What Is Intermittent Fasting? Differential diagnosis of reactive gastropathy. Gastritis is a condition that leads to stomach lining inflammation, causing stomach pain, bloating, and nausea. [Full Text]. Bacterial infections, such as those caused by H. pylori, H. heilmannii, and streptococci, Viral infections, for example, caused by cytomegalovirus, Fungal infections, like candidiasis, histoplasmosis, and phycomycosis, Ischemia, which refers to damage due to lack of blood supply to the stomach, Medications such as NSAIDs, aspirin, naproxen, iron supplements, cocaine, steroids, and chemotherapy agents, Using a warm compress or hot water bottle on the site of discomfort, Increasing fluid intake by drinking more water or juice. 2007 Jan. 131(1):86-90. Reactive gastropathy is characterized, histologically, by 21: If long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) leads to reactive gastropathy, your doctor may recommend that you stop taking NSAIDs, take a lower dose, or take a different medicine for pain. Surg Clin North Am. Aliment Pharmacol Ther. [3] and occasionally after cholecystectomy and ampullary sphincterotomy. * Lives in the mucus layer of stomach lumen and can bind to gastric . Stool changes. In situations of upper gastrointestinal (GI) stasis, as is seen after gastric surgery, bacterial overgrowth occurs within the proximal small intestine. 352(25):2576-8. Semin Diagn Pathol. Common types of gastritis and gastropathy include . 1995 Apr. 2003 Jan. 15(1):35-40. Reactive gastropathy is characterized, histologically, by 21: Although the findings are not specific, several authors claim that weight loss and a hypochromic microcytic anemia are also associated features 3. Reflux gastritis in the intact stomach. Gastroenterol Clin North Am. 2001 Aug. 39(2):133-40. Lanza FL, Royer GL Jr, Nelson RS. These alterations in mucin expression were shown in cases of both nonsteroidal anti-inflammatory drug (NSAID)-associated and bile refluxassociated reactive gastropathy (chemical gastropathy). Prostaglandins are derived from arachidonic acid via the cyclooxygenase (COX) pathway. Genta, RM. 1990 Apr. Two other features, (4) acute and (5) chronic inflammatory cells, were graded separately; scores for each ranged from 0 (severe increase) to 3 (absence of inflammatory cells), for a combined score of 0 to 6. When associated with bile reflux secondary to partial gastrectomy, the lesions develop near the surgical stoma 18, but the more proximal oxyntic mucosa may also be affected. Reactive gastropathy diagnosis is by examination of tissue, e.g. Drugs that cause erosions and/or ulcers - adapted from Genta:[1], Not well-developed with minimal inflammation. Pathol Res Pract. Stump carcinoma has been reported in postgastrectomy stomachs. [4] The secondary (deoxycholic and lithocholic) and deconjugated bile acids are more injurious to the gastric mucosa than the primary (colic and chenodeoxycholic) and conjugated bile acids. The mucosa becomes inflamed when something damages or weakens this protective layer, resulting in gastritis. lack of large numbers of neutrophils and plasma cells. In the stomach, it may be called gastric intestinal metaplasia. The ingredients are tested by the manufacturer for. The endoscopic findings of reactive gastropathy are mostly nonspecific. The esophagus reacts to the injury and tries to repair itself. A stomach, or gastric, polyp is an unusual growth of tissue within the inner lining of the stomach. Gastric oxyntic and antral mucosa with active chronic h.p associated gastritis. Mod Pathol. Mar 16, 2018 #6 In humans, it is about 1 mm thick, and its surface is smooth, soft, and velvety. The diagnosis of reactive gastritis is made after a pathologist examines a tissue sample from the inside of the stomach under the microscope. Immediately after peeling back the label, using a sterile blunt instrument, remove the specimen from the biopsy forceps and place it onto the reactive yellow pad. Other causes include alcohol and non-steroidal anti-inflammatory drugs (NSAIDS). [26]. 