Benign Breast Intraductal Papillomas Without Atypia at Core Needle Biopsies: Is Surgical Excision Necessary?

PURPOSE: The aim of this study was to determine the upgrade rate of image-guided core needle biopsy (CNB)-proven benign breast intraductal papillomas (IDPs) without atypia to high-risk benign lesions or malignancy after surgical excision. METHODS: A retrospective database search at a single institution identified 102 adult female patients with benign breast IDPs without atypia diagnosed on imaging-guided CNBs who subsequently had surgical excisions between 2011 and 2016. Patient characteristics, imaging features, biopsy techniques, and the pathology reports from imaging-guided CNBs and subsequent surgical excisions were reviewed. The upgrade rate to malignancies or high-risk benign lesions was determined at the patient level. RESULTS: The upgrade rate to malignancy was 2.9% (3/102), including two cases of ductal carcinoma in situ (DCIS) and one case of microinvasive (< 1 mm) ductal carcinoma arising from DCIS. The upgrade rate to high-risk benign lesions was 7.8% (8/102), with seven cases of atypical ductal hyperplasia and one case of atypical lobular hyperplasia. A personal history of breast cancer and a larger mean lesion size were significantly associated with an upgrade to malignancy (p < 0.05). CONCLUSIONS: The management of benign breast IDPs without atypia detected on imaging-guided CNBs is controversial. Our results suggest risk stratification is important in approaching these patients. Although surgical excision should be considered for all benign breast IDPs without atypia, observation with serial imaging may be appropriate in selected low-risk patients. This approach will save many women from surgeries and decrease the cost of medical care.

The effect of age on race-related breast cancer survival disparities.

BACKGROUND: Breast cancer survival disparities by race are likely multifactorial. In a small pilot cohort, we demonstrated a statistical interaction between age and race. The purpose of this study was to validate earlier findings in a larger, more diverse cohort and to test the hypothesis that breast cancer survival is influenced by the dependent relationship of age and race. METHODS: We conducted a retrospective analysis of a multi-institutional breast cancer database for patients treated between 1999 and 2009. Study variables included age and disease stage at diagnosis, race, treatment (surgery, chemotherapy, radiotherapy, hormone therapy) and overall survival. Statistical analysis and regression models were performed by Stata software. RESULTS: A total of 9,249 patients were included in this study. African American, Hispanic, and Asian patients were more likely to present at a younger age with metastases. African American and Hispanic race were associated with increased mortality after adjusting for stage, age, and treatment. A 2-way interaction between age and race was identified in the Cox regression model (p < 0.001). To further define this interaction, a postestimation analysis was performed to determine the predicted relative hazard for each race with age fixed at 40, 50, 60, 70, and 80 years. At younger ages, the predicted relative hazard was significantly higher for both African American and Hispanic race. CONCLUSIONS: Despite adjusting for stage and treatment differences, African American and Hispanic race predicted poor survival. The effect of age and treatment on breast cancer survival differs across races. Additional research is needed to accurately determine the reasons for worsened survival.

Relationship between documentation status and survival for medically underserved Hispanic breast cancer patients.

BACKGROUND: Undocumented immigrants have been shown to be predisposed to worse clinical outcomes than the general population. This study examines survival in socioeconomically disadvantaged Hispanic documented and undocumented breast cancer patients. METHODS: Analysis of a prospective breast cancer database of patients treated in a safety-net hospital system. Overall survival was the primary outcome, and advanced stage at diagnosis (regional and metastatic) was a secondary outcome. Survival analysis and multivariate regression modeling were performed. RESULTS: Seven hundred fifty-one breast cancer patients were identified. Undocumented patients presented at an earlier age and were likely to present with advanced stage. After adjusting for covariates, undocumented status was not associated with increased mortality. The diagnosis-to-treatment interval was significantly longer in undocumented patients. CONCLUSIONS: Despite undocumented patients presenting at a younger age, they have similar mortality compared with documented patients. This finding is partly explained by the local treatment afforded by undocumented patients, further studies are necessary to detail the reasons for these differences in presentation and outcome.

Improving Hepatobiliary Imaging as a Physiologic Test with Superior Clinical Outcomes.

