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At least 1,603 records · Page 89Linked to original sources
PubMed2000

High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy.

BACKGROUND & AIMS: The multidrug resistance (MDR) gene codes for a drug efflux pump P-glycoprotein 170 (Pgp-170) expressed on the surface of lymphocytes and intestinal epithelial cells. Inflammatory bowel disease (IBD) poorly responsive to medical therapy may relate to MDR expression because glucocorticoids are known Pgp-170 substrates. METHODS: Using flow cytometry, we measured peripheral blood lymphocyte (PBL) MDR in 153 IBD patients and 50 healthy volunteers, and assessed the relationship between PBL, mucosal intraepithelial lymphocyte (IEL), and mucosal epithelial cell (EC) MDR expression in a further 20 IBD patients and 19 controls. RESULTS: Compared with controls, PBL MDR was significantly elevated in patients with Crohn's disease who required bowel resection for failed medical therapy (mean +/- SEM, 26.7 +/- 2.8 vs. 11.9 +/- 1.0; P <0.0001) and patients with ulcerative colitis who required proctocolectomy for failed medical therapy (20.3 +/- 2.5 vs. 11.9 +/- 1.0; P = 0.001). PBL MDR remained stable over time and was not influenced by disease activity or glucocorticoid therapy. Both PBL and mucosal MDR expression appeared independent of disease activity, and there was a significant correlation between PBL MDR expression and both IEL expression (r = 0.92; P < 0.0001) and EC expression (r = 0.54; P < 0.001). CONCLUSIONS: PBL and mucosal MDR expression may play an important role in determining the response of IBD patients to glucocorticoid therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Glial-derived neurotrophic factor regulates apoptosis in colonic epithelial cells.

BACKGROUND & AIMS: Ablation of the enteric glia leads to a fulminant hemorrhagic jejunoileitis. We hypothesized that glial-derived neurotrophic factor (GDNF) may be involved in mucosal protection of the gut. Therefore, we examined the regulation of GDNF and its receptor (GFR-alpha1) in colonic inflammation and its effects on colonic epithelial cell apoptosis. METHODS: The expression of GDNF and GFR-alpha1 was investigated in experimental colitis of rats and in human inflammatory bowel disease (IBD). GDNF-induced activation of Akt (protein kinase B [PKB]) and mitogen-activated protein kinase (MAPK) in the colonic epithelial cell lines HT-29 and SW480 was studied. Furthermore, the antiapoptotic potency of GDNF in SW480 cells was evaluated. RESULTS: GDNF was specifically up-regulated in experimental rat colitis and in IBD. In contrast, GFR-alpha1 was constitutively expressed in rat and human colonic epithelium. GDNF potently activated MAPK and Akt (PKB) in colonic epithelial cells. Moreover, GDNF strongly prevented apoptosis in SW480 cells. Our data show that GDNF-mediated protection against apoptosis depends on activation of the MAPK and phosphatidylinositol 3-kinase/Akt (PKB) pathways. CONCLUSIONS: GDNF is up-regulated in IBD and has strong antiapoptotic properties in colonic epithelial cells. This points to a novel role of the neurotrophic factor GDNF for mucosal protection and regeneration in IBD.

Apoptosis↗
PubMed2003

6-thioguanine can cause serious liver injury in inflammatory bowel disease patients.

BACKGROUND & AIMS: Thioguanine (6-TG) has been studied as an alternative thiopurine in inflammatory bowel disease (IBD). Short-term safety and efficacy data were favorable. Experience with 6-TG in patients with acute lymphoblastic leukemia raised long-term safety concerns when implicated in nodular regenerative hyperplasia (NRH) of the liver and portal hypertension. The aim of this study was to describe the association between 6-TG and NRH in IBD. METHODS: Liver chemistries and complete blood counts were monitored, and patients were encouraged to undergo liver biopsy. Clinical data were collected by chart review, and associations were tested by univariate and multivariable analyses. Patients were classified based on the presence (group 1) or absence (group 2) of laboratory abnormalities. RESULTS: Laboratory abnormalities occurred in 29 of 111 patients (26%). Elevations of liver enzymes and a decrease in platelet counts (<200,000) were most commonly observed. Male gender (odds ratio, 2.9; 95% CI, 1.1-7.3; P < 0.03) and preferential 6-methylmercaptopurine production on 6-mercaptopurine/azathioprine (odds ratio, 3.0; 95% CI, 1.2-7.4; P < 0.04) were independently associated with laboratory abnormalities. No association was seen with duration of 6-TG treatment, cumulative dose, or 6-TG nucleotide levels. The median increase in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels was 39, 30, and 75 U/L, respectively, in group 1, and the median decrease in platelet count was 115,000 in group 1 versus 7000 in group 2 (P < 0.001). NRH occurred in 76% of patients undergoing biopsy in group 1 and 33% in group 2. CONCLUSIONS: NRH is a common finding in 6-TG-treated patients with IBD. The progression or reversibility of NRH remains unknown. Our findings suggest that 6-TG should not be considered as therapy for patients with IBD.