352(25):2576-8. It is considered an autoimmune disorder, meaning your body's immune system attacks healthy cells,. what does this really mean? Hepatologist & Transplant Hepatologist, Sign up for our free Health Library Daily Newsletter, What Is Antral Gastritis? Dixon MF, OConnor HJ, Axon AT, King RF, Johnston D. Reflux gastritis: distinct histopathological entity?. Wilson P, Jamieson JR, Hinder RA, et al. Cytoskeletal and kinetic epithelial differences between NSAID gastropathy and Helicobacter pylori gastritis: an immunohistochemical determination. By partnering with patients, healthcare providers, and hospitals, we hope to provide all patients with the tools and knowledge to understand their pathology report. Schoenfeld P, Kimmey MB, Scheiman J, Bjorkman D, Laine L. Review article: nonsteroidal anti-inflammatory drug-associated gastrointestinal complications--guidelines for prevention and treatment. Bile reflux is thought to play a key role in the development of dysplasia and carcinoma in the gastric remnant. Triad rarely present; mild inflammation common. Drinking milk causes an increase in stomach acid production, which might aggravate gastritis symptoms. for quality and safety during the production process. MRCP (UK), FRCP(GLASGOW), CCT(GASTRO), Liver Transplant Fellow(BIRMINGHAM, UK), In fact, some studies have reported improvement of preneoplastic changes after diversion of the enteric reflux23. The most common cause of reactive gastropathy is the movement of bile or pancreatic secretions into the stomach from the small bowel. Definition: The antral mucosa (Synonym: pyloric mucosa) is the mucosa found in the gastric antrum. Iacobuzio-Donahue, Christine A.; Montgomery, Elizabeth A. The cumulative reflux gastritis score therefore ranged from 0 to 15. 2008 Oct. 132(10):1586-93. Gastritis in patients on non-steroidal anti-inflammatory drugs. http://emedicine.medscape.com/article/175909-overview#a6. 27:1348-54. [QxMD MEDLINE Link]. 1990 Apr. They generate the mucus inside the stomach that's accountable for shielding the tummy from the gastric acids. Aliment Pharmacol Ther. Traditional teaching holds that the normal stomach has three types of mucosae. Antral gastritis refers to the inflammation in the stomach lining found in the antral area of the stomach. gi doctor told me to check up in a year. Never ignore professional medical advice in seeking treatment because of something you have read on the MyPathologyReport site. Malagelada JR, Phillips SF, Shorter RG, et al. Schoenfeld P, Kimmey MB, Scheiman J, Bjorkman D, Laine L. Review article: nonsteroidal anti-inflammatory drug-associated gastrointestinal complicationsguidelines for prevention and treatment. Alkaline reflux gastritis. Privacy Policy. An interaction between the bacteria and the food in the digestive system might produce certain chemicals that cause the cells to change. Differential diagnosis of reactive gastropathy. An antral ulcer is a form of peptic ulcer as it is concentrated in the stomach lining. Eur J Gastroenterol Hepatol. Discomfort. [10]. Owen DA. Maguilnik, I.; Neumann, WL. Home Colon And Digestive What causes antral gastritis and how to treat it? Share cases and questions with Physicians on Medscape consult. [24]. The microscopic features of reactive gastropathy were well characterized by Dixon et al in their original description of reflux gastritis as a distinct histopathologic entity. Reactive gastropathy refers to a group of endoscopic and histologic findings caused by chemical injury to the gastric mucosa1. 2005 Nov. 22(4):273-83. 2005 Nov. 22(4):273-83. Although a correlation between histological evidence of chemical gastropathy and clinical manifestations, particularly risk of bleeding, is yet to be documented, reporting the suspicion of drug-induced gastric damage may help clinicians to identify patients that might benefit from change, reduction, or discontinuation of certain medications 5. [29] Regular endoscopic surveillance starting 10 to 15 years after surgery is recommended. There is smooth muscle hyperplasia in the lamina propria with edema and congestion of superficial capillaries. Doctors may also recommend taking a PPI along with NSAIDs to prevent or treat reactive gastropathy and its possible complications. Reactive gastropathy, chemical gastropathy also called gastritis of C type or "chemical gastritis" is an abnormality in the stomach caused by chemicals, . It is considered an autoimmune disorder, meaning your bodys immune system attacks healthy cells, causing the symptoms. [QxMD MEDLINE Link]. Rom J Morphol Embryol. Only after we are satisfied with the products. Poor digestion, stretching, and increment of the stomach takes place during Foveolar Hyperplasia. BIOPSY: GASTRIC ANTRAL MUCOSA WITH MILD REACTIVE CHANGES; NEGATIVE FOR HELICOBACTER PYLORI TYPE ORGANISMS. by Jason Wasserman MD PhD FRCPC Antral Gastritis: Gastritis refers to inflammation of the inner stomach lining. The increased concentration of the more toxic forms of bile acid, coupled with the