This study aims at prospectively evaluating the difference in the effect of cholecystokinin (CCK) and half-and-half milk (HHM) administered in the same patient on gallbladder contractility and correlation with clinical outcomes. Upon gallbladder visualization during standard hepatobiliary imaging, 0.02 µg/kg of CCK was injected over 3 min, and additional 30 min of dynamic imaging was obtained. Patients with gallbladder ejection fraction (GBEF) <35% after CCK were administered 8 oz of HHM followed by 30 min of imaging. The GBEF was recalculated. The number of patients whom GBEF changed from below 35% (abnormal) after CCK to above 35% (normal) after HHM was recorded. Follow-up of the clinical outcome at 6 months was performed. Fifty patients with abnormal GBEF were prospectively included. The average GBEF after CCK was 14.7% ± 8.5% and after HHM was 30.7% ± 20.8%. The average increase in GBEF with HHM was 16.0% ± 22.2%. The GBEF changed from abnormal to normal in 17 patients (34%). The remaining 33 patients remained abnormal. Clinical outcomes at 6 months were available in 47 patients. Cholecystectomy was performed in 60% of patients with abnormal GBEF with CCK and HHM with resolution or improvement of pain. Two of 16 patients (12%) with abnormal GBEF after CCK but normal after HHM had cholecystectomies with pain improvement, while 8 out of these patients (50%) were diagnosed and treated with other disorders and improved. Hepatobiliary imaging with HHM stimulation is a superior physiologic test which can lower the number of unnecessary cholecystectomies and misdiagnoses as functional cholecystitis.

Differential effects of luminal arginine and glutamine on metalloproteinase production in the postischemic gut.

BACKGROUND: Matrix metalloproteinases (MMPs) are a group of endopeptidases induced under inflammatory conditions in the intestine which possess the capacity to degrade components of the extracellular matrix. We have previously demonstrated that MMP-2 expression correlates with increased inducible nitric oxide synthase (iNOS) production in the stomach and that iNOS is upregulated in the postischemic gut by the luminal nutrient arginine and repressed by luminal glutamine. We therefore hypothesized that arginine would enhance expression of MMP-2 in the postischemic gut. METHODS: Jejunal sacs were created in rats at laparotomy and filled with either 60 mM glutamine, arginine, or magnesium sulfate (osmotic control) followed by 60 minutes of superior mesenteric artery occlusion (SMAO) and 6 hours of reperfusion and compared with shams. Jejunum was harvested, and membrane type-1 matrix metalloproteinase (MT1-MMP), MMP-2, and iNOS protein expression was determined by Western analysis and MMP-9 production by gelatin zymography. RESULTS: MMP-2, MT1-MMP, MMP-9, and iNOS were all increased after SMAO compared with shams. Arginine maintained while glutamine inhibited the increase in iNOS, MT1-MMP, and MMP-2 expression in the postischemic gut. Pretreatment of the arginine group with a selective iNOS inhibitor blunted the induction of MMP-2 in the postischemic gut. There was no differential modulation of MMP-9 by the luminal nutrients. CONCLUSIONS: The arginine-induced upregulation of iNOS may contribute to increased activity of MT1-MMP and MMP-2. The mechanism for this differential regulation by arginine warrants further investigation.

Effect of NOS inhibition on rat gastric matrix metalloproteinase production during endotoxemia.

UNLABELLED: Matrix metalloproteinases (MMPs) degrade the extracellular matrix and contribute to LPS-induced gastric injury. MMPs are closely modulated by their activators, membrane type-MMP (MT-MMPs) and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). As LPS-induced gastric injury is mediated in part by iNOS, and NO modulates MMP production in vitro, we hypothesized that NOS inhibition would similarly modulate LPS-induced gastric MMP production. Therefore, the purpose of these studies was to compare the effects of selective and nonselective NOS inhibition on LPS-induced gastric MMP production. METHODS: Sprague-Dawley rats were given either the nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 5 mg/kg, s.c.), a selective iNOS inhibitor, aminoguanidine (45 mg/kg, i.p.) or L-N-iminoethyl-lysine (L-NIL; 10 mg/kg, i.p.), or vehicle 15 min before saline or LPS (20 mg/kg, i.p.) and killed 24 h after LPS administration. Stomachs were assessed for macroscopic injury (computed planimetry), and gastric mucosal MMP production was assessed by gelatin zymography, in situ zymography, and Western analysis for MMP-2, MT1-MMP, and TIMP-2. (n > or = 4/group; ANOVA). RESULTS: Aminoguanidine treatment decreased LPS-induced macroscopic gastric injury as well as MMP-2 and MT1-MMP protein production while having no effect on TIMP-2 protein levels. L-NIL similarly attenuated the induction of MMP-2 and MT1-MMP by LPS. L-NAME failed to attenuate LPS induced gastric injury or MT1-MMP protein induction and increased MMP-2 levels. L-NAME similarly had no effect on gastric TIMP-2 production. CONCLUSIONS: Selective iNOS inhibition decreases gastric MMP-2 activity after LPS administration, whereas nonselective inhibition increases MMP-2 levels. The ability of selective iNOS inhibition to ameliorate LPS-induced gastric injury may be due in part to its inhibition of active MMP-2 production, whereas nonselective NOS inhibitors increase MMP-2 levels and maintain gastric injury after LPS administration.

