Characterization of a partial-body irradiation model with oral cavity shielding in nonhuman primates.

Purpose: Characterization of a novel partial-body irradiation (PBI) shielding strategy in nonhuman primates (NHP; rhesus macaques), aimed at protecting the oral cavity, with respect to various gastrointestinal acute radiation syndrome (GI-ARS) syndrome parameters as well as buccal ulceration development.Materials and methods: NHPs were irradiated using a Cobalt-60 gamma source, in a single uniform dose, ranging from 9-13 Gy and delivered at 0.60-0.80 Gy min-1. Animals were either partially shielded via oral cavity shielding (PBIOS) or underwent total-body irradiation (TBI).Results: Clinical manifestations of GI-ARS, and also radiation-induced hematology and clinical chemistry changes, following PBIOS were comparable to the PBI NHP GI-ARS model utilizing shielding of the distal pelvic limbs and were significantly milder than TBI at similar radiation doses. Nadir citrulline levels were comparable between PBIOS and TBI but signs of recovery appeared earlier in PBIOS-treated animals. The PBIOS model prevented oral mucositis, whereas the TBI model presented buccal ulcerations at all tested radiation dose levels.Conclusions: Taken together, these results suggest that the PBIOS model is a suitable alternative to traditional PBI. For GI-ARS investigations requiring orally administered medical countermeasures, PBIOS confers added value due to the prevention of oral mucositis over traditional PBI.

Faecal but not serum calprotectin levels look promising in predicting active disease in Behçet's syndrome patients with gastrointestinal involvement.

OBJECTIVES: The faecal calprotectin (FC) test is widely used as a non-invasive method for identifying intestinal inflammation. A recent study suggested FC may help to diagnose gastrointestinal involvement of Behçet's syndrome (GIBS). We aimed to determine whether FC helps to distinguish active from inactive intestinal involvement in GIBS. METHODS: We tried to contact 70 GIBS patients registered in our tertiary multidisciplinary clinic. We prospectively collected faecal specimens and serum from 39 GIBS patients who gave informed consent assessing calprotectin and CRP levels followed by a colonoscopy. We included 47 Crohn's disease (CD) patients as controls. Active disease was defined as having ulcer/s on colonoscopy. We filled the Disease Activity Index for Intestinal Behçet's Disease (DAIBD) and Crohn's Disease Activity Index (CDAI). The cut-off for positive FC was defined as ≥150 µg/g. RESULTS: Ulcers were detected in 12/39 GIBS patients. Sensitivity and specificity of the FC test for active disease was 91.7 (95%CI:61.5-99.8) and 74.1% (95%CI:53.7-88.9). Median FC and CRP levels and DAIBD scores were higher among patients with ulcers, whereas serum calprotectin and CDAI scores were not. A negative FC test was the only significant predictor of remission (OR:37.04, 95%CI:2.4-561.6; p=0.009) on multivariate analysis. Among CD patients, 16/25 active patients and 3/22 patients in endoscopic remission had a positive FC test (OR:11, 95%CI:11-49). CONCLUSIONS: FC, but not serum calprotectin seems to be a useful non-invasive tool for assessing disease activity in GIBS. Whether the presence of oral ulcers can cause false positive results remains to be studied.

Clinical features of chronic enteropathy associated with SLCO2A1 gene: a new entity clinically distinct from Crohn's disease.

BACKGROUND: Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a hereditary disease caused by mutations in the SLCO2A1 gene and characterized by multiple small intestinal ulcers of nonspecific histology. SLCO2A1 is also a causal gene of primary hypertrophic osteoarthropathy (PHO). However, little is known about the clinical features of CEAS or PHO. METHODS: Sixty-five Japanese patients recruited by a nationwide survey of CEAS during 2012-2016 were enrolled in this present study. We reviewed the clinical information of the genetically confirmed CEAS patients. RESULTS: We identified recessive SLCO2A1 mutations at 11 sites in 46 patients. Among the 46 patients genetically confirmed as CEAS, 13 were men and 33 were women. The median age at disease onset was 16.5 years, and parental consanguinity was present in 13 patients (28%). Anemia was present in 45 patients (98%), while a single patient experienced gross hematochezia. All patients showed relatively low inflammatory markers in blood tests (median CRP 0.20 mg/dl). The most frequently involved gastrointestinal site was the ileum (98%), although no patient had mucosal injuries in the terminal ileum. Mild digital clubbing or periostosis was found in 13 patients (28%), with five male patients fulfilling the major diagnostic criteria of PHO. CONCLUSIONS: The clinical features of CEAS are distinct from those of Crohn's disease. Genetic analysis of the SLCO2A1 gene is therefore recommended in patients clinically suspected of having CEAS.