decreased gastric emptying time of the refluxed bile, results in gastric mucosal injury and subsequent reactive gastropathy (chemical gastropathy). Moderate reactive gastropathy. - Scant or minimal inflammatory cells (white arrow), i.e. In reactive gastropathy (chemical gastropathy), the distribution of CK8, CK18, and CK19 was normally distributed but increased in intensity. The signs and symptoms of gastritis include: Gnawing or burning ache or pain (indigestion) in your upper abdomen that may become either worse or better with eating. dad and aunt had precancerous polyps too. B: Sections from the distal esophagus show portions of squamous and glandular mucosa. Wolf, EM. No statement herein is to be construed as a diagnosis, treatment, preventative, or cure for any disease, disorder or abnormal physical state. GASTRIC ANTRAL AND OXYNTIC MUCOSA WITH CHRONIC INACTIVE GASTRITIS: . Dixon MF, O'Connor HJ, Axon AT, King RF, Johnston D. Reflux gastritis: distinct histopathological entity?. Ritchie WP Jr. Alkaline reflux gastritis. Gastritis and gastropathy may be chronic, developing slowly and lasting a long time, or acute, developing suddenly and lasting a short time. Gastritis is usually not serious and can be treated through various treatment options. Bile gastritis occurring after cholecystectomy. The tissue sample is removed in a procedure called a biopsy. Surgery. Mine said something similar. Carrasco G, Corvalan AH. Evolving patterns in the diagnosis of reactive gastropathy: data from a prospective Central European multicenter study with proposal of a new histologic scoring system. "Clinical perspectives on the rationale for potassium supplementation.". Mamoun Younes, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, American Society of Clinical Oncology, College of American Pathologists, United States and Canadian Academy of PathologyDisclosure: Nothing to disclose. do they get our quality seal of approval. What are reactive changes? This low-acid fruit can benefit those who suffer from acid reflux by soothing an inflamed esophagus lining and therefore alleviating discomfort. Characterized by scars and lesions, this form is considered difficult to treat. [26] Aberrant expression of the secreted mucins was also demonstrated. There are no serious issues with the tissue submitted to pathology. All Rights Reserved. Indigestion is usually temporary and does not necessitate medical attention. Severe reactive gastropathy with mucosal erosion of gastric antral mucosa (original magnification 200). [QxMD MEDLINE Link]. Antral Gastritis: Gastritis refers to inflammation of the inner stomach lining. Had endoscopy done extremely mild im found. Br Med J (Clin Res Ed). 39(5):524-30. The articles on MyPathologyReport are intended for general informational purposes only and they do not address individual circumstances. Histopathology. [QxMD MEDLINE Link]. [27]. Take antacids and other medications to lower stomach acid, Combination of antibiotics and an acid-blocking medication to treat gastritis caused by H. pylori infection, B12 vitamin shots (if gastritis is caused by pernicious anemia), Getting rid of irritants in the diet, such as lactose from dairy or gluten from wheat. The common underlying causes of reactive gastropathy include chronic bile reflux and long-term intake of nonsteroidal anti-inflammatory drugs (NSAIDs) 2. DOI: 10.1111/j.1365-2362.2004.01358.x Corpus ID: 25298464; Role of apoptosis and CD95receptor/ligand system in aspirin and Helicobacter pyloriinduced cell death @article{Domhan2004RoleOA, title={Role of apoptosis and CD95receptor/ligand system in aspirin and Helicobacter pyloriinduced cell death}, author={Sophie Domhan and Wolfgang Stremmel and Jochen Rudi}, journal={European . The lessons of Vioxx--drug safety and sales. Reactive gastropathy refers to the constellation of endoscopic and histologic findings caused by chemical injury to the gastric mucosa. Waxman HA. Other symptoms associated with antral gastritis are: Almost everyone has experienced indigestion and stomach discomfort at some point in their lives. These are lined by mucus cells that are interspersed with endocrine cells (chiefly G and D types), and a few parietal cells. Heart Inside Out Everything About Your Heart, All You Need to Know About High Cholesterol, Hodgkins Lymphoma Disease: Causes, Symptoms and Treatment, Glioblastoma: Types, Symptoms, Causes, Treatment and Diagnosis, Choriocarcinoma Cancer: Symptoms, Causes, Treatment and Diagnosis. A: Sections from the gastric antrum show portions of antral and oxyntic-type gastric mucosa with edema, vascular congestion and patchy chronic inflammation of the lamina propria. This region is responsible for releasing the contents of the stomach into the small intestine. Am J Gastroenterol. 