Durable Response in Patients With Refractory Fistulizing Perianal Crohn's Disease Using Autologous Mesenchymal Stem Cells on a Dissolvable Matrix: Results from the Phase I Stem Cell on Matrix Plug Trial.

BACKGROUND: Refractory perianal Crohn's disease remains notoriously difficult to treat. We developed a novel technology using a commercially available bioabsorbable fistula plug to deliver autologous adipose-derived mesenchymal stem cells. OBJECTIVE: This study aimed to assess therapeutic safety and feasibility in the completed STOMP (stem cells on matrix plugs) phase 1 clinical trial. DESIGN: Prospective single-arm phase I clinical trial. SETTING: Tertiary academic medical center. PATIENTS: Adults (aged 18-65 y) with complex single-tract Crohn's disease perianal fistula who have failed conventional therapy were included in this study. INTERVENTION: Autologous adipose-derived mesenchymal stem cells were isolated, ex vivo culture expanded, and seeded onto a commercially available bioabsorbable fistula plug. Six weeks later, patients returned to the operating room for removal of the seton and placement of the stem cell-loaded plug. MAIN OUTCOME MEASURES: Patients were followed up for a total of 8 visits through 12 months. Safety was the primary end point; clinical healing and MRI response were secondary end points. RESULTS: Twenty patients (12 females; mean age 36 y) were treated with the stem cell-loaded plug. Of the 20 patients enrolled, 3 were not included in the 12-month analysis because of study withdrawal. Through 12 months, no patient experienced a serious adverse event related to the stem cell-loaded plug. Four patients experienced 7 serious adverse events and 12 patients experienced 22 adverse events. Complete clinical healing occurred in 14 of 18 patients at 6 months and 13 of 17 patients at 12 months. MRI response was observed in 12 of 18 patients at 6 months. LIMITATIONS: The main limitations were the small sample size and restrictive inclusion criteria. CONCLUSIONS: A stem cell-loaded plug can safely and effectively deliver cell-based therapy for patients with single-tract fistulizing perianal Crohn's disease. See Video Abstract at http://links.lww.com/DCR/C70 . RESPUESTA DURADERA OBSERVADA EN PACIENTES CON ENFERMEDAD DE CROHN PERIANAL FISTULIZANTE REFRACTARIA MEDIANTE EL USO DE CLULAS MADRE MESENQUIMALES AUTLOGAS EN UNA MATRIZ DISOLUBLE RESULTADOS DEL ENSAYO DE FASE I STEM CELL ON MATRIX PLUG: ANTECEDENTES:La enfermedad de Crohn perianal refractaria sigue siendo notoriamente difícil de tratar. Desarrollamos una tecnología novedosa utilizando un tapón de fístula bioabsorbible disponible comercialmente para administrar células madre mesenquimales derivadas de tejido adiposo autólogo.OBJETIVO:Evaluar la seguridad y viabilidad terapéutica en el ensayo finalizado STOMP.DISEÑO:Ensayo clínico prospectivo de fase I de un solo brazo.AJUSTE:Centro médico académico terciario.PACIENTES:Adultos (18-65) con fístula perianal compleja de la enfermedad de Crohn de un solo tracto que han fracasado con la terapia convencional.INTERVENCIÓN:Se aislaron células madre mesenquimales derivadas de tejido adiposo autólogo, se expandieron en cultivo ex vivo y se sembraron en un tapón de fístula bioabsorbible disponible comercialmente. Seis semanas después, los pacientes regresaron al quirófano para retirar el setón y colocar el tapón cargado de células madre.PRINCIPALES MEDIDAS DE RESULTADO:Los pacientes fueron seguidos durante un total de 8 visitas durante 12 meses. La seguridad fue el criterio principal de valoración; la curación clínica y la respuesta a la resonancia magnética fueron criterios de valoración secundarios.RESULTADOS:Veinte pacientes (12 mujeres, edad media 36 años) fueron tratados con el tapón cargado de células madre. De los 20 pacientes inscritos, tres no se incluyeron en el análisis de 12 meses porque se retiraron del estudio. A lo largo de 12 meses, ningún paciente experimentó un evento adverso grave relacionado con el tapón cargado de células madre. Cuatro pacientes experimentaron 7 eventos adversos graves y 12 pacientes experimentaron 22 eventos adversos. La curación clínica completa ocurrió en 14 de 18 pacientes a los 6 meses y en 13 de 17 pacientes a los 12 meses. La respuesta a la resonancia magnética se observó en 12 de 18 pacientes a los 6 meses.LIMITACIONES:Las principales limitaciones son el tamaño pequeño de la muestra y los criterios de inclusión restrictivos.CONCLUSIONES:Un tapón cargado de células madre se puede administrar de manera segura y efectiva, una terapia basada en células para pacientes con enfermedad de Crohn perianal fistulizante de un solo tracto. Consule Video Resumen en http://links.lww.com/DCR/C70 . (Traducción- Dr. Yesenia Rojas-Khalil ).

