Food impaction: etiology over 35 years and association with eosinophilic esophagitis.

With the emergence of eosinophilic esophagitis (EoE) as a common cause of food impaction (FI) and a presumed increase in incidence of EoE in the population, the effect on the incidence of FI has not been well described. The aim of this study is to describe the incidence of FI and endoscopic findings in these patients and the association with EoE. A population-based retrospective chart review of the Rochester Epidemiology Project database was performed to identify all patients within Olmsted County that presented with FI from 1976 to 2012. A review of all endoscopic findings, biopsy results, and demographic data was performed. 497 patients were identified with FI from 1976 to 2012. The overall incidence of FI has changed from 1976 to 2012 (Fig. 1) (P < 0.001). The peak incidence of 17.12 per 100,000 people occurred in the time period 1995 to 2000. Both the incidence of comorbid gastroesophageal reflux disease (GERD) and proton pump inhibitor (PPI) use increased over the time period of the study (P < 0.001 for both). Of these patients, 188 (46.7%) had no abnormalities on their endoscopy. The most common endoscopic finding was stricture in 71 (17.6%) patients followed closely by Schatzki's ring in 68 (16.9%) patients. 139 patients had biopsies performed within 2 years of FI and 50 (36.0%) of those were diagnosed with EoE. We present for the first time the changing incidence of FI over the last 35 years in a population-based setting. We also demonstrate the rise of EoE as an important clinical consideration in patients with FI.

Quantifying Rome symptoms for diagnosis of the irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder, diagnosed on symptom-based criteria. Many have reported discrepancies between formal Rome criteria and diagnoses made in clinical practice. The aim of the study was to explore whether a quantitative version of the Rome criteria would better represent a clinical diagnosis of IBS than the current dichotomous criteria for symptom measure. METHODS: As part of a large, case-control study, participants completed a validated bowel disease questionnaire. Rome criteria were analyzed based on 15 individual symptoms. Penalized logistic regression model with stepwise selection was used to identify significant symptoms of IBS which were independently associated with case-control status. KEY RESULTS: In cases with a clinical diagnosis of IBS, 347 (70%) met Rome criteria for IBS. Increasing number of Rome symptoms were found related to the odds of being diagnosed with IBS. Nearly half of the Rome-negative case group experienced infrequent symptoms suggesting milder disease. Five of 15 Rome symptoms were associated with predicting case-control status in the final model, with 96% correctly classified among Rome-positive cases, 76% for Rome-negative cases, and 91% for controls. CONCLUSIONS AND INFERENCES: Irritable bowel syndrome appears to be a spectrum disorder. Quantifying individual symptoms of Rome criteria has greater utility than the current application in representing the degree of IBS affectedness and appears to better reflect a clinical diagnosis of IBS applied by physicians. The use of a quantitative diagnostic Rome "score" may be helpful in clinical practice and research studies to better reflect the degree an individual is affected with IBS.

Novel Toxoplasma gondii inhibitor chemotypes.

We profiled three novel T. gondii inhibitors identified from an antimalarial phenotypic high throughput screen (HTS) campaign: styryl 4-oxo-1,3-benzoxazin-4-one KG3, tetrahydrobenzo[b]pyran KG7, and benzoquinone hydrazone KG8. These compounds inhibit T. gondii in vitro with IC50 values ranging from 0.3 to 2µM, comparable to that of 0.25 to 1.5µM for the control drug pyrimethamine. KG3 had no measurable cytotoxicity against five mammalian cell lines, whereas KG7 and KG8 inhibited the growth of 2 of 5 cell lines with KG8 being the least selective for T. gondii. None of the compounds were mutagenic in an Ames assay. Experimental gLogD7.4 and calculated PSA values for the three compounds were well within the ranges predicted to be favorable for good ADME, even though each compound had relatively low aqueous solubility. All three compounds were metabolically unstable, especially KG3 and KG7. Multiple IP doses of 5mg/kg KG7 and KG8 increased survival in a T. gondii mouse model. Despite their liabilities, we suggest that these compounds are useful starting points for chemical prospecting, scaffold-hopping, and optimization.

Undetectable negative tissue transglutaminase IgA antibodies predict mucosal healing in treated coeliac disease patients.