2005. This page was last edited on 17 June 2016, at 17:47. 2015 May. The term chemical gastropathy was recommended by the Updated Sydney System 7, because it indicates an underlying chemical injury that is not associated with infection 8. and third party partners. This is called reflux. N Engl J Med. [2, 3, 4] It has since become apparent, however, that the constellation of histologic features seen in reactive gastropathy is a nonspecific response to chemical injury of the gastric mucosa. The following are examples of well-known foods to eat and foods to avoid in case of gastritis: Related:Bowel movements: How often should you poop? When signs and symptoms of gastritis do appear, they include stomach discomfort and burning, nausea, and vomiting. The bile reflux may be visible 20. what is the treatment for this? Although it is known that NSAIDs that selectively inhibit COX-2 cause significantly fewer gastrointestinal complications than nonselective COX inhibitors do, it is still unclear whether administration of selective inhibitors results in less severe reactive gastropathy (chemical gastropathy)15. It may range from mild to severe, triggering vomiting in some cases. 2005 Jun 23. The clinical features associated with reactive gastropathy are determined by its underlying cause. Press J to jump to the feed. It means that the cells lining the inside of the stomach have become injured by substances not normally found in the stomach. An antral ulcer is also known as an antral gastric ulcer. Reactive gastropathy diagnosis is by examination of tissue, e.g. International Workshop on the Histopathology of Gastritis, Houston 1994. google_ad_client: "ca-pub-9759235379140764", The following symptoms may be experienced: Indigestion. A number of things, including chronic reflux (regurgitation) of stomach contents up into the esophagus, trauma from taking medicines, and infections can injure the squamous lining of the esophagus. Postoperative reflux gastritis: pathophysiology and long-term outcome after Roux-en-Y diversion. The stomach has three tasks. Histological features do not define NSAID-induced gastritis. certain illnesses, such as diabetes or kidney failure. Stomach, antrum, biopsy: Reactive (chemical) gastropathy No Helicobacter organisms identified on routine H&E stained sections . The results probably reflect regeneration process from an. Bel Marra products are produced a stomach biopsy. It has since become apparent, however, that the constellation of histologic features seen in reactive gastropathy is a nonspecific response to chemical injury of the gastric mucosa 4. Despite the occasional development of stump carcinomas in postgastrectomy stomachs, reactive gastropathy is not a major risk factor for the development of gastric carcinoma. after finishing therapy. [8] The bile reflux may be visible. Discomfort may be experienced in the epigastric region after eating. Nausea. Diagnosis is by endoscopy. Gastritis can develop quickly (acute gastritis) or gradually over time (chronic gastritis). It consists of simple columnar epithelium, lamina propria, and the . May be seen post-Bilroth II (distal gastrectomy). 12(6):592-8. Histology of the postoperative stomach before and after diversion of bile. Another name for this condition is chemical gastropathy. The damage causes abdominal pain which is often worse after a meal. By following a healthy lifestyle and a well-balanced diet, most people can prevent gastritis from developing. 46(4):269-74. Gastric antral vascular ectasia (GAVE) should be considered in the differential diagnosis. [13], Although it is known that NSAIDs that selectively inhibit COX-2 cause significantly fewer GI complications than nonselective COX inhibitors do, it is still unclear whether administration of selective inhibitors results in less severe reactive gastropathy (chemical gastropathy). Considered one of the most common symptoms of antral gastritis, as it affects the process of digestion as well as emptying food into the intestines. Stump carcinoma has been reported in postgastrectomy stomachs. What causes reactive gastropathy? lack of large numbers of neutrophils and plasma . The increased concentration of the more toxic forms of bile acid, coupled with the decreased gastric emptying time of the refluxed bile, results in gastric mucosal injury and subsequent reactive gastropathy (chemical gastropathy). 