Diagnostic Performance in Low- and High-Contrast Tasks of an Image-Based Denoising Algorithm Applied to Radiation Dose-Reduced Multiphase Abdominal CT Examinations.

BACKGROUND. Anatomic redundancy between phases can be used to achieve denoising of multiphase CT examinations. A limitation of iterative reconstruction (IR) techniques is that they generally require use of CT projection data. A frequency-split multi-band-filtration algorithm applies denoising to the multiphase CT images themselves. This method does not require knowledge of the acquisition process or integration into the reconstruction system of the scanner, and it can be implemented as a supplement to commercially available IR algorithms. OBJECTIVE. The purpose of the present study is to compare radiologists' performance for low-contrast and high-contrast diagnostic tasks (i.e., tasks for which differences in CT attenuation between the imaging target and its anatomic background are subtle or large, respectively) evaluated on multiphase abdominal CT between routine-dose images and radiation dose-reduced images processed by a frequency-split multiband-filtration denoising algorithm. METHODS. This retrospective single-center study included 47 patients who underwent multiphase contrast-enhanced CT for known or suspected liver metastases (a low-contrast task) and 45 patients who underwent multiphase contrast-enhanced CT for pancreatic cancer staging (a high-contrast task). Radiation dose-reduced images corresponding to dose reduction of 50% or more were created using a validated noise insertion technique and then underwent denoising using the frequency-split multi-band-filtration algorithm. Images were independently evaluated in multiple sessions by different groups of abdominal radiologists for each task (three readers in the low-contrast arm and four readers in the high-contrast arm). The noninferiority of denoised radiation dose-reduced images to routine-dose images was assessed using the jackknife alternative free-response ROC (JAFROC) figure-of-merit (FOM; limit of noninferiority, -0.10) for liver metastases detection and using the Cohen kappa statistic and reader confidence scores (100-point scale) for pancreatic cancer vascular invasion. RESULTS. For liver metastases detection, the JAFROC FOM for denoised radiation dose-reduced images was 0.644 (95% CI, 0.510-0.778), and that for routine-dose images was 0.668 (95% CI, 0.543-0.792; estimated difference, -0.024 [95% CI, -0.084 to 0.037]). Intraobserver agreement for pancreatic cancer vascular invasion was substantial to near perfect when the two image sets were compared (κ = 0.53-1.00); the 95% CIs of all differences in confidence scores between image sets contained zero. CONCLUSION. Multiphase contrast-enhanced abdominal CT images with a radiation dose reduction of 50% or greater that undergo denoising by a frequency-split multiband-filtration algorithm yield performance similar to that of routine-dose images for detection of liver metastases and vascular staging of pancreatic cancer. CLINICAL IMPACT. The image-based denoising algorithm facilitates radiation dose reduction of multiphase examinations for both low- and high-contrast diagnostic tasks without requiring manufacturer-specific hardware or software.

Estimating the Clinical Impact of Photon-Counting-Detector CT in Diagnosing Usual Interstitial Pneumonia.