Ketamine attenuates liver injury attributed to endotoxemia: role of cyclooxygenase-2.

BACKGROUND: Endotoxic shock can cause end-organ dysfunction and liver injury. Critically ill patients frequently require surgical intervention under general anesthesia for source control. However, the effects of anesthetics on organ function during sepsis and their influence on inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) remain to be fully elucidated. Because ketamine anesthesia has anti-inflammatory effects in some tissues, we hypothesized that it would attenuate lipopolysaccharide (LPS)-induced liver injury. METHODS: Adult rats were given no anesthesia (saline), continuous isoflurane inhalation, or intraperitoneal (i.p.) injection of ketamine 70 mg/kg. One hour later, the rats received saline or LPS (20 mg/kg i.p.) for 5 hours. The rats were killed, and serum hepatocellular enzymes, liver COX-2, iNOS protein (Western immunoblot), and nuclear factor kappa B (NF-kappaB)-binding activity (electrophoretic mobility shift assay) determined. In a separate study, the role of COX-2 in LPS-induced liver injury was examined by pretreating rats with the selective COX-2 inhibitor NS-398 (3 mg/kg, i.p.) and the role of iNOS examined with the use of the selective inhibitor aminoguanidine (45 mg/kg, i.p.) 1 hour before LPS. RESULTS: LPS increased serum aspartate aminotransferase and alanine aminotransferase levels, hepatic iNOS and COX-2 protein, and nuclear factor NF-kappaB. Ketamine, but not isoflurane, attenuated these effects caused by LPS. COX-2 inhibition with NS-398 as well as iNOS inhibition with aminoguanidine diminished LPS-induced changes in aspartate aminotransferase and alanine aminotransferase levels. CONCLUSIONS: These data indicate that anesthetics differ in their effects on liver injury caused by LPS. Ketamine has hepatoprotective effects, while isoflurane does not. Moreover, the protective effects of ketamine are mediated, at least in part, through a reduction in COX-2 and iNOS protein that could be regulated via changes in NF-kappaB-binding activity.

Rat gastric injury after lipopolysaccharide: role of inducible nitric oxide synthase.

BACKGROUND: Short-term treatment with lipopolysaccharide (LPS) causes morphologic, but not macroscopic, gastric injury and decreases gastric injury caused by a subsequent challenge with a luminal irritant. This effect is abrogated by inducible nitric oxide synthase (iNOS) inhibition. The effects of long-term treatment with LPS on gastric injury are unknown as is the role of iNOS. We hypothesized that LPS would cause macroscopic gastric injury at later time points through an iNOS-dependent pathway. METHODS: Conscious rats were given saline or LPS (1 or 20 mg/kg intraperitoneal) as a single intraperitoneal injection and killed 24 to 72 hours after injection. Macroscopic gastric injury (computerized planimetry), gastric luminal fluid volume and pH, and iNOS protein levels were assessed. RESULTS: When compared with saline, high-dose but not low-dose LPS caused macroscopic gastric injury, increased gastric luminal fluid and pH, and up-regulated iNOS at 24 and 48 hours. All assessments returned to baseline by 72 hours. Inhibition of iNOS with 1400W (1 mg/kg intraperitoneal) given 15 minutes before saline or LPS (20 mg/kg) attenuated the deleterious effects of LPS on gastric injury and pH, but not fluid accumulation. CONCLUSIONS: These data suggest that prolonged treatment with high-dose LPS causes gastric injury through an iNOS-mediated pathway.