Acute hemorrhagic rectal ulcer syndrome: Comparison with non-hemorrhagic rectal ulcer lower gastrointestinal bleeding.

OBJECTIVE: The aim of this study was to describe the clinical characteristics of acute hemorrhagic rectal ulcer (AHRU) and to elucidate its predictive factors. METHODS: The medical records of patients with AHRU were retrospectively reviewed. Their baseline clinical characteristics were compared with those of patients with non-AHRU lower gastrointestinal bleeding to identify predictive factors for AHRU. RESULTS: Among the 118 patients who underwent emergency endoscopy due to acute massive hematochezia from 2013 to 2015, 25 (21.2%) were diagnosed as having AHRU. Of them, 22 (88.0%) were successfully managed endoscopically and 3 (12.0%) underwent surgery. Six (24.0%) patients developed rebleeding within 1-9 days after the initial bleeding, which was controlled by a repeat endoscopy. Five (20.0%) died during follow-up. A multivariate-adjusted logistic regression analysis revealed that a lower serum albumin level, worse Eastern Cooperative Oncology Group (ECOG) performance status and history of constipation were significant factors for predicting AHRU. Hypoalbuminemia (<30 g/L) had a sensitivity, specificity and positive and negative predictive values of 84.0%, 78.5%, 51.2% and 94.8% for predicting AHRU, respectively. CONCLUSIONS: Approximately 20% of patients with massive hematochezia had AHRU. Most patients with AHRU can be managed endoscopically. Low serum albumin level, poor ECOG performance status and prior constipation could be used in distinguishing patients with and without AHRU, facilitating the selection of optimal bowel preparation method for massive hematochezia.

Associations between circulating endostatin levels and vascular organ damage in systemic sclerosis and mixed connective tissue disease: an observational study.

INTRODUCTION: Systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are chronic immune-mediated disorders complicated by vascular organ damage. The aim of this study was to examine the serum levels of the markers of neoangiogenesis: endostatin and vascular endothelial growth factor (VEGF), in our unselected cohorts of SSc and MCTD. METHODS: Sera of SSc patients (N = 298) and MCTD patients (N = 162) from two longitudinal Norwegian cohorts were included. Blood donors were included as controls (N = 100). Circulating VEGF and endostatin were analyzed by enzyme immunoassay. RESULTS: Mean endostatin levels were increased in SSc patients 93.7 (37) ng/ml (P < .001) and MCTD patients 83.2 (25) ng/ml (P < .001) compared to controls 65.1 (12) ng/ml. Median VEGF levels were elevated in SSc patients 209.0 (202) pg/ml compared to MCTD patients 181.3 (175) pg/ml (P = .017) and controls 150.0 (145) pg/ml (P < .001). Multivariable analysis of SSc subsets showed that pulmonary arterial hypertension (coefficient 15.7, 95 % CI: 2.2-29.2, P = .023) and scleroderma renal crisis (coefficient 77.6, 95 % CI: 59.3-100.0, P < .001) were associated with elevated endostatin levels. Multivariable analyses of MCTD subsets showed that digital ulcers were associated with elevated endostatin levels (coefficient 10.5, 95 % CI: 3.2-17.8, P = .005). The risk of death increased by 1.6 per SD endostatin increase (95 % CI: 1.2-2.1, P = .001) in the SSc cohort and by 1.6 per SD endostatin increase (95 % CI: 1.0-2.4, P = .041) in the MCTD cohort after adjustments to known risk factors. CONCLUSIONS: Endostatin levels were elevated in patients with SSc and MCTD, particularly SSc patients with pulmonary arterial hypertension and scleroderma renal crisis, and MCTD patients with digital ulcers. Elevated endostatin levels were also associated with increased all-cause mortality during follow-up in both groups of patients. We propose that endostatin might indicate the degree of vascular injury in SSc and MCTD patients.

25-Hydroxyvitamin D2 /D3 levels and factors associated with systemic inflammation and melanoma survival in the Leeds Melanoma Cohort.