43(4):303-6. 1996. Antral gastritis can cause excessive discomfort in the gastrointestinal tract of those affected. The mucosal changes seen in reactive gastropathy are usually most prominent in the antrum and prepyloric region. Go to Peptic Ulcer Disease for complete information on this topic. "Differential diagnosis of reactive gastropathy.". The prostaglandin E1 analog drug, Cytotec (misoprostol) has proven to be an effective preventative medication for gastric lesions associated with high-dose . The oxyntic mucosa of the gastric body and fundus has glands with parietal cells that secrete acid, and chief cells that secrete digestive enzymes. Superficial erosions may be observed. Wolf EM, Plieschnegger W, Schmack B, et al. I was diagnosed with functional dyspepsia and told to try brain-gut meds (antidepressants). 2003 Jan. 15(1):35-40. a stomach biopsy. For more information about this site, contact us at info@mypathologyreport.ca. Persistent epithelial damage may result in the release of platelet-derived growth factor (PDGF), which stimulates smooth muscle proliferation, followed by fibroblastic proliferation 12. [QxMD MEDLINE Link]. Excess gas may also build up within the stomach, leading to burping. By using our website, you consent to our use of cookies. Dr. Myron Arlen answered Surgical Oncology 66 years experience Precancer: The antrum is that portion of the lower stomach above the pylorus. The lessons of Vioxxdrug safety and sales. Mod Pathol. Northeast Ohio 216.444.7000 Appointments & Locations For EGD, an Olympus GIF-Q200 (Olympus Optical Co. Ltd., Tokyo, Japan) was used. As a result of the neutral pH within the surface epithelial cells, the NSAID compound dissociates into its ionized form, contributing to direct cell injury 14. It is where digestion of protein begins. https://emedicine.medscape.com/article/1962893-overview. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. Abha Goyal, MD Associate Staff Pathologist, Cleveland Clinic The localization of CK7 and CK20 staining was modified, with extension toward the deep foveolar region. [QxMD MEDLINE Link]. Nausea, bilious vomiting, and other dyspeptic symptoms may also be present. J Clin Pathol. specifications following safe manufacturing practices. [23] Although the findings are not specific, several authors claim that weight loss and a hypochromic microcytic anemia are also associated features. Extreme stomach cramps and pain Shortness of breath or light-headedness Fatigue Vomiting blood or vomit that looks like ground coffee Sometimes you will have mild bleeding in your stomach but may. [2], A prospective multicenter study by Wolf et al developed a new score with visual analog scales. Scant acute & chronic inflammatory cells. Devon Andre has been involved in the health and dietary supplement industry for a number of years. Yes. Reactive increase in gastric mucus secretion is an adaptive defense mechanism against low-dose aspirin-induced gastropathy. The mucosa may be normal or may exhibit erythema, congestion, edema, or erosions8. [1] because it indicates an underlying chemical injury that is not associated with infection. The following are other causes of gastritis pain: The primary mode of symptom formation is the development of inflammation in the antrumthe lower portion of the stomach. The gastric antral mucosa shows expansion of the lamina propria by chronic inflammatory cells, consisting of plasma cells and small lymphocytes, predominantly located toward the luminal aspect of the mucosa, a pattern that is suggestive of H pylori infection. These gastric mucosal protection and ulcer healing effects are associated with antioxidant effects and the augmentation of prostaglandin E2 and suggest that P. cuspidatum might be a promising . Copyright 2023 Bel Marra Health. Persistent epithelial damage may result in the release of platelet-derived growth factor (PDGF), which stimulates smooth muscle proliferation, followed by fibroblastic proliferation. 