Does upregulation of inducible nitric oxide synthase play a role in hepatic injury?

Lipopolysaccharide (LPS) and gut ischemia/reperfusion (I/R) injury cause reversible liver injury. Because nitric oxide (NO) can have both beneficial and deleterious effects in the gastrointestinal tract, and because the role of NO in gut I/R-induced hepatic injury is unknown, this study examined its role in LPS and gut I/R-induced hepatic injury in the rat. Both LPS and gut I/R caused a similar increase in serum hepatocellular enzymes. LPS but not gut I/R caused a significant increase in upregulation of hepatic inducible NO synthase (iNOS) according to quantitative real-time RT-PCR and Western immunoblot analysis. Aminoguanidine, a selective iNOS inhibitor, attenuated LPS-induced hepatic injury and hypotension, but did not prevent gut I/R-induced hepatic injury. In contrast, the non-selective NOS inhibitor N(G)-nitro-L-arginine methyl ester aggravated liver damage from both LPS and gut I/R. These data indicate that iNOS plays a role in mediating LPS-induced hepatic injury, but not gut I/R-induced hepatic injury. The data also suggest that the constitutive isoforms of NOS play a hepatoprotective role in both models of hepatic injury.

Standardized patient care guidelines reduce infectious morbidity in appendectomy patients.

BACKGROUND: Surgical wound infection and intra-abdominal abscess remain common infectious complications after appendectomy, especially in the setting of a perforated or gangrenous appendix. We therefore developed a clinical protocol for the management of appendicitis to decrease postoperative infectious complications. METHODS: Between January 1, 1999, and December 31, 1999, 206 patients with appendicitis were treated on protocol. Retrospectively, the charts were reviewed for all protocol patients as well as for 232 patients with appendicitis treated in the year prior to protocol initiation. Data were collected on surgical wound infections and intra-abdominal abscesses. RESULTS: There were significantly fewer infectious complications in the protocol group than in the nonprotocol group (20 [9%] versus 8 [4%]; P <0.05). In patients with a perforated or gangrenous appendix, the infectious complication rate was reduced from 33% to 13% (P <0.05). CONCLUSIONS: The incidence of infectious complications after appendectomy can be significantly reduced with a standardized approach to antibiotic therapy and wound management.

Diverticulitis in the younger patient.

BACKGROUND: The purpose of this study was to examine the presentation of diverticulitis at an urban county hospital serving predominantly indigent patients and to analyze the differences, if any, in presentation and treatment in younger patients. METHODS: A retrospective review of medical records from 1995 to 2001 was performed at a single institution to identify patients admitted to the surgical service with the diagnosis of diverticular disease. Inclusion criteria were either diverticulitis confirmed at operation or radiographic findings consistent with the disease. Patient demographics, history, pertinent physical findings, and treatment were recorded. The data were analyzed after dividing the patients into two populations: a younger population 50 years of age or less, and a second population of patients older than 50. RESULTS: During the interval, a total of 64 patients were admitted to the surgical service with the diagnosis of diverticulitis. The mean age of this population was 45.5 years (range 21 to 86). Forty-six patients were under 50 years of age (72%). Analysis of sex differences, type and timing of surgical procedure, and complication rate with respect to age showed no significant difference between the two age groups. CONCLUSIONS: We are clearly treating a younger patient population than previous reports on patients with diverticulitis. Although there was a trend toward increased surgical intervention in the younger population, this number did not reach statistical significance. Diverticulitis in young patients at our institution does not appear to take a more aggressive course than the same disease in older patients.

Cytomegalovirus enteritis manifesting as recurrent bowel obstruction and jejunal perforation in patient with acquired immunodeficiency syndrome: rare report of survival and review of the literature.

BACKGROUND: Cytomegalovirus (CMV) enteritis presenting with perforation in the setting of acquired immunodeficiency syndrome (AIDS) represents a particularly deadly combination. METHODS: Case report and review of the pertinent literature. CASE REPORT: The authors report a patient with AIDS and CMV enteritis presenting as recurrent small-bowel obstruction and leading to perforation of the jejunum with subsequent survival. CONCLUSION: This is believed to represent the second case in the English-language literature of survival after CMV-induced small intestinal perforation in a patient with AIDS.