Adolescent↗
PubMed1998

Altered frequency of a promoter polymorphic allele of the kinin B1 receptor gene in inflammatory bowel disease.

BACKGROUND & AIMS: Evidence of kinin-mediated inflammation in the gastrointestinal tract is accumulating. The genes and some polymorphic sites have been characterized for both kinin B1 and B2 receptors. These candidate genes were studied for their possible association with inflammatory bowel disease (IBD). METHODS: In a retrospective study, the prevalence of allele pairs for four polymorphic sites of the two kinin receptor genes was determined in 53 patients with IBD and in 110 healthy volunteers similar in age, body weight, and gender proportions, using polymerase chain reaction and other techniques. RESULTS: Only the B1 receptor promoter polymorphism (G-699-->C) exhibited a significantly different allele frequency between the two groups (prevalence of the C allele of 5.7% in patients with IBD compared with 33.6% in controls; P = 0.0002) or between the controls and either etiologic subgroup (ulcerative colitis and Crohn's disease). Allelic polymorphisms affecting exon 3 of the B1 receptor gene (A1098-->G) or exon 2 (C181-->T) or 1 (a 9-base pair deletion) of the B2 receptor gene were found to be neutral. CONCLUSIONS: The gene corresponding to the B1 receptor for kinins may be a nonetiologic marker of symptomatic IBD, as suggested by the altered prevalence of a polymorphism presumably affecting its regulation.

Adult↗
PubMed1998

Diagnostic accuracy of serological assays in pediatric inflammatory bowel disease.

BACKGROUND & AIMS: Accurate serological assays are desirable for the diagnosis of inflammatory bowel disease (IBD) types in the pediatric age group. The aim of this study was to test the diagnostic accuracy of modified assays for perinuclear (p) antineutrophil cytoplasmic antibodies (ANCAs) and anti-Saccharomyces cerevisiae antibodies (ASCAs) in patients with pediatric ulcerative colitis (UC) and Crohn's disease (CD) and in those without IBD. METHODS: With observers blinded to patients' diagnoses, serum specimens were analyzed for immunoglobulin (Ig) A and IgG ASCAs and ANCAs by enzyme-linked immunosorbent assay. The perinuclear location of ANCAs visualized by indirect immunofluorescence was confirmed by its disappearance after administration of deoxyribonuclease. RESULTS: IgA and IgG ASCA titers were significantly greater and highly specific for CD (95% for either, 100% if both positive). pANCA was 92% specific for UC and absent in all non-IBD controls. The majority of patients with CD positive for pANCA had a UC-like presentation. Disease location, duration, activity, complications, and treatment with immunosuppressive drugs did not have an impact on the ASCA or pANCA assay results. After resection, UC patients remained pANCA positive, in contrast to patients with CD, in whom ASCA titers decreased toward normal values postoperatively. CONCLUSIONS: ASCA and pANCA assays are highly disease specific for CD and UC, respectively. These serological tests can assist clinicians in diagnosing and categorizing patients with IBD and may be useful in making therapeutic decisions.

Adolescent↗
PubMed1996

Colonic mucosal abnormalities associated with oral sodium phosphate solution.