BACKGROUND: Tissue transglutaminase (tTG) immunoglobulin A (IgA) testing is a sensitive adjunct to the diagnosis of coeliac disease. The threshold for positivity was developed for diagnosis, with negative results reported as below the reference value (<4 U/mL). AIM: To investigate if an undetectable (tTG IgA<1.2 U/mL) is more predictive of healing compared to patients with negative but detectable serology (1.2-3.9 U/mL). METHODS: We performed a retrospective study of 402 treated coeliac disease patients seen at the Mayo Clinic with negative tTG IgA values drawn within 1 month of duodenal biopsy between January 2009 and December 2015. The Corazza-Villanacci score was used to assess mucosal healing. The presence of gastrointestinal symptoms was also collected. Logistic regression was used to assess the relationship of clinical variables with a normal biopsy. RESULTS: Patients with undetectable titres more frequently had normal duodenal histology compared to patients with detectable tTG IgA levels (117/240 vs. 53/162; OR=1.96; 1.292, 2.961). Asymptomatic patients more frequently had normal duodenum as compared to symptomatic patients (88/163 vs. 82/239; OR=2.25; CI: 1.494, 3.377). Patients with undetectable serology and on a gluten-free diet for ≥2 years were more likely to have no villous atrophy compared to patients with detectable serology (148/192 vs. 55/88; OR=2.02; CI: 1.17, 3.49). CONCLUSION: In subjects recovering from coeliac disease with negative tTG IgA serology, an undetectable titre is associated with normal histology on follow-up biopsy.

Oesophageal narrowing on barium oesophagram is more common in adult patients with eosinophilic oesophagitis than PPI-responsive oesophageal eosinophilia.

BACKGROUND: To date there have been no clear features that aid in differentiating patients with eosinophilic oesophagitis (EoE) from PPI-responsive oesophageal eosinophilia (PPI-REE). However, barium swallow roentgenography is a more sensitive and specific measure to detect subtle fibrostenotic remodeling changes present in EoE. We aim to characterise any clinical, endoscopic, histiological or barium roentgenographic differences between EoE and PPI-REE. AIM: To characterise any clinical, endoscopic, histiological or barium roentgenographic differences between EoE and PPI-REE. METHODS: We performed a retrospective cohort analysis on data collected from a tertiary referral centre population from 2010 to 2015. Data from 66 patients with EoE and 28 patients with PPI-REE were analysed. Cases were adults who met consensus guidelines for EOE, and had a barium swallow study within 6 months of the index endoscopy. Clinical, endoscopic, histiological and barium swallow findings were collected. RESULTS: Patients with EoE reported similar characteristics as PPI-REE patients, except EoE patients were younger (35.6 vs. 46.6 years; P = 0.011), had earlier symptom onset (29.0 vs. 38.0 years; P = 0.026), and smaller oesophageal diameters on barium swallow (19.5 mm vs. 20; P = 0.042). Patients with EoE were more likely to have distal strictures (EoE 77% vs. 25%; P = 0.02) and, importantly, a greater likelihood of small calibre oesophagus (51.5% vs. 17.9%; P = 0.002). Moreover, EoE patients had a higher probability of developing small calibre oesophagus after 20 years of symptoms (72.3% vs. 30.2%; P = 0.074) compared to PPI-REE patients. CONCLUSIONS: When compared with eosinophilic oesophagitis, PPI-REE patients demonstrate findings that suggest PPI-responsive oesophageal eosinophilia to be a later onset, less aggressive form of oesophageal stricturing disease than eosinophilic oesophagitis.

Impact of MELD on waitlist outcome of retransplant candidates.

Under the current allocation system for liver transplantation (LTx), primary and retransplantation (ReTx) are treated identically. The aims of this study were (1) to compare the risk of death between ReTx and primary LTx candidates at a given MELD score and (2) to gauge the impact of the MELD-based allocation system on the waitlist outcome of ReTx candidates. Based on data of all waitlist registrants in the United States between 2000 and 2006, unique adult patients with chronic liver disease were identified and followed forward to determine mortality within six months of registration. There were a total of 45,943 patients waitlisted for primary LTx and 2081 registered for ReTx. In the MELD era (n = 30,175), MELD was significantly higher among ReTx candidates than primary LTx candidates (median, 21 vs. 15). Within a range of MELD scores where most transplantation took place, mortality was comparable between ReTx and primary candidates after adjusting for MELD. The probability for LTx increased significantly following implementation of the MELD-based allocation in both types of candidates. We conclude that by and large, primary and ReTx candidates fare equitably under the current MELD-based allocation system, which has contributed to a significant increase in the probability of LTx.