Lower 25-hydroxyvitamin D2 /D3 levels at melanoma diagnosis are associated with thicker primaries and poorer survival. We postulated that this might relate to the deleterious effect of systemic inflammation as 25-hydroxyvitamin D2 /D3 levels are inversely associated with levels of C-reactive protein. 2,182 participants in the Leeds Melanoma Cohort (median follow-up 7.98 years) provided data on drug exposure, comorbidities and a serum 25-hydroxyvitamin D2 /D3 level at recruitment. Factors reported to modify systemic inflammation (low vitamin D levels, high body mass index, use of aspirin or nonsteroidal anti-inflammatory drugs or smoking were tested as predictors of microscopic ulceration (in which primary tumors are inflamed) and melanoma-specific survival (MSS). Ulceration was independently associated with lower 25-hydroxyvitamin D2 /D3 levels (odds ratio (OR) = 0.94 per 10 nmol/L, 95% CI 0.88-1.00, p = 0.05) and smoking at diagnosis (OR = 1.47, 95% CI 1.00-2.15, p = 0.04). In analyses adjusted for age and sex, a protective effect was seen of 25-hydroxyvitamin D2 /D3 levels at diagnosis on melanoma death (OR = 0.89 per 10 nmol/L, 95% CI 0.83-0.95, p < 0.001) and smoking increased the risk of death (OR = 1.13 per 10 years, 95% CI 1.05-1.22, p = 0.001). In multivariable analyses (adjusted for tumor thickness) the associations with death from melanoma were low 25-hydroxyvitamin D2 /D3 level at recruitment (<20 nmol/L vs. 20-60 nmol/L, hazard ratio (HR) = 1.52, 95% CI 0.97-2.40, p = 0.07) and smoking duration at diagnosis (HR = 1.11, 95% CI 1.03-1.20, p = 0.009). The study shows evidence that lower vitamin D levels and smoking are associated with ulceration of primary melanomas and poorer MSS. Further analyses are necessary to understand any biological mechanisms that underlie these findings.

Endoscopic findings of gastrointestinal involvement in Chinese patients with Behcet's disease.

AIM: To report the incidence, clinical features and outcomes of gastrointestinal (GI) involvement in Behcet's disease (BD). METHODS: A total of 168 consecutive patients with BD were screened and upper and lower GI endoscopies were performed in 148 patients. Four hundred age- and sex-matched controls were enrolled for comparison. RESULTS: Fifty-two (35.1%) patients had GI lesions. After a mean follow-up of 10 mo, ileocecal ulcers had been confirmed in 20 patients, including active ulcer(s) in 18 patients, but no ileocecal ulceration was found in controls. GI symptoms were present in 14 patients with active ulcer(s), while 4 patients with smaller ulcer were asymptomatic. Endoscopic features of ileocecal ulcer were: a single ulcer (50%), larger than 1 cm in diameter (72.2%), and round/oval or volcano-type in shape (83.3%). Compared with patients without GI involvement, less ocular lesions, lower levels of albumin, erythrocyte count and hemoglobin, and higher levels of C-reactive protein and erythrocyte sedimentation rate were confirmed in the intestinal BD group. Four patients had esophageal ulcers in the BD group but no case in controls. The other endoscopic findings were similar between the two groups. The prevalence of Helicobacter pylori infection was similar in both groups. Most patients received an immunomodulator and responded well. CONCLUSION: GI lesions commonly occur in Chinese BD patients. The most frequently involved area is the ileocecal region. Esophageal ulcer might be a rare but unique lesion.

Prognostic value of sustained elevated C-reactive protein levels in patients with acute aortic intramural hematoma.

OBJECTIVES: The appropriate management of aortic intramural hematoma is still controversial, because a variety of aortic events can arise during follow-up in some patients. However, simplified identification of these patients remains challenging. The present study aimed to determine the prognostic significance of serial C-reactive protein measurements for the prediction of adverse events in patients with acute aortic intramural hematoma. METHODS: A total of 180 patients with aortic intramural hematoma were retrospectively reviewed. The C-reactive protein data were obtained at admission and 2 days, 1 week, and 2 weeks from the onset, and the maximum value was obtained during the acute phase. Adverse aorta-related events were defined by a composite of aortic rupture, aortic aneurysm, and surgical or endovascular aortic repair. RESULTS: The C-reactive protein value was 3.0 ± 4.6, 8.7 ± 5.9, 9.0 ± 5.5, and 5.7 ± 4.5 mg/dL on admission and 2 days, 1 week, and 2 weeks from the onset, respectively. The maximal value of C-reactive protein was 12.4 ± 6.3 mg/dL at a mean of 4 days from the onset. Patients with elevated C-reactive protein levels (≥7.2 mg/dL) at 2 weeks had significantly greater rates of aorta-related events (P < .001). On multivariate analysis, an elevated C-reactive protein level at 2 weeks (hazard ratio, 3.16; P < .001) and the development of an ulcer-like projection (hazard ratio, 2.68; P = .002) were independent predictors of adverse aorta-related events. In addition, an elevated C-reactive protein level at 2 weeks had incremental value compared with the development of an ulcer-like projection (chi-square, 16.94 for ulcer-like projection only vs 34.32 with the addition of C-reactive protein at 2 weeks, P < .001). CONCLUSIONS: C-reactive protein was a simple and useful marker providing incremental prognostic information compared with the development of an ulcer-like projection in patients with aortic intramural hematoma.