BACKGROUND: Oral sodium phosphate (NaP) is increasingly used as a colonic cleansing agent for colonoscopy. It has been shown to be efficacious, well-tolerated, and safe. Mucosal abnormalities associated with NaP have recently been described. We carried out this controlled study to assess whether bowel cleansing preparations commonly used in colonoscopy are associated with colonic mucosal changes that may mimic inflammatory bowel disease (IBD). METHOD: All patients undergoing colonoscopy from January 1994 to June 1994 were considered for the study. Patients with history or symptoms suggestive of IBD were excluded. Patients were randomized to receive polyethylene glycol-based lavage (PEG-ELS) or NaP solution as their bowel cleansing preparation. Two gastroenterologists performing the colonoscopies were blinded to the type of preparation. Any mucosal abnormalities were noted and photographic documentation and biopsy specimens were taken. RESULTS: Ninety-seven patients were studied, 44 receiving PEG-ELS and 53 receiving NaP. Both groups were similar with regard to sex, age, and indication for colonoscopy. Fourteen patients were found to have nonspecific aphthoid-like erosions similar in appearance to Crohn's disease. These lesions, however, were not friable and biopsy results were not compatible with IBD. This mucosal abnormality was found in 13 patients who received NaP (24.5%) and only 1 patient who received PEG-ELS (2.3%). CONCLUSION: Nonspecific aphthoid-like mucosal lesions occur frequently in patients who received NaP for colonoscopy preparation. These lesions are endoscopically similar to those seen in Crohn's disease. Because of the potential for misinterpretation of these lesions, we do not recommend the use of NaP as a colonic cleansing preparation for patients with chronic diarrhea or in whom the diagnosis of IBD is suspected.

Administration, Oral↗
PubMed2002

Inflammatory bowel disease: developing a short disease specific scale to measure health related quality of life.

AIM: To report on the preliminary development of a short scale, the Edinburgh inflammatory bowel disease questionnaire (EIBDQ) to measure disease specific aspects of inflammatory bowel disease (IBD) in terms of both physical impact and health related quality of life (HRQoL) consequences. METHODS: A survey of individuals with Crohn's disease (n=50), ulcerative colitis (n=50) and psoriatic arthritis (n=28) was carried out using the EIBDQ. The data were subject to factor analysis in order to investigate underlying dimension of the EIBDQ which were then analysed for internal consistency. Data for disease specific aspects of the EIBDQ were compared between IBD patients and psoriatic arthritis patients using contingency tables and the underlying dimension of the EIBDQ were correlated with measures of quality of life and psychological morbidity and a disease specific measure. RESULTS: There are three underlying dimensions to the EIBDQ: a disease specific factor, a bowel specific factor and an information factor. The disease specific factor and the bowel specific factor are internally consistent and correlate with other measures of disease activity, quality of life and psychological morbidity. The EIBDQ is able to discriminate between IBD and another inflammatory disease: psoriatic arthritis. CONCLUSION: The EIBDQ is a reliable and valid instrument for measuring disease specific aspects of IBD but further development is required.

Arthritis, Psoriatic↗
PubMed2003

Evaluation of 99mTc-HMPAO leukocyte scintigraphy in the investigation of pediatric inflammatory bowel disease.

OBJECTIVE: To evaluate (99m)Tc-HMPAO leukocyte scintigraphy as an investigation for inflammatory bowel disease (IBD). STUDY DESIGN: Scintigraphy was performed in 95 children undergoing investigation for IBD in a tertiary Gastroenterology Department. Diagnosis was based on conventional investigations including small bowel barium contrast radiology (BCR), upper gastrointestinal endoscopy (UGIE), colonoscopy, and endoscopic biopsy (the "gold standards"). IBD was confirmed in 73 (57 Crohn's disease; 10 ulcerative colitis; 6 indeterminate colitis) and excluded in 22 (controls). Scintigraphy was (1) evaluated as a screening test, (2) compared with individual conventional tests, (3) assessed for each gut segment. RESULTS: Screening test: sensitivity 0.75 (95% CI, 0.63-0.85), specificity 0.82 (95% CI, 0.59-0.94), PPV 0.93, NPV 0.5. Comparison with BCR: sensitivity 0.87 (95% CI, 0.72-0.96), specificity 0.57 (95% CI, 0.39-0.73), PPV 0.69, NPV 0.2. Comparison with UGIE: specificity 0.9 (95% CI, 0.79-0.96), NPV 0.13 (sensitivity and PPV unavailable). Comparison with colonoscopy: sensitivity 0.57 (95% CI, 0.41-0.73), specificity 0.71 (95% CI, 0.54-0.85), PPV 0.71, NPV 0.42. Comparison with biopsies paralleled that with endoscopy. False negatives were especially common (NPV< or =0.2) in the proximal gut. CONCLUSIONS: (99m)Tc-HMPAO leukocyte scintigraphy should not be relied on as a screening test for IBD because false negative results are common. This method is especially unreliable at detecting disease in the proximal gut.