OBJECTIVE: The aim of this study was to evaluate the clinical impact of a higher spatial resolution, full field-of-view investigational photon-counting detector computed tomography (PCD-CT) on radiologist confidence in imaging findings and diagnosis of usual interstitial pneumonia (UIP) compared with conventional energy-integrating detector CT (EID-CT). MATERIALS AND METHODS: Patients suspected of interstitial lung disease were scanned on a PCD-CT system after informed consent and a clinically indicated EID-CT. In 2 sessions, 3 thoracic radiologists blinded to clinical history and scanner type evaluated CT images of the right and left lungs separately on EID- or PCD-CT, reviewing each lung once/session, rating confidence in imaging findings of reticulation, traction bronchiectasis, honeycombing, ground-glass opacities (GGOs), mosaic pattern, and lower lobe predominance (100-point scale: 0-33, likely absent; 34-66, indeterminate; 67-100, likely present). Radiologists also rated confidence for the probability of UIP (0-20, normal; 21-40, inconsistent with UIP; 41-60, indeterminate UIP; 61-81; probable UIP; 81-100, definite UIP) and graded image quality. Because a confidence scale of 50 represented completely equivocal findings, magnitude score (the absolute value of confidence scores from 50) was used for analysis (higher scores were more confident). Image noise was measured for each modality. The magnitude score was compared using linear mixed effects regression. The consistency of findings and diagnosis between 2 scanners were evaluated using McNemar test and weighted κ statistics, respectively. RESULTS: A total of 30 patients (mean age, 68.8 ± 11.0 years; M:F = 18:12) underwent conventional EID-CT (median CTDI vol , 7.88 mGy) and research PCD-CT (median CTDI vol , 6.49 mGy). The magnitude scores in PCD-CT were significantly higher than EID-CT for imaging findings of reticulation (40.7 vs 38.3; P = 0.023), GGO (34.4 vs 31.7; P = 0.019), and mosaic pattern (38.6 vs 35.9; P = 0.013), but not for other imaging findings ( P ≥ 0.130) or confidence in UIP (34.1 vs 22.2; P < 0.059). Magnitude score of probability of UIP in PCD-CT was significantly higher than EID-CT in one reader (26.0 vs 21.5; P = 0.009). Photon-counting detector CT demonstrated a decreased number of indeterminate GGO (17 vs 26), an increased number of unlikely GGO (74 vs 50), and an increased number of likely reticulations (140 vs 130) relative to EID-CT. Interobserver agreements among 3 readers for imaging findings and probability of UIP were similar between PCD-CT and EID-CT (intraclass coefficient: 0.507-0.818 vs 0.601-0.848). Photon-counting detector CT had higher scores in overall image quality (4.84 ± 0.38) than those in EID-CT (4.02 ± 0.40; P < 0.001) despite increased image noise (mean 85.5 vs 36.1 HU). CONCLUSIONS: Photon-counting detector CT provided better image quality and improved the reader confidence for presence or absence of imaging findings of reticulation, GGO, and mosaic pattern with idiosyncratic improvement in confidence in UIP presence.

Utility of an automatic adaptive iterative metal artifact reduction AiMAR algorithm in improving CT imaging of patients with hip prostheses evaluated for suspected bladder malignancy.

PURPOSE: To compare the utility of a novel metal artifact reduction algorithm to standard imaging in improving visualization of key structures, diagnostic confidence, and patient-level confidence in malignancy in patients with suspected bladder cancer. METHODS: Patients with hip implants undergoing CT urography for suspected bladder malignancy were enrolled. Images were reconstructed using 3 methods: (1) Filtered Back Projection (FBP), (2) Iterative Metal Artifact Reduction (iMAR), and (3) Adaptive Iterative Metal Artifact Reduction (AiMAR) strength 4. In multiple reading sessions, three radiologists graded visualization of critical anatomic structures and artifact severity (6-point scales, lower scores desirable), and diagnostic confidence in blinded fashion. They also graded patient-level confidence in malignancy based on imaging findings in each patient. RESULTS: Thirty-two patients (8 females) with a mean age of 74.5 ± 8.5 years were included. The median (range) visualization scores for FBP, iMAR, and AiMAR were 3.6 (1.1-4.9), 1.6 (0.3-2.8), and 1.6 (0.3-2.6), respectively. Both iMAR and AiMAR had anatomic visualization and artifact scores better than FBP (P < 0.001 for both) and similar to each other (P > 0.05). Structures with the most improvement in visualization score with the use of metal artifact reduction algorithms included the obturator internus muscle, internal and external iliac nodal chains, and vagina. iMAR and AiMAR improved diagnostic confidence (P < 0.001) and patient-level confidence in malignancy (P ≤ 0.24). CONCLUSION: For patients with hip prostheses and suspected bladder malignancy, the use of iMAR or AiMAR was shown to significantly reduce metal artifacts, thus improving diagnostic confidence and patient-level confidence in malignancy.