A critical role of surgery in the treatment for paraneoplastic pemphigus caused by localized Castleman's disease.

Paraneoplastic pemphigus (PNP) is an autoimmune mucocutaneous disease associated with lymphoproliferative tumors, and sometimes with a very rare tumor, Castleman's disease (CD). PNP can present as a variety of dermatological diseases, and so far, only limited studies of PNP caused by CD have been reported, resulting in its higher possibility of misdiagnosis. Because of the variability of clinical presentation of PNP caused by CD, selection of the appropriate therapeutic approach remains unclear. To investigate the efficacy of surgery to patients with PNP caused by localized CD, the clinical, laboratory and pathological data of 5 patients with PNP caused by localized CD, 3 females and 2 males, aged 34 years (ranging from 29 to 42), with the tumor size from 6 x 4 x 4 cm(3) to 8 x 8 x 7 cm(3), located in the mediastinum (n = 3) and retroperitoneum (n = 2), were compared before and after surgery. All patients underwent surgery, and the diagnosis was confirmed by pathological examination. Surgery significantly improved mucosal lesions, cured skin lesions and decreased serum pemphigus autoantibody 6 months after surgery. Most patients were followed up for 6-48 months, and they all had no clinical or radiological recurrence and remain disease free. Therefore, surgery is an effective approach to cure patients with PNP caused by localized CD.

Effects of cholecystokinin-8 induced gastric dysmotility on bile regurgitation during stress and molecular mechanisms.

OBJECTIVE: To illustrate the existence of bile regurgitation under stress condition, and explore the possible effects and related mechanism of changes of plasma cholecystokinin octapeptide (CCK-8) and intragastric pH on stress-induced bile regurgitation in rats. METHODS: (1) Changes in plasma CCK-8 and gastric bile concentration were respectively measured by using radioimmunoassay (RIA) method while simultaneously calculating gastric ulcer index (UI) and intragastric pH; (2) Each isolated gastric strips were suspended in a tissue chamber to record the contractile responses by polyphysiograph; (3) The responsiveness of gastric smooth muscle cells (SMCs) to sulfated cholecystokinin octapeptide (CCK-8S) were examined using fura-2-loaded microfluorimetric measurement of intracellular calcium concentration ([Ca(2+)]i); (4) The current of L-type calcium channels (I(CaL)) of SMCs were recorded by patch clamp techniques. RESULTS: (1) Compared with the normal control group, plasma CCK-8 and gastric bile concentration significantly increased during stress (p<0.01) and both simultaneously reached the peak at the time point of 2 h after stress; UI and intragastric pH apparently increased (p<0.01); (2) Significant changes to CCK-8S were found in the mean contractile amplitude and frequency of circular muscle (CM) and longitudinal muscle (LM) of gastric antrum and pylorus; (3) CCK-8S-evoked significant increase in [Ca(2+)]i (p<0.01) could be suppressed by CCK-A receptor (CCK-AR) antagonist; whereas a small but significant increase was still elicited by CCK-8S under condition of the removal of extracellular calcium or by given nifidipine; (4) CCK-8S-intensified calcium current (I(CaL)) apparently inhibited by respective administration of nifidipine, Ca(2+)-ATPase inhibitors or calcium dependent chloride channel (I(Cl-Ca)) blocker (p<0.01). CONCLUSION: Gastric mucosal damage induced by bile regurgitation is closely connected with gastric antrum and pylorus dysmotility evoked by CCK-8 during the stress. CCK-8S-evoked [Ca(2+)]i increase in gastric antrum and pylorus SMC depends on the release of intracellular calcium stores which activates L-type voltage-dependent calcium channels (VDCC) through the activation of calcium dependent chloride channels.

One-month-old infant with multiple ulcers of stomach, small bowel, large bowel, and protein-losing enteropathy: case report.