Adolescent↗
PubMed2000

Mediators of stress effects in inflammatory bowel disease: not the usual suspects.

UNLABELLED: Empirical efforts to prove or disprove an association between stress and the course of inflammatory bowel disease (IBD) have had inconsistent results. Direct study of mediators of stress-related physiological processes may clarify this important area. METHODS: candidate mediators were selected based on evidence that they have a role in the pathophysiology of IBD. Medline searches for original articles addressing each putative mediator and psychological stress were conducted. Articles were reviewed with goals of synthesis and hypothesis generation. RESULTS: there is evidence that substance P (SP), vasoactive intestinal protein (VIP), tumour necrosis factor alpha (TNFalpha), oxidant molecules, endogenous glucocorticoids and heat shock proteins (HSPs) are involved in the stress response. DISCUSSION: two principles emerge which should inform efforts to investigate stress in IBD. First, stress effects are regulated by highly interdependent systems. Second, the effects of mediators are highly specific to the location of their activity, and so, investigations in IBD are likely to require direct investigation of inflamed and unaffected gut tissue.

Arousal↗
PubMed1994

The role of endoscopy in inflammatory bowel disease.

Endoscopy has assumed a preeminent role in the diagnostic approach to IBD. It is more sensitive than radiography in detecting early, subtle changes of IBD, both through endoscopic appearance and histologic sampling of mucosa. Endoscopy also appears to be a safe technique in patients presenting with severe forms of colitis and can play an important role in defining the etiologic basis of disease in this subgroup of patients. In addition to its diagnostic role, endoscopy has proven useful in surveying disease activity, through the development of endoscopic disease activity indices. Endoscopy has also found a prominent role in the diagnostic and therapeutic approach to IBD complications. Endoscopic surveillance of chronic UC patients at risk for colon carcinoma has helped to define a therapeutic approach to this serious complication of UC. Endoscopic therapy has been applied to treat stricture formation associated with long-standing CD. Biliary endoscopy also represents the strategy of choice for diagnosing primary sclerosing cholangitis, an extraintestinal complication occurring in 5% of UC patients. Finally, endoscopy may help facilitate the discovery of disease pathogenesis in IBD, through the use of endoscopically recovered biopsy specimens in the research laboratory. Endoscopy allows for ready access to human tissue that has been the cornerstone of disease-related research over the past two decades.

Diagnosis, Differential↗
PubMedDate not supplied

Evaluation of B and T lymphocytes and plasma cells in colonic mucosa from healthy dogs and from dogs with inflammatory bowel disease.

The aim of this study was to investigate the subpopulations of lymphocytes in the colonic mucosa of healthy dogs and dogs with inflammatory bowel disease (IBD). Fourteen normal dogs and 13 dogs with IBD were examined. Endoscopic biopsy specimens of colonic mucosa from each dog were stained specifically for pan T lymphocytes (CD3) and pan B lymphocytes (CD79a), and for plasma cells with methyl green pyronin (MGP) stain. Cells were counted by means of a grid and statistical analysis was performed on the data collected. B and T lymphocytes were also counted in the glandular epithelium of normal dogs and dogs with IBD and the normal and abnormal groups compared statistically. Healthy dogs had significantly lower numbers of T cells in the lamina propria and glandular epithelium and significantly lower numbers of B cells in the lamina propria. Significant group differences for plasma cells were not evident. Our results indicate that in IBD a chronic cellular immune reaction is present in the diseased gut involving increased numbers of B and T lymphocytes.

Animals↗
PubMed2003

A model for the length of tracts of identity by descent in finite random mating populations.