Impact of dual-energy 50-keV virtual monoenergetic images on radiologist confidence in detection of key imaging findings of small hepatocellular carcinomas using multiphase liver CT.

BACKGROUND: Dual-energy virtual monoenergetic images can increase iodine signal, potentially increasing the conspicuity of hepatic masses. PURPOSE: To determine if dual-energy 50-keV virtual monoenergetic images improve visualization of key imaging findings or diagnostic confidence for small (≤2 cm) hepatocellular carcinomas (HCC) at multiphase, contrast-enhanced liver computed tomography (CT). MATERIAL AND METHODS: Patients with chronic liver disease underwent multiphase dual-energy CT imaging for HCC, with late arterial and delayed phase dual-energy 50-keV images reconstructed. Two non-reader subspecialized gastrointestinal (GI) radiologists established the reference standard, determining the location and diagnosis of all hepatic lesions using predetermined criteria. Three GI radiologists interpreted mixed kV CT images without or with dual-energy 50-keV images. Radiologists identified potential HCCs and rated their confidence (0-100 scales) in imaging findings of arterial enhancement, enhancing capsule, tumor washout, and LI-RADS 5 (2018) category. RESULTS: In total, 45 patients (14 women; mean age = 59.5 ± 10.9 years) with chronic liver disease were included. Of them, 19 patients had 25 HCCs ≤2 cm (mean size = 1.5 ± 0.4 cm). There were 17 LI-RADS 3 and 4 lesions and 19 benign lesions. Reader confidence in imaging findings of arterial enhancement, enhancing capsule, and non-peripheral washout significantly increased with dual-energy images (P ≤ 0.022). Overall confidence in HCC diagnosis increased significantly with dual-energy 50-keV images (52.4 vs. 68.8; P = 0.001). Dual-energy images demonstrated a slight but significant decrease in overall image quality. CONCLUSION: Radiologist confidence in key imaging features of small HCCs and confidence in imaging diagnosis increases with use of dual-energy 50-keV images at multiphase, contrast-enhanced liver CT.

CT or MR Enterography to Assess Response During Vedolizumab Therapy for Small Bowel Crohn's Disease.

Background: To describe response to therapy of small bowel (SB) Crohn's disease (CD) at CT or MR enterography (CTE/MRE) in patients on vedolizumab. Methods: Patients with SB CD who underwent CTE/MRE exams greater than 12 months apart on vedolizumab therapy were included. Length (in cm) and inflammation severity (EMBARK score) of inflamed SB segments were assessed. Changes in inflammation length of 3.4 cm or greater or inflammation severity of 2 EMBARK points or greater was categorized as response or progression, as appropriate, with development of newly inflamed segments, strictures, or penetrating complications also indicating progression. Patients not meeting the criteria for response or progression were categorized as having stable disease. Results: Of 36 SB CD patients, the large majority had prior surgery (86%; 31), anti-TNF use (92%; 33), and internal penetrating (78%; 28) disease. Thirty-two patients had paired baseline and follow-up CTE/MRE exams without interval surgery, with clinical response observed in 24/32 (75%). Based on imaging response criteria, 22% (7/32; 95% CI: 9%-40%) had response, 50% (16/32; 95% CI: 32%-68%) were stable, and 28% (9/32; 95% CI: 14%-47%) had disease progression. Fifty-six percent of (18/32; 95% CI: 38%-74%) patients had clinical improvement with response or stable disease by imaging. Patients with stable disease had shorter median baseline lengths of SB inflammation (P = .012). Proportion of patients with colonic inflammation, perianal disease, or penetrating complications did not change. Conclusions: Most patients on vedolizumab for over 12 months demonstrated response or stable SB disease when using objective cross-sectional radiologic imaging criteria using CTE/MRE.

Renal Cell Carcinoma Metastasis to Anterior Orbit.

Renal cell carcinoma (RCC) is a rare malignancy that often metastasizes to the lung, bones, liver, and brain. Only a few cases of RCC metastasis in periocular areas have been reported in the literature. This case report describes a 70-year-old male who was presented to the University of Florida, Gainesville ophthalmology clinic with two-day symptoms of diplopia, decreased vision, and mechanical ptosis of the left eye with superior temporal mass. The patient had a history of both prostate and RCC that were in remission for five years leading to his presentation. Excisional biopsy confirmed the metastasis of RCC to the eye. The patient reported no systemic symptoms. This report also reviews existing literature on RCC metastasis to the eye and orbit. Ultimately, RCC metastasis to the eye in patients with a history of known RCC should be considered in the differential diagnosis in those presenting with an atypical mass in periocular regions.

