Biallelic EPCAM deletions induce tissue-specific DNA repair deficiency and cancer predisposition.

We report a case of Mismatch Repair Deficiency (MMRD) caused by germline homozygous EPCAM deletion leading to tissue-specific loss of MSH2. Through the use of patient-derived cells and organoid technologies, we performed stepwise in vitro differentiation of colonic and brain organoids from reprogrammed EPCAMdel iPSC derived from patient fibroblasts. Differentiation of iPSC to epithelial-colonic organoids exhibited continuous increased EPCAM expression and hypermethylation of the MSH2 promoter. This was associated with loss of MSH2 expression, increased mutational burden, MMRD signatures and MS-indel accumulation, the hallmarks of MMRD. In contrast, maturation into brain organoids and examination of blood and fibroblasts failed to show similar processes, preserving MMR proficiency. The combined use of iPSC, organoid technologies and functional genomics analyses highlights the potential of cutting-edge cellular and molecular analysis techniques to define processes controlling tumorigenesis and uncovers a new paradigm of tissue-specific MMRD, which affects the clinical management of these patients.

Brine-driven destruction of clay minerals in Gale crater, Mars.

Mars' sedimentary rock record preserves information on geological (and potential astrobiological) processes that occurred on the planet billions of years ago. The Curiosity rover is exploring the lower reaches of Mount Sharp, in Gale crater on Mars. A traverse from Vera Rubin ridge to Glen Torridon has allowed Curiosity to examine a lateral transect of rock strata laid down in a martian lake ~3.5 billion years ago. We report spatial differences in the mineralogy of time-equivalent sedimentary rocks <400 meters apart. These differences indicate localized infiltration of silica-poor brines, generated during deposition of overlying magnesium sulfate-bearing strata. We propose that destabilization of silicate minerals driven by silica-poor brines (rarely observed on Earth) was widespread on ancient Mars, because sulfate deposits are globally distributed.

Synergistic Ground and Orbital Observations of Iron Oxides on Mt. Sharp and Vera Rubin Ridge.

Visible/short-wave infrared spectral data from the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) show absorptions attributed to hematite at Vera Rubin ridge (VRR), a topographic feature on northwest Mt. Sharp. The goals of this study are to determine why absorptions caused by ferric iron are strongly visible from orbit at VRR and to improve interpretation of CRISM data throughout lower Mt. Sharp. These goals are achieved by analyzing coordinated CRISM and in situ spectral data along the Curiosity Mars rover's traverse. VRR bedrock within areas that have the deepest ferric absorptions in CRISM data also has the deepest ferric absorptions measured in situ. This suggests strong ferric absorptions are visible from orbit at VRR because of the unique spectral properties of VRR bedrock. Dust and mixing with basaltic sand additionally inhibit the ability to measure ferric absorptions in bedrock stratigraphically below VRR from orbit. There are two implications of these findings: (1) Ferric absorptions in CRISM data initially dismissed as noise could be real, and ferric phases are more widespread in lower Mt. Sharp than previously reported. (2) Patches with the deepest ferric absorptions in CRISM data are, like VRR, reflective of deeper absorptions in the bedrock. One model to explain this spectral variability is late-stage diagenetic fluids that changed the grain size of ferric phases, deepening absorptions. Curiosity's experience highlights the strengths of using CRISM data for spectral absorptions and associated mineral detections and the caveats in using these data for geologic interpretations and strategic path planning tools.

Evidence for a Diagenetic Origin of Vera Rubin Ridge, Gale Crater, Mars: Summary and Synthesis of Curiosity's Exploration Campaign.

This paper provides an overview of the Curiosity rover's exploration at Vera Rubin ridge (VRR) and summarizes the science results. VRR is a distinct geomorphic feature on lower Aeolis Mons (informally known as Mount Sharp) that was identified in orbital data based on its distinct texture, topographic expression, and association with a hematite spectral signature. Curiosity conducted extensive remote sensing observations, acquired data on dozens of contact science targets, and drilled three outcrop samples from the ridge, as well as one outcrop sample immediately below the ridge. Our observations indicate that strata composing VRR were deposited in a predominantly lacustrine setting and are part of the Murray formation. The rocks within the ridge are chemically in family with underlying Murray formation strata. Red hematite is dispersed throughout much of the VRR bedrock, and this is the source of the orbital spectral detection. Gray hematite is also present in isolated, gray-colored patches concentrated toward the upper elevations of VRR, and these gray patches also contain small, dark Fe-rich nodules. We propose that VRR formed when diagenetic event(s) preferentially hardened rocks, which were subsequently eroded into a ridge by wind. Diagenesis also led to enhanced crystallization and/or cementation that deepened the ferric-related spectral absorptions on the ridge, which helped make them readily distinguishable from orbit. Results add to existing evidence of protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars' rock record.