Linkage disequilibrium (LD) reflects coinheritance of an ancestral segment by chromosomes in a population. To begin to understand the effects of population history on the extent of LD, we model the length of a tract of identity-by-descent (IBD) between two chromosomes in a finite, random mating population. The variance of an IBD tract is large: a model described by (Genet. Res. Cambridge 35 (1980) 131) underestimates this variance. Using Fisher's concept of junctions, we predict the mean length of an IBD tract, given the age of the population and the population sizes over time. We derive results also for subdivided populations, given times of subdivision events and sizes of the resulting subpopulations. The model demonstrates that population growth and subdivision strongly affect the expected length of an IBD tract in small populations. These effects are less dramatic in large populations.

Chromosomes↗
PubMed1990

A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease.

Antineutrophil cytoplasmic antibodies (ANCAs) have recently been demonstrated to be of importance in Wegener's granulomatosis and certain other forms of vasculitis associated with glomerulonephritis. With a fixed-cell ELISA, we demonstrated that ANCAs occur in the serum of patients with inflammatory bowel disease (IBD) involving the colon. In a blinded study, sera from 21 of 25 patients with ulcerative colitis (UC) and five of 25 patients with Crohn's disease had binding in the fixed-cell ELISA. The five reactive sera from patients with Crohn's disease were associated with the presence of clear colonic involvement. The presence of ANCA in patients with UC was not influenced by disease distribution or activity. Indeed, such antibodies were present in four subjects with UC more than 5 years after colectomy. The IBD-associated ANCAs were distinct from ANCAs reported in patients with Wegener's granulomatosis since the pattern of staining on indirect immunofluorescence exhibited a nongranular perinuclear distribution (P-ANCA). The P-ANCA observed in IBD did not react with myeloperoxidase and thus was distinct from the P-ANCA observed in vasculitis with cresentric glomerulonephritis. IBD and, in particular, UC, is associated with a distinct subset of P-ANCA, which may have important diagnostic and potential pathophysiologic implications.

Adult↗
PubMed2001

Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations.

Background Genetic predisposition to inflammatory bowel disease (IBD) has been shown by epidemiological and linkage studies. Genetic linkage of IBD to chromosome 16 has been previously observed and replicated in independent populations. The recently identified NOD2 gene is a good positional and functional candidate gene since it is located in the region of linkage on chromosome 16q12, and activates nuclear factor (NF) kappaB in response to bacterial lipopolysaccharides. Methods We sequenced the coding region of the NOD2 gene and genotyped an insertion polymorphism affecting the leucine-rich region of the protein product in 512 individuals with IBD from 309 German or British families, 369 German trios (ie, German patients with sporadic IBD and their unaffected parents), and 272 normal controls. We then tested for association with Crohn's disease and ulcerative colitis. Findings Family-based association analyses were consistently positive in 95 British and 99 German affected sibling pairs with Crohn's disease (combined p<0.0001); the association was confirmed in the 304 German trios with Crohn's disease. No association was seen in the 115 sibling pairs and 65 trios with ulcerative colitis. The genotype-specific disease risks conferred by heterozygous and homozygous mutant genotypes were 2.6 (95% CI 1.5-4.5) and 42.1 (4.3-infinity), respectively. Interpretation The insertion mutation in the NOD2 gene confers a substantially increased susceptibility to Crohn's disease but not to ulcerative colitis.

Alleles↗
PubMed1997

Association of autonomic nervous hyperreflexia and systemic inflammation in patients with Crohn's disease and ulcerative colitis.

The autonomic nervous system modulates gastrointestinal motility, secretion and mucosal immunity. Its dysfunction may be of pathogenetic importance in inflammatory bowel disease (IBD). This study aimed at investigating the autonomic nervous function in patients with IBD. Forty-seven patients with IBD, 28 with Crohn's disease (CD) and 19 with ulcerative colitis (UC), were investigated by means of 5 cardiovascular and 2 pupillary standardized autonomic nervous function tests. In CD and UC, cardiovascular autonomic neuropathy was very rare (0%, 5%), whereas pupillary autonomic neuropathy was more prevalent (21%, 21%). In contrast to autonomic neuropathy, overall cardiovascular (CD: 29%, UC: 26%) and pupillary autonomic hyperreflexia (46%, 37%) were found more often. Patients with CD and UC demonstrated elevated percentiles in the respiratory sinus arrhythmia test as compared to controls (RSA: 82.3 +/- 3.9%, 80.0 +/- 5.9%, controls: 50.0% +/- 1.5%, p < 0.0001). CD patients with, as compared to patients without, RSA hyperreflexia had significantly higher CDAIs (p < 0.001), increased erythrocyte sedimentation rates (p < 0.005) and more often extraintestinal disease manifestations (p < 0.001). UC patients with, as compared to patients without, pupillary latency time hyperreflexia had lower hemoglobin (p < 0.05), lower albumin (p < 0.01) and increased erythrocyte sedimentation rates (p < 0.05). Autonomic hyperreflexia was significantly associated with more severe inflammation and systemic disease in IBD. Hyperreflexia may be a response to inflammation or a pathogenetic element that drives mucosal inflammation.