Mathematical model of 5-[125I]iodo-2'-deoxyuridine treatment: continuous infusion regimens for hepatic metastases.

PURPOSE: Due to the cytotoxicity of DNA-bound iodine-125, 5-[125I]Iodo-2'-deoxyuridine ([125I]IUdR), an analog of thymidine, has long been recognized as possessing therapeutic potential. In this work, the feasibility and potential effectiveness of hepatic artery infusion of [125I]IUdR is examined. METHODS: A mathematical model has been developed that simulates tumor growth and response to [125I]IUdR treatment. The model is used to examine the efficacy and potential toxicity of prolonged infusion therapy. Treatment of kinetically homogeneous tumors with potential doubling times of either 4, 5, or 6 days is simulated. Assuming uniformly distributed activity, absorbed dose estimates to the red marrow, liver and whole-body are calculated to assess the potential toxicity of treatment. RESULTS: Nine to 10 logs of tumor-cell kill over a 7- to 20-day period are predicted by the various simulations examined. The most slowly proliferating tumor was also the most difficult to eradicate. During the infusion time, tumor-cell loss consisted of two components: A plateau phase, beginning at the start of infusion and ending once the infusion time exceeded the potential doubling time of the tumor; and a rapid cell-reduction phase that was close to log-linear. Beyond the plateau phase, treatment efficacy was highly sensitive to tumor activity concentration. CONCLUSIONS: Model predictions suggest that [125I]IUdR will be highly dependent upon the potential doubling time of the tumor. Significant tumor cell kill will require infusion durations that exceed the longest potential doubling time in the tumor-cell population.

Formation of intracerebral cavernous malformations after radiation treatment for central nervous system neoplasia in children.

OBJECT: Radiation is a common treatment modality for pediatric brain tumors. The authors present a retrospective review of six children who developed cerebral cavernous malformations after they underwent radiation treatment for central nervous system (CNS) neoplasia and propose two possible models to explain the formation of cavernous malformations. METHODS: Three boys, aged 13, 9, and 17 years, suffered intracerebral hemorrhages from cerebral cavernous malformations 87, 94, and 120 months, respectively, after they received whole-brain radiation therapy (WBRT) for acute lymphocytic leukemia. A 10-year-old girl and a 19-year-old man developed temporal lobe cavernous malformations 46 and 48 months, respectively, after they received radiation therapy for posterior fossa astrocytomas. A 12-year-old girl developed a temporal lobe cavernous malformation 45 months after WBRT was administered for a medulloblastoma. In all of these cases the cavernous malformation appeared in the irradiated field, was not known to be present prior to radiation therapy, and developed after a latency period following treatment. The incidence of cavernous malformations in these patients suggests that children who undergo radiation therapy of the brain may have an increased risk of hemorrhage. CONCLUSIONS: Two possible models may explain the formation of cavernous malformations following brain radiation in these patients. First, the cavernous malformations may form de novo in response to the radiation. Second, the cavernous malformations may have been present, but radiographically occult, at the time of radiation therapy and may have hemorrhaged in response to the radiation. The authors conclude that cavernous malformations may develop after brain radiation and propose a possible mechanism for this formation.

Protein and messenger RNA expression of connexin43 in astrocytomas: implications in brain tumor gene therapy.

The expression of connexin43, the primary gap-junction constituent of glial cells, was evaluated at the messenger RNA and protein levels in different grades of astrocytoma to investigate the relevance of gap junctions in herpes simplex virus-thymidine kinase (HSV-tk)-mediated gene therapy of brain tumors. Transduction of the retroviral-mediated HSV-tk gene into tumor cells with subsequent administration of ganciclovir has recently been used as an experimental therapeutic strategy for treatment of brain tumors. One aspect of this approach is the bystander effect, which augments the efficacy of this therapeutic approach. Glioblastoma cells with minimum levels of connexin43 protein were transfected with a connexin43 complementary DNA. These cells manifested a marked increase in the in vitro bystander effect, supporting the contention that the in vitro bystander effect is a consequence of metabolic cooperation between cells mediated by gap junctions. To assess relative levels of gap-junction protein expression in the relevant tumor type, we examined primary astrocytomas, primary astrocytoma cell cultures, and glioblastoma cell lines. Although most astrocytoma tumor samples expressed connexin43, they differed in the level of expression, with the greatest variation exhibited in high-grade astrocytomas. Primary glioblastoma cell cultures and established glioblastoma cell lines also displayed some variability in connexin43 levels. In aggregate, our results anticipate that glioblastomas will have a varied bystander effect during HSV-tk gene therapy depending on the level of connexin43 expression.

