic lung tumour xenografts. However, most of the treated mice developed tumours once therapy was removed. In this study, mice were treated aggressively using one of four drug treatment schedules. Mice were treated with either intravenous or subcutaneous injections of AR209 over a 2 week period. The data indicate that AR209 significantly reduced the size of tumours and upon microscopic analysis at necropsy, some mice were cured. However, despite the treatment schedule used, many mice contained residual tumour. Residual tumours expressed the ErbB-2 protein, indicating that more aggressive treatment with AR209 may have resulted in higher rates of cure.

PURPOSE Thrombospondin-1 (THBS1) has been suggested as a corneal wound-healing modulator. Therefore, we compromised the integrity of the cornea to elucidate the role of THBS1. METHODS Full-thickness penetrating corneal incisions (1.5 mm) were created in wild type (WT, 129S2/SvPas) and THBS1-deficient mice (Thbs1⁻/⁻), 129S2/SvPas-Thbs1(tm1Hyn)/Thbs1(tm1Hyn)), and allowed to heal up to 1 month, while being monitored by slit-lamp and intravital corneal examinations. Corneas also were examined by transmission electron microscopy and indirect immunofluorescence. To determine how THBS1 was involved in the healing process, we examined THBS1 and α-smooth muscle actin (SMA), a marker of myofibroblasts and myoepithelial cells. RESULTS In WT mice by 1 month, corneas appeared transparent with a thin scar, and endothelium and Descemet's membrane (DM) were restored. In contrast, Thbs1⁻/⁻ corneas exhibited chronic edema and persistent opacity after wounding. The DM and endothelium were not restored, and wound contraction was impaired. The THBS1 was localized in epithelial cells at early stages of the healing process, and in the stroma and endothelial cells during later stages. The SMA-positive epithelial cells and myofibroblasts were observed within the healing area at day 4, peaked at day 14, and disappeared at day 30. The SMA-positive cells were reduced greatly in Thbs1⁻/⁻ mice. CONCLUSIONS In the current study, we demonstrated that corneal restoration is strikingly compromised by a penetrating incision in Thbs1⁻/⁻ mice. The wound results in persistent edema and wound gaping. This appears to be the result of the lack of endothelial migration and DM restoration. In addition, myofibroblast formation is compromised, resulting in the lack of wound contraction.

Background: Acute Myeloid Leukemia (AML) without favorable and particular unfavorable cytogenetic aberrations is classified as intermediate prognosis. Recurrent somatic genomic mutations through The Cancer Genome Atlas (TCGA) have provided valuable prognostic information in AML. There are very few studies that have incorporated the cytogenetics (Cy), Next Generation sequencing (NGS) and Overall Survival (OS) in AML. Moreover prognostic NGS studies have a limited collective context without a quantifiable stratification. For the purpose of prognostic risk stratification, we utilized the TCGA data by Ley et.al and developed a system of Integer Weights for the Genomic Mutation Score (IWGMS) obtained by targeted NGS at Houston Methodist Hospital. We then correlated the IWGMS with patients' outcomes in a retrospective manner. Methods: The patient data was queried from METEOR (Methodist Environment for Translational Enhancement and Outcomes Research), a clinical data warehouse that integrates existing data with internal and external research databases and national registries. We queried for the diagnosis of AML and demographics, Cy, NGS and OS. We divided the patients into 3 groups according to their MRC cytogenetic risks- Favorable (FCy), Intermediate (ICy), Poor (PCy)). Mutations in 54 genes associated with myeloid disorders were tested in NGS by using the TruSight Myeloid Sequencing Panel (Illumina) (Table 1). Briefly, genomic DNA was extracted from sorted specimens using automated methods on the MagnaPure Compact instrument (Roche Diagnostics). Sequencing libraries were prepared using TruSight reagents and sequenced on a MiSeq instrument using a 2x300 bp paired end strategy. Read alignment and variant calling for minimum of 100x amplicon coverage was performed using VariantStudio Software (Illumina). The biologic significance of detected variants was determined using VarView5 (an in-house developed bioinformatics tool). Interpretations are reviewed in a consensus conference. For the data described herein, interpretations were limited to known nonsynonymous (single nucleotide polymorphsims and insertions or deletions) somatic mutations. Results: Of the 1200 AML patients reviewed, 100 patients meet the criteria for having the information on Cy and NGS. The mortality rate for FCy, ICy and PCy groups are 43%, 52%, and 51% respectively. IWGMS was designed by assigning a score for each genomic mutation between the range of negative 2 (-2) for good risk to positive 2 (+2) for each of 9 TCGA mutation categories (Transcription- Factor Fusion, Nucleophosmin (NPM1), Tumor Suppressor Genes, DNA-Methylation related genes, Signaling Genes, Chromatin Modifying Genes, Myeloid Transcription Factor Genes, Cohesion complex Genes and Spliceosome-complex genes). The total IWGMS for each patient was calculated by the sum of mutation scores in each 9 categories. The score greater than 3 was defined as high risk. By univariate analysis, in the ICy, high IWGMS was associated with significantly higher mortality rate than low IWGMS (80% vs 44%, p=0.045). In PCy, patients with high IWGMS and low IWGMS had similar mortality rate (50% vs 52%, p=0.910) (Table 1). Conclusions: We have developed an IWGMS system to stratify patients with ICy into high and low risk groups. Our result demonstrated the significance of high mutation score in this group of patients, which will impact the management. The identification of genomic alterations along with the scoring system has a great potential for developing rationally-targeted therapies and improving outcomes. Further analysis along with the treatment outcomes will be presented at the ASH meeting in San Diego. Disclosures Rice: Novartis Pharma: Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Participation in registry studies; Apellis/Synergy: Other: Data Safety Monitoring Committee member; Ablynx: Other: Participation in multi-center research trial; Selexys: Other: Participation in multi-center research trial; Incyte: Other: Participation in multi-center research trial. Iyer:Genentech: Research Funding; Seattle Genetics: Research Funding; BMS: Research Funding; Incyte: Research Funding; Arog: Research Funding; Celgene: Research Funding.