Multiple inflammatory ulcers of the gastrointestinal tract are rare in young infants. Most cases are caused by infectious organisms, vasculitis, or an autoimmune process. We report a 1-month-old infant who was healthy until he presented with an inflammatory mesenteric cyst, and multiple ulcers of the stomach, duodenum, jejunum, ileum, and colon. Histologically, the ulcerations were sharply demarcated, full thickness, and filled with macrophages. He had a low serum albumin and IgG due to protein-losing enteropathy. He was treated with supportive care and immunomodulating drugs. The gastrointestinal inflammation resolved by 3 and 1/2 years of age. The medications were withdrawn at 5 and 1/2 years of age he had no relapse of clinical symptoms. He continues to have asymptomatic mild hypoalbuminemia and low serum IgG. We could not find a report of a similar clinical presentation and outcome.

Intestinal ulceration, obstruction, and haemorrhage in congenital syphilis.

Intestinal obstruction and bleeding are uncommon complications of congenital syphilis (CS). A VDRL-positive infant developed incomplete intestinal obstruction and rectal bleeding. Despite conservative management, his symptoms continued. At laparotomy, terminal ileal inflammation and stenosis were demonstrated. He underwent ileal resection and primary end-to-end anastomosis with resolution of his symptoms. Histopathological examination demonstrated heavy plasmacytic infiltration of the lamina propria and submucosa with ulceration of the mucosa, consistent with syphilitic ileitis. This report documents for the first time bleeding from ileal ulcers associated with intestinal obstruction in CS and highlights an unusual presentation of the disease.

Chronic idiopathic esophageal ulceration in the acquired immunodeficiency syndrome. Characterization and treatment with corticosteroids.

Study objectives were to characterize the clinical syndrome of chronic idiopathic esophageal ulceration in patients with acquired immunodeficiency syndrome (AIDS), to determine the extent of local human immunodeficiency virus (HIV) infection, and to evaluate the effect of corticosteroid therapy upon symptoms and healing. Twelve AIDS patients with chronic esophageal ulcers whose etiology remained unknown after clinical evaluation were the subjects. All patients complained of severe odynophagia, chest pain, and weight loss. Barium radiography and endoscopy demonstrated large, undermined ulcers with severe acute inflammation. No evidence of herpes simplex viruses I or II, cytomegalovirus, fungi, or tumors were found histologically. Evidence of HIV was found in all ulcers using a combination of RNA in situ hybridization, immunohistochemistry, and quantitative antigen capture enzyme-linked immunosorbent assay of tissue homogenates. Steroid therapy by the oral or intravenous routes or by direct intralesional injection resulted in pain relief, weight gain in 10 patients, and ulcer healing in five patients. A characteristic clinical syndrome of chronic idiopathic esophageal ulceration may occur in patients with AIDS, related to local HIV infection in the esophagus. Corticosteroids relieve symptoms and may promote healing of the ulcer.

The in vitro cytotoxic effect of leukocytes from patients with recurrent aphthous ulceration upon mouse 3T3 fibroblasts.

This study compared the in vitro cytotoxic activity against cultured NIH 3T3 mouse fibroblasts of peripheral blood leukocytes (PBL) from 13 patients with minor recurrent aphthous ulceration (RAU), 5 patients with non-aphthous oral ulceration and 23 age- and sex-matched healthy control subjects. Leukocytes from patients with RAU exerted a significantly greater degree of cytotoxicity towards the 3T3 cells than did those of control subjects. This enhanced cytotoxicity was abrogated by depletion of PBL bearing the CD5 antigen (T-lymphocytes). In contrast, PBL from patients with non-aphthous oral ulceration failed to exert an enhanced cytotoxic activity against 3T3 fibroblasts, when compared to PBL from healthy control subjects. It was concluded that PBL from patients with RAU exert a significantly enhanced cytotoxicity towards an unrelated xenogeneic target cell. This activity is a specific feature of RAU and in the assay system described appears to be mediated by T-lymphocytes.

Stomatitis and recurrent oral ulceration: is a full blood screen necessary?

A full haematology screen was carried out on 398 patients under investigation for recurrent oral ulceration or stomatitis. Thirty-three patients were found to have lowered serum folate and/or red cell folate levels without iron deficiency. Of these only six were found to have a mean corpuscular volume (MCV) outside normal limits or to have recognisable erythrocyte abnormalities. No correlation was found between serum or red cell folate levels and the MCV. Eighteen patients were found to have lowered serum B12 levels without iron deficiency, of these seven were found to have a MCV outside normal limits. A significant negative correlation was found between serum B12 levels and the MCV. It is concluded that haematological screening in these cases should include estimations of serum folate, red cell folate and serum B12 levels even in the face of an apparently normal peripheral blood film.