Entertainment education for breast cancer surgery decisions: a randomized trial among patients with low health literacy.

OBJECTIVE: To evaluate an entertainment-based patient decision aid for early stage breast cancer surgery in low health literacy patients. METHODS: Newly diagnosed female patients with early stage breast cancer from two public hospitals were randomized to receive an entertainment-based decision aid for breast cancer treatment along with usual care (intervention arm) or to receive usual care only (control arm). Pre-decision (baseline), pre-surgery, and 1-year follow-up assessments were conducted. RESULTS: Patients assigned to the intervention arm of the study were more likely than the controls to choose mastectomy rather than breast-conserving surgery; however, they appeared better informed and clearer about their surgical options than women assigned to the control group. No differences in satisfaction with the surgical decision or the decision-making process were observed between the patients who viewed the intervention and those assigned to the control group. CONCLUSIONS: Entertainment education may be a desirable strategy for informing lower health literate women about breast cancer surgery options. PRACTICE IMPLICATIONS: Incorporating patient decision aids, particularly computer-based decision aids, into standard clinical practice remains a challenge; however, patients may be directed to view programs at home or at public locations (e.g., libraries, community centers).

Salicylate enhances rat gastric gelatinase activity.

BACKGROUND: Increased matrix metalloproteinase (MMP) activity is associated with tissue injury in some organs. Their role in gut injury remains to be fully elucidated. We recently demonstrated that increased MMP-2 activity participated in lipopolysaccharide (LPS)-induced gastric injury. Thus we hypothesized that MMPs may play a role in other models of gastric injury. MATERIALS AND METHODS: The effect of L-NAME (10 mg/kg IP) or salicylate (100 mg/kg IP) on gastric injury from 20% ethanol was evaluated in an anesthetized model of gastric injury. In a separate experiment, gastric metalloproteinase activity was assessed after salicylate or L-NAME administration. Rats were given either L-NAME (10 mg/kg), salicylate (100 mg/kg), or saline IP and sacrificed after 6 hours. Gastric mucosa was harvested and portions of the glandular stomach snap frozen for gelatin and in situ zymography as indices of MMP activity. Subsequently the effect of MMP inhibition on macroscopic gastric injury from salicylate and a dilute luminal irritant was determined. RESULTS: Both L-NAME and salicylate significantly increased gastric injury from 20% ethanol versus saline controls. Salicylate treatment significantly increased gelatinase activity as determined by in situ zymography and gelatin zymography while L-NAME did not. MMP inhibition ameliorated macroscopic gastric injury secondary to salicylate and a dilute luminal irritant. CONCLUSIONS: This is the first study to report that MMP activity increases in the stomach following salicylate treatment. These data suggest that MMPs may play a role in the ability of salicylate to exacerbate gastric injury from irritants, but likely do not play a role in mediating the deleterious effects of L-NAME.

Rat gastric gelatinase induction during endotoxemia.

Despite continued investigation, the pathogenesis of tissue injury secondary to sepsis remains elusive. Further evaluation of the mechanisms by which endotoxemia and sepsis induce tissue injury is necessary to formulate rational and effective treatment strategies. The purpose of these studies was to evaluate the role of the matrix metalloproteinases MMP-2 and MMP-9 in gastric injury during lipopolysaccharide induced endotoxemia. Lipopolysaccharide increased gastric gelatinase activity as determined by in situ and gelatin zymography. Specifically, lipopolysaccharide induced MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) transcription, with subsequent increases in MMP-2 and TIMP-1 protein expression. Furthermore, selective metalloproteinase inhibition ameliorated gastric injury in this model. These data suggest that lipopolysaccharide-induced gastric injury is mediated, at least in part, by increased MMP-2 production.

Preliminary testing of a just-in-time, user-defined values clarification exercise to aid lower literate women in making informed breast cancer treatment decisions.