Imaging Findings of Ileal Inflammation at Computed Tomography and Magnetic Resonance Enterography: What do They Mean When Ileoscopy and Biopsy are Negative?

BACKGROUND AND AIMS: Our goal was to determine the importance of ileal inflammation at computed tomography or magnetic resonance enterography in Crohn's disease patients with normal ileoscopy. METHODS: Patients with negative ileoscopy and biopsy within 30 days of CT or MR enterography showing ileal inflammation were included. The severity [0-3 scale] and length of inflammation within the distal 20 cm of the terminal ileum were assessed on enterography. Subsequent medical records were reviewed for ensuing surgery, ulceration at ileoscopy, histological inflammation, or new or worsening ileal inflammation or stricture on enterography. Imaging findings were classified as: Confirmed Progression [subsequent surgery or radiological worsening, new ulcers at ileoscopy or positive histology]; Radiologic Response [decreased inflammation with medical therapy]; or Unlikely/Unconfirmed Inflammation. RESULTS: Of 1471 patients undergoing enterography and ileoscopy, 112 [8%] had imaging findings of inflammation with negative ileoscopy, and 88 [6%] had negative ileoscopy and ileal biopsy. Half [50%; 44/88] with negative biopsy had moderate/severe inflammation at enterography, with 45%, 32% and 11% having proximal small bowel inflammation, stricture or fistulas, respectively. Two-thirds with negative biopsy [67%; 59/88] had Confirmed Progression, with 68%, 70% and 61% having subsequent surgical resection, radiological worsening or ulcers at subsequent ileoscopy, respectively. Mean length and severity of ileal inflammation in these patients was 10 cm and 1.6. Thirteen [15%] patients had Radiologic Response, and 16 [18%] had Unlikely/Unconfirmed Inflammation. CONCLUSION: Crohn's disease patients with unequivocal imaging findings of ileal inflammation at enterography despite negative ileoscopy and biopsy are likely to have active inflammatory Crohn's disease. Disease detected by imaging may worsen over time or respond to medical therapy.

The evolving role of imaging for small bowel neuroendocrine neoplasms: estimated impact of imaging and disease-free survival in a retrospective observational study.

PURPOSE: To determine how small bowel neuroendocrine neoplasms (SBNEN's) are diagnosed and examine the effect of CT enterography (CTE) on diagnosis and rates of disease-free survival. METHODS: Histopathologically-confirmed SBNEN's diagnosed at our institution between 1996 and 2016 were identified. Clinical presentation, radiology, endoscopy, surgery, and pathology reports were reviewed and compared between consecutive 5-year periods. RESULTS: Of the 178 SBNEN initially diagnosed at our institution, the incidence increased 12-fold from 9 (during 1996-2000) to 114 (during 2011-2016). Comparing the first 5 to the last 5 years, GI bleeding and abdominal pain increased significantly as indications (with both increasing from 0 to > 25%, p ≤ 0.023). Initial diagnosis by radiology increased 2-fold [from 33% (n = 3) to 66% (n = 75); p = 0.263]. Detection of a small bowel mass and the suggestion that SBNEN was present varied significantly between imaging modalities (p < 0.0001; CTE - 95% (52/55) and 91% (50/55) vs. abdominal CT 45% (37/85) and 35% (29/85), respectively). Recurrence rates increased with SBNEN size (p = 0.012; e.g., of SBNEN diagnosed by endoscopy, 18% of SBNEN measuring 0.6 ± 0.3 cm recurred vs. 75% measuring 3.7 ± 1.0 cm). Rates of disease-free survival, and the incidence of local and liver metastases were decreased when tumors were first identified by CTE rather than other CT/MR imaging modalities (p = 0.0034, 0.0475, and 0.0032, respectively). CONCLUSION: There has been a dramatic increase in SBNENs detected by CTE and endoscopy over the last 20 years. SBNEN's detected by CTE and small tumors detected at endoscopy have longer disease-free survival after surgical resection.

Findings of CT-Derived Bone Strength Assessment in Inflammatory Bowel Disease Patients Undergoing CT Enterography in Clinical Practice.