[Figure][1] An 18-year-old man with no past medical history presented to an outside hospital with acute respiratory distress syndrome complicating a previously undiagnosed interstitial lung disease. While awaiting transplant at our institution, his course was complicated by numerous

fMRI points to a contribution of left-hemisphere (LH) perilesional tissue and right-hemisphere (RH) homologues of the perisylvian “language zones” to aphasia recovery.1 Since, however, “language representation” may vary across individuals, both in terms of gyral topography and lateralization,2 the interpretation of poststroke fMRI data obtained in aphasic patients may face difficulties, e.g., in terms of a differentiation between hemodynamic responses of residual eloquent cortex and perilesional reorganization of tissue adjacent to perisylvian “language areas.” We had the extraordinary opportunity to compare fMRI data obtained during the same speech task prior to and after LH ischemic infarction—providing further insights into the development of perilesional hemodynamic responses. To our knowledge, this is the first prestroke/poststroke follow-up study in aphasia. ### Methods. #### Clinical history. At 33 years of age, the patient had participated as a healthy control subject in a language fMRI study (pre).3 Six years later, he experienced sudden right-sided hemiplegia and Broca aphasia. MRI revealed a large ischemic infarction within the territory of the left middle cerebral artery (figure, A). One year after stroke, the patient was re-examined (post), using the same design and measurement protocol (fMRI, neuropsychology). At post, the patient still had right-sided hemiparesis, but speech/language functions had almost entirely …

Cocaine is considered a superb anesthetic for many otolaryngologic procedures and has been shown to be positive in the urine of patients for up to 72 hours after surgery with a standard radioimmunoassay test. The standard cutoff for drug screening of benzoylecgonine, the main urine metabolite of cocaine, has been 300 ng/ml. However, the new threshold value in many laboratories is now 150 ng/ml. In review of the literature, no study has been performed that quantitates the actual level of the urine cocaine metabolite after a routine otolaryngologic procedure in both physicians and their patients with the gold standard for urine testing, gas chromatography. This study documents the quantitative level of the urine cocaine metabolite in patients and reveals that there are metabolite levels present in physicians during a single exposure, although they are below the current cutoff level that will be picked up on current screening assays. Evidence has also been presented demonstrating a cumulative effect on the benzoylecgonine levels in physicians who clinically use cocaine anesthesia more frequently; these levels can be above the cutoff level on current screening assays.

Six cases of dematiaceous fungal sinusitis are reported, together with a review of 33 other cases collated from a review of the English literature. The sinusitis was more often unilateral vs. bilateral. A characteristic serpiginous hyperdense intrasinus opacification, as well as sinus expansion with bone erosion, was often seen on CT scan. MRI scan showed lucent sinus cavities on T1 and T2 weighting. A comparison of surgical treatment vs. surgery with systemic antifungal therapy revealed decreased recurrence and complication statistics in the combined therapy group. There was a trend toward increased recurrence/persistence and complications associated with invasive histologic findings and only surgical treatment, but not statistically significant. At the present time, we recommend comprehensive surgical treatment followed by systemic antifungal therapy, though clinical judgment and individualization should occur. Future studies are planned to further define the disease entity and its therapy.