Adolescent↗
PubMed2000

HLA class II haplotype associations with inflammatory bowel disease in Jewish (Ashkenazi) and non-Jewish caucasian populations.

Ulcerative colitis (UC) and Crohn's disease (CD) are the clinical entities comprising idiopathic inflammatory bowel disease (IBD). Previous studies on the association of IBD and human leukocyte antigen (HLA) class II genes suggested a role for HLA in this disease. Here we present HLA class II (DRB1, DQB1, DQA1, DPB1) allele and haplotype distributions determined using the polymerase chain reaction and sequence-specific oligonucleotide probe methods. A total of 578 UC and CD Caucasian patients and controls from Jewish (Ashkenazi) and non-Jewish populations was examined. Our previously reported association of DR1-DQ5 with CD was attributable to DRB1*0103. A dramatic association with IBD and the highly unusual DRB1*0103-DQA1*0501-DQB1*0301 haplotype (OR = 6.6, p = 0.036) was found. The more common DR1 haplotype, DRB1*0103-DQA1*0101-DQB1*0501, was also associated with IBD (OR = 3.1, p = 0.014), a result suggesting that interaction between DR and DQ may determine the extent of disease risk. Our previously reported association of DR2 with UC was attributable to DRB1*1502 (OR = 2.6, p = 0.006). At the DPB1 locus, a significant association of DPB1*0401 with CD was observed for the combined populations (OR = 1.85, p = 0.007). These observations indicate that some class II alleles and haplotypes confer susceptibility to both UC and CD, implying common immunogenetic mechanisms of pathogenesis, while others confer risk to only one of these diseases, and illustrate the value of DNA HLA typing in disease susceptibility analyses.

California↗
PubMed2002

Endoscopy in inflammatory bowel disease.

With the heterogeneous clinical presentation of IBD, endoscopy plays an integral role in the initial diagnosis of ulcerative colitis and Crohn's disease. Although radiographic tests often are supplemental in the work-up of IBD, colonoscopy with biopsy is the test of choice if IBD is suspected and is more sensitive than radiographic tests. Endoscopic features can be helpful in differentiating ulcerative colitis and Crohn's disease. Currently the only mode for detecting dysplasia and stratifying the risk of developing colorectal cancer is through complete colonoscopy with multiple biopsy specimens. Complications of IBD can be managed effectively with endoscopic therapy. The role of endoscopic ultrasound and future developments in endoscopic therapy need to be defined by future studies.

Colonoscopy↗
PubMed2003

Inflammatory bowel disease emergencies.

Emergency complications of IBD are rare, but may be life-threatening, require surgery, and result in permanent end organ damage. The most common complications associated with UC are fulminant colitis, toxic megacolon, and bleeding. Each of these complications may resolve with aggressive medical therapy but often result in a total proctocolectomy. The most common complications associated with CD are abscesses and intestinal obstruction. Although initial treatment includes medical treatment, these Crohn's-related complications usually require a surgical intervention and intestinal resection. Finally, the most common extraintestinal manifestations that present as an emergency include thromboembolic events, ocular complications, and hepatobiliary disease. Some of these complications may parallel the course of the underlying disease and respond to IBD treatment, but thromboemboli, uveitis, and PSC do not. In the last decade there has been an explosion of knowledge and discovery into the pathogenesis of IBD. These findings have led to better and earlier treatment of IBD that it is hoped will alter the natural course of disease and prevent many of the complications outlined in this article.

Emergencies↗