BACKGROUND: Inflammatory bowel disease (IBD) patients are at risk of developing complications from metabolic bone disease, but the exact prevalence is unknown. We evaluated fracture risk in IBD patients using (1) biomechanical CT analysis (BCT) using bone strength and bone mineral density (BMD), (2) Cornerstone guidelines, and (3) other clinical features predicting fracture risk. METHODS: A retrospective review of consecutive IBD patients who underwent CT enterography (CTE) with BCT from March 2014 to March 2017 was performed. Measured outcomes were overall fracture risk classification (not increased, increased, or high) and femoral neck BMD World Health Organization classification (normal, osteopenia, or osteoporosis). RESULTS: Two hundred fifty-seven patients with IBD underwent CTE and BCT. Fracture risk was classified as not increased in 45.5% (116/255) of patients, increased in 44.7% (114/255), and high in 9.8% (25/255). Femoral neck BMD was classified as normal in 56.8% (142/250), osteopenia in 37.6% (94/250), and osteoporosis in 5.6% (14/250). In multivariate analysis, only increasing age was associated with increased fracture risk (odds ratio, 1.06; 95% confidence interval, 1.04-1.08; P < 0.001). Cornerstone guidelines were met by 35.3% (41/116), 56.1% (64/114), and 76.0% (19/25) of patients in the not increased, increased, and high-risk groups, respectively (P = 0.0001). No Cornerstone criteria were met by 40% (56/139) of patients in the increased and high-risk groups. CONCLUSIONS: Using BCT, increased or high fracture risk was detected in more than half of this cohort, the prevalence being associated with increased age. A significant proportion of patients with increased or high fracture risk did not meet Cornerstone guidelines. Therefore, IBD patients who do not meet Cornerstone guidelines may benefit from BCT screening.

Salicylic acid-based poly(anhydride-ester) nerve guidance conduits: Impact of localized drug release on nerve regeneration.

Nerve guidance conduits (NGCs) can serve as physical scaffolds aligning and supporting regenerating cells while preventing scar tissue formation that often interferes with the regeneration process. Numerous studies have focused on functionalizing NGCs with neurotrophic factors, for example, to support nerve regeneration over longer gaps, but few directly incorporate therapeutic agents. Herein, we fabricated NGCs from a polyanhydride comprised of salicylic acid (SA), a nonsteroidal anti-inflammatory drug, then performed in vitro and in vivo assays. In vitro studies included cytotoxicity, anti-inflammatory response, and NGC porosity measurements. To prepare for implantation, type I collagen hydrogels were used as NGC luminal fillers to further enhance the axonal regeneration process. For the in vivo studies, SA-NGCs were implanted in femoral nerves of mice for 16 weeks and evaluated for functional recovery. The SA-based NGCs functioned as both a drug delivery vehicle capable of reducing inflammation and scar tissue formation because of SA release as well as a tissue scaffold that promotes peripheral nerve regeneration and functional recovery.

Aldose reductase: an aldehyde scavenging enzyme in the intraneuronal metabolism of norepinephrine in human sympathetic ganglia.

The neurotransmitter norepinephrine is metabolized by monoamine oxidase into an aldehyde intermediate that is further metabolized to the stable glycol derivative, 3,4-dihydroxyphenylglycol (DHPG). In this study, the possible role of aldose reductase in reducing this aldehyde intermediate in human sympathetic neurons has been examined. DHPG is formed when norepinephrine is incubated with aldose reductase in the presence of monoamine oxidase. DHPG metabolism is inhibited by the monoamine oxidase inhibitor, pargyline which prevents the deamination of norepinephrine, and by the aldose reductase inhibitor AL 1576, which inhibits DHPG formation without affecting the deamination of norepinephrine. Although similar formation of DHPG was observed with human liver aldehyde reductase, the production of DHPG was more effective with aldose reductase than aldehyde reductase. Two peaks of reductase activity corresponding to aldose reductase and aldehyde reductase were observed when sympathetic ganglia were chromatofocused. Molecular modeling studies indicate that the energy-minimized structure of 3,4-dihydroxymandelaldehyde bound to aldose reductase is similar to that of glyceraldehyde where the 2'-hydroxyl group forms hydrogen bonds with Trp111 and NADPH. These results suggest that aldose reductase may be important in metabolizing the potentially toxic aldehyde intermediate formed from norepinephrine in human sympathetic ganglia.