Evidence for clonal spread in the development of multiple meningiomas.

Meningiomas are common intracranial tumors that arise from the arachnoid cells of the meninges. Occasionally patients develop multiple meningiomas. Because the underlying mechanism of multiple meningioma formation is unknown, the authors examined the pattern of X chromosome inactivation in multiple meningiomas. Fifteen intracranial meningiomas were resected in four patients with multiple meningiomas to determine whether the tumors in patients with multiple meningiomas originate from a common progenitor cell or arise independently. Specimens were examined using polymerase chain reaction assays to detect the pattern of X chromosome inactivation. In each patient, all tumors showed inactivation of the same X chromosome, suggesting that tumors arose from the same clone of cells (p < 0.0005). The authors conclude that multiple meningiomas arise from the uncontrolled spread of a single progenitor cell.

Allelic losses on chromosomes 14, 10, and 1 in atypical and malignant meningiomas: a genetic model of meningioma progression.

To investigate chromosomal events that underlie formation and progression of meningiomas, we have examined a set of 18 benign (WHO grade I), 15 atypical (grade II), and 13 anaplastic/malignant (grade III) meningiomas for loss of heterozygosity (LOH) on chromosomes 1p, 6p, 9q, 10q, and 14q. Frequent loss of loci on these chromosomes was seen in grade II and grade III tumors, specifically, 14q (II and III, 47 and 55%), 1p (40 and 70%), and 10q (27 and 40%). In contrast, LOH for these loci was infrequent in benign meningiomas, specifically, 14q (0%), 1p (11%), and 10q (12%). The smallest common regions of deletion that could be defined were 14q24-q32, 1p32-pter, and 10q24-qter. These observations indicate the likely presence of tumor suppressor genes in these regions that are involved in the development of WHO grade II and grade III meningiomas. Because LOH for loci on chromosomes 1p and 10q was found in tumors of all grades and because the frequency of LOH in all three regions increased with tumor grade, these results would support a model for the formation of aggressive meningiomas through tumor progression.

Evidence of meningioma infiltration into cranial nerves: clinical implications for cavernous sinus meningiomas.

Anatomical and biological studies of cavernous sinus meningiomas help us understand the biological heterogeneity of these tumors. The question of whether cavernous sinus meningiomas infiltrate cranial nerves is clinically important because of the effect on treatment planning. In the authors' experience of treating 36 patients with cavernous sinus meningiomas, tumor invasion into a cranial nerve was documented in two patients in whom a cranial nerve was resected during the cavernous sinus dissection. In both patients, histological examination using hematoxylin and eosin and bodian stains showed infiltration of the cranial nerves by a benign meningioma which, to the best of the authors' knowledge, is a condition previously unreported. This histological finding of meningioma invasion into a cranial nerve demonstrates the biological heterogeneity of cavernous sinus meningiomas and raises concern about the invasive character of meningioma. Because not all tumor cells can be identified radiologically or by direct visualization at surgery, occult tumor infiltration predisposes a patient to recurrence despite the best neurosurgical efforts. Evidence of cranial nerve infiltration by meningioma suggests that, in some circumstances, cavernous sinus dissection in the hope of total removal of a meningioma may be futile and, in the long term, may provide no advantage over treatment options with lower morbidity.

Expression of N-cadherin and alpha-catenin in astrocytomas and glioblastomas.

We examined levels of mRNA and protein for N-cadherin, the predominant cadherin in neural tissues, and mRNA levels for the cadherin-associated protein, alpha-catenin, in a series of gliomas and in glioblastoma cell lines. mRNA levels for N-cadherin and alpha-catenin were significantly higher in glioblastomas than in low-grade astrocytomas or normal brain, while the levels of intact N-cadherin protein were similar in glioblastomas, low-grade astrocytomas and brain. In addition, there was no consistent relationship between invasiveness and expression of N-cadherin and alpha-catenin in highly invasive vs minimally invasive tumours within the same histopathological grade. To assess further the relationship between cadherin expression and neural tumour invasion, we measured N-cadherin expression, calcium-dependent cell adhesion and motility of several glioblastoma cell lines. While all N-cadherin-expressing lines were adhesive, no correlation was seen between the level of N-cadherin expression and cell motility. Together, these findings imply that, in contrast to the role played by E-cadherin in carcinomas, N-cadherin does not restrict the invasion of glioblastomas.