1994 Jun. Reactive gastropathy has also been referred to as chemical gastropathy, reflux gastritis, and type C gastritis6. Sepulveda AR, Patil M. Practical approach to the pathologic diagnosis of gastritis. Erythemayohus mucosa in the gastric fundus. [QxMD MEDLINE Link]. These foveolar cells have a vital function to perform. The bile reflux may be visible 20. If left untreated, reactive gastropathy can lead to ulcers or bleeding in the stomach. Semin Diagn Pathol. [1] The histologic picture is characterized by foveolar hyperplasia with edema, smooth muscle hyperplasia, and congestion of superficial capillaries in the lamina propria in the absence of significant inflammation (see an example in the image below). Create an account to follow your favorite communities and start taking part in conversations. What are reactive changes? [QxMD MEDLINE Link]. Representative histology of healthy antral mucosa (A), antral . Are there neutrophils in the mucosa? 303(3):136-8. Finally . All rights reserved. Of all the antral gastritis symptoms, one of the most common symptoms is indigestion. Genta RM, Sonnenberg A. Characteristics of the gastric mucosa in patients with intestinal metaplasia. Genta RM. Reactive (chemical) gastropathy is a gastric mucosal pattern of injury induced by endogenous (bile / pancreatic reflux) or exogenous (chronic use of NSAIDs, acetylsalicylic acid, ethanol or chemotherapeutics) agents . N Engl J Med. Patients with reactive gastropathy secondary to bile reflux typically have an enterogastric anastomosis and most commonly present with continuous burning midepigastric pain that is often exacerbated by food and recumbency. Antonia R Sepulveda, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Gastroenterological Association, American Society for Investigative Pathology, College of American Pathologists, United States and Canadian Academy of PathologyDisclosure: Nothing to disclose. Cleveland Clinic is a non-profit academic medical center. [14, 17], This condition was originally described in patients who had undergone partial gastrectomymost frequently, Billroth II gastric reconstruction. [QxMD MEDLINE Link]. Devon is keenly aware of trends and new developments in the area of health and wellness. Gastropathy is a broad term for any kind of stomach disease. The presence of fibrin thrombi in the mucosal capillaries is a characteristic feature of GAVE rather than of reactive gastropathy. For potential or actual medical emergencies, immediately call 911 or your local emergency service. Yes. [QxMD MEDLINE Link]. Iijima K, Iwabuchi T, Ara N, et al. Arrow points to smooth muscle fibers in superficial lamina propria (original magnification 200). Ritchie WP Jr. Alkaline reflux gastritis. The presence of blood in the stool may also be detected. Bile reflux usually occurs in patients who have undergone a Billroth 2 partial gastrectomy; it is also recognized to occur in intact stomachs in individuals with alcohol abuse, cigarette smoking, chronic respiratory disease, or duodenal ulcer, and even in healthy subjects 11. After a meal, avoid lying down for up to 2 to 3 hours. Most people have a problem with their stomach at one time or another. N Engl J Med. 1. Gastritis pain due to infection can be remedied by antibiotics targeting the specific causative bacteria. Once there, food contents may begin fermenting for extended periods of time, leading to bloating and flatulence. 27:1348-54. Maguilnik I, Neumann WL, Sonnenberg A, Genta RM. [2] The accompanying histamine-mediated vascular response leads to edema and hyperemia. 1985 Aug. 103(2):178-83. N Engl J Med. Gastric antral vascular ectasia (GAVE) is the underlying cause for 4% of nonvariceal upper GI bleeding. [QxMD MEDLINE Link]. (Aug 2012). [8]. Mucin expression is reported to be altered in reactive gastropathy in comparison with normal gastric mucosa as well as H pylori gastritis. Avoid foods that are greasy, fried, spicy, or acidic. here is what was written: antral-type and body type gastric mucosa with focal intestinal metaplasia. J Clin Pathol. Educational text answers on HealthTap are not intended for individual diagnosis, treatment or prescription. The mucosa may be normal or may exhibit erythema, congestion, edema, or erosions 8. Digestive fluids can harm and inflame your stomach lining if the mucus-lined barrier that covers your stomach wall is damaged. Reactive gastropathy may range from mild to severe and, as noted (see Pathophysiology and Etiology), may involve the oxyntic mucosa as well as the antral mucosa (see the images below). We herein, through this case, would like to highlight that high clinical suspicion is required to diagnose . Waxman HA. Chronic gastritis can also be seen in people who have previously been treated for Helicobacter pylori. J Clin Pathol. Aliment Pharmacol Ther. [14] However, most of these COX-2 inhibitors have been withdrawn from the market or have had their indications drastically limited in view of their potential serious cardiovascular side effects.