OBJECTIVE: To report on the initial testing of a values clarification exercise utilizing a jewellery box within a computerized patient decision aid (CPtDA) designed to assist women in making a surgical breast cancer treatment decision. DESIGN: Pre-post design, with patients interviewed after diagnosis, and then after completing the CPtDA sometime later at their preoperative visit. SAMPLE: Fifty-one female patients, who are low literate and naïve computer users, newly diagnosed with early stage breast cancer from two urban public hospitals. INTERVENTION: A computerized decision aid that combines entertainment-education (edutainment) with enhanced (factual) content. An interactive jewellery box is featured to assist women in: (1) recording and reflecting over issues of concern with possible treatments, (2) deliberating over surgery decision, and (3) communicating with physician and significant others. OUTCOMES: Patients' use of the jewellery box to store issues during completion of the CPtDA, and perceived clarity of values in making a treatment decision, as measured by a low literacy version of the Decisional Conflict Scale (DCS). RESULTS: Over half of the participants utilized the jewellery box to store issues they found concerning about the treatments. On average, users flagged over 13 issues of concern with the treatments. Scores on the DCS Uncertainty and Feeling Unclear about Values subscales were lower after the intervention compared to before the decision was made. CONCLUSIONS: A values clarification exercise using an interactive jewellery box may be a promising method for promoting informed treatment decision making by low literacy breast cancer patients.

Entertainment education for informed breast cancer treatment decisions in low-literate women: development and initial evaluation of a patient decision aid.

BACKGROUND: We report on the development and initial evaluation of a novel computerized decision support system (CDSS) that utilizes concepts from entertainment education (edutainment) to assist low-literate, multiethnic women in making initial surgical treatment decisions. METHOD: We randomly assigned 51 patients diagnosed with early stage breast cancer to use the decision aid. RESULTS: Patients who viewed the CDSS improved their knowledge of breast cancer treatment; found the application easy to use and understand, informative, and enjoyable; and were less worried about treatment. CONCLUSION: The system clearly reached its intended objectives to create a usable decision aid for low-literate, novice computer users.

Time-dependent aggravation or attenuation of lipopolysaccharide-induced gastric injury by nitric oxide synthase inhibition.

BACKGROUND: This study was conducted to test the hypothesis that nonselective nitric oxide synthase (NOS) inhibitors have different effects on lipopolysaccharide (LPS)-induced gastric injury depending upon whether they are given concurrently with LPS or after LPS at a time point that inducible NOS is up-regulated. MATERIALS AND METHODS: Female Sprague-Dawley rats received intraperitoneal (IP) LPS (20 mg/kg) for 3 h. Western immunoblot was used to determine iNOS, eNOS, and nNOS immunoreactivity after 3 h. In an additional set of experiments, we assessed the time dependent effects of nitric oxide synthase inhibition by giving rats LPS (20 mg/kg, IP) concurrently with Nitro-l-arginine methyl ester (l-NAME; 2-5 mg/kg, SC) or l-N(G)-(1-iminoethyl) lysine (l-NIL; 10 mg/kg, IP) for 5 h or LPS and delayed administration of l-NAME or l-NIL 3 h following LPS injection in identical doses. For these NOS inhibition experiments microscopic and macroscopic injury was assessed by a blinded observer using previously published scoring systems. Injury studies were conducted by exposing the stomach to 3 ml of 5 mM acidified taurocholate for 5 minutes in an anesthetized prep. RESULTS: A 3-h treatment with LPS (20 mg/kg IP) significantly increased iNOS protein immunoreactivity (Western immunoblot) but not eNOS or nNOS. N(G)-l-NAME (2-5 mg/kg SC) dose dependently aggravated macroscopic (computerized planimetry) and morphological gastric injury caused by the intraluminal bile irritant 5 mm acidified taurocholate for 10 min when given concurrently with LPS, an effect reversed by l- but not D-arginine (300 mg/kg). In contrast, delayed administration of l-NAME (3 h after LPS) dose dependently attenuated the ability of LPS to exacerbate gastric injury from bile. Both concurrent and delayed administration of the selective iNOS inhibitor, l-NIL (10 mg/kg IP) attenuated the effects of LPS. CONCLUSIONS: These data indicate that during endotoxemia, the stomach is rendered more susceptible to damage from luminal irritants such as bile, a frequent occurrence in septic patients with a gastrointestinal ileus. In this setting, iNOS has a pathologic role while the constitutive NOS isoforms play gastroprotective roles.