Treatment of aneurysms of the internal carotid artery by intravascular balloon occlusion: long-term follow-up of 58 patients.

Long-term evaluation of patients with aneurysms of the internal carotid artery (ICA) treated by intravascular balloon occlusion has not been reported. From 1977 to 1992, 58 patients (age 14 to 81 years) with ICA aneurysms were treated at our institution by this technique. The aneurysms included 40 intracavernous carotid, 5 petrous carotid, 3 cervical carotid, and 10 ophthalmic segment aneurysms. Presenting symptoms were caused by mass effect in 45 patients, transient ischemia or cerebral infarction as a result of emboli in 6, subarachnoid hemorrhage in 4, and epistaxis in 3. Preoperative temporary balloon occlusion of the ICA combined with cerebral blood flow monitoring and induced hypotension were used to determine tolerance for occlusion. Two patients not tolerating test occlusion required an extracranial-intracranial bypass procedure, and another patient underwent extracranial-intracranial bypass prior to test occlusion because of contralateral ICA stenosis. In 55 patients, aneurysms were excluded from the circulation by either occluding the proximal ICA or trapping the aneurysm neck. In three patients, the aneurysm was directly obliterated with intravascular balloons with preservation of the parent ICA. Three patients died during treatment, one from subarachnoid hemorrhage and two from cerebral infarction. Mean follow-up was 76 months (range, 6 months to 15 years). Six patients who developed transient ischemia caused by emboli responded to volume expansion and anticoagulation treatment. Two patients developed a delayed infarction, and one patient developed aneurysm enlargement that required surgical clipping and obliteration. (ABSTRACT TRUNCATED AT 250 WORDS)

RNA expression of complement regulatory proteins in human brain tumors.

The expression of complement regulatory proteins (CRP) on the surface of neoplastic cells has been proposed as a mechanism by which these cells evade immune surveillance. We have examined the RNA expression of the genes that encode 5 kinds of CRP in various human brain tumors to determine whether CRP expression might play a role in the malignant progression of these tumors. The benign and atypical meningiomas, and the astrocytomas showed high expression of SP-40,40, low expression of CD59, and barely detectable expression of CD46, CD55 and S-protein. The benign and atypical menigiomas showed significantly greater expression of SP-40,40 at the RNA level when compared to malignant meningiomas. This study describes the mRNA expression of meningiomas, astrocytomas, tumor cell lines and normal human tissues.

Association of meningiomas with dural "tails"; surgical significance.

Intracranial meningiomas are characteristically benign tumours with a tendency to recur following surgical resection. Our group is investigating the pathogenesis of meningioma recurrence. In our initial studies we identified two cases of dural "tails" associated with intracranial meningiomas. Gadolinium-enhanced magnetic resonance images were utilized to identify the dural "tails" preoperatively. These images aided us in performing a more complete surgical resection of the meningiomas. Histopathological confirmation of meningotheliomatous cell infiltration into the dural "tails" demonstrates their surgical significance.

Physical map and genetic early region of the T7-related coliphage, BA14.

The chromosome of the bacterial virus, BA14, a member of the T7 lytic coliphage group, was characterized by direct measurement of its length and construction of a restriction map. The chromosome (39.6 kb) is essentially the same size as T7 (39.9 kb), is devoid of a large number of restriction sites expected for a DNA of this size, and moreover, lacks modification sites for the Escherichia coli Dam and Dcm methyltransferases. The BA14 early region was assigned by testing the ability of specific chromosomal restriction fragments to direct RNA synthesis by E. coli RNA polymerase, and analysis of in vitro RNase III cleavage products of the transcripts. The data support and extend the previous assertion that BA14 is a representative of a distinct T7 subgroup, and limited nucleotide sequence analysis of the BA14 DNA ligase-encoding gene suggests a closer relationship of BA14 to T7 than to T3 phage, another member of the T7 group.