Ancient aqueous environments at Endeavour crater, Mars.

Opportunity has investigated in detail rocks on the rim of the Noachian age Endeavour crater, where orbital spectral reflectance signatures indicate the presence of Fe(+3)-rich smectites. The signatures are associated with fine-grained, layered rocks containing spherules of diagenetic or impact origin. The layered rocks are overlain by breccias, and both units are cut by calcium sulfate veins precipitated from fluids that circulated after the Endeavour impact. Compositional data for fractures in the layered rocks suggest formation of Al-rich smectites by aqueous leaching. Evidence is thus preserved for water-rock interactions before and after the impact, with aqueous environments of slightly acidic to circum-neutral pH that would have been more favorable for prebiotic chemistry and microorganisms than those recorded by younger sulfate-rich rocks at Meridiani Planum.

Development and validation of an equine nerve block simulator to supplement practical skills training in undergraduate veterinary students.

Lameness is the most common presenting complaint in equine practice. Performing diagnostic nerve blocks is an integral part of any lameness work-up, and is therefore an essential skill for equine practitioners. However, the opportunities for veterinary students to practice this skill are limited. The aim of this study was to design and validate an equine nerve block simulator. It was hypothesised that the simulator would improve students' ability and enhance their confidence in performing nerve blocks. A simulator was built using an equine forelimb skeleton and building foam. Wire wool targets were placed under the foam in the positions corresponding to the anatomical location of the most palmar digital, abaxial and low four-point nerve blocks and attached to an electrical circuit. The circuit became complete when the operator placed a needle in the correct position and immediate audible feedback with a buzzer was provided. To validate the simulator, it was compared with two established teaching methods: cadaver training and theoretical training with a hand-out. Cadaver-trained students achieved the best results (73 per cent correct blocks), compared with simulator-trained students (71 per cent correct blocks), and a hand-out trained group (58 per cent correct blocks). Feedback obtained with a questionnaire showed that students enjoyed simulator training more, and that they felt more confident in performing diagnostic nerve blocks than the other two groups. The equine nerve block simulator provides a safe, cost-effective method to supplement the teaching of diagnostic analgesia to undergraduate veterinary students.

Modelling thirty-day mortality in the Acute Respiratory Distress Syndrome (ARDS) in an adult ICU.

Variables predicting thirty-day outcome from Acute Respiratory Distress Syndrome (ARDS) were analysed using Cox regression structured for time-varying covariates. Over a three-year period, 1996-1998, consecutive patients with ARDS (bilateral chest X-ray opacities, PaO2/FiO2 ratio of <200 and an acute precipitating event) were identified using a prospective computerized data base in a university teaching hospital ICU. The cohort, 106 mechanically ventilated patients, was of mean (SD) age 63.5 (15.5) years and 37% were female. Primary lung injury occurred in 45% and 24% were postoperative. ICU-admission day APACHE II score was 25 (8); ARDS onset time from ICU admission was 1 day (median: range 0-16) and 30 day mortality was 41% (95% CI: 33%-51%). At ARDS onset, PaO2/FiO2 ratio was 92 (31), 81% had four-quadrant chest X-ray opacification and lung injury score was 2.75 (0.45). Average mechanical ventilator tidal volume was 10.3 ml/predicted kg weight. Cox model mortality predictors (hazard ratio, 95% CI) were: APACHE II score, 1.15 (1.09-1.21); ARDS lag time (days), 0.72 (0.58-0.89); direct versus indirect injury, 2.89 (1.45-5.76); PaO2/FiO2 ratio, 0.98 (0.97-0.99); operative versus non-operative category, 0.24 (0.09-0.63). Time-varying effects were evident for PaO2/FiO2 ratio, operative versus non-operative category and ventilator tidal volume assessed as a categorical predictor with a cut-point of 8 ml/kg predicted weight (mean tidal volumes, 7.1 (1.9) vs 10.7 (1.6) ml/kg predicted weight). Thirty-day survival was improved for patients ventilated with lower tidal volumes. Survival predictors in ARDS were multifactorial and related to patient-injury-time interaction and level of mechanical ventilator tidal volume.

Diagnosis and management of MNGIE syndrome in children: case report and review of the literature.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is a rare disorder that presents in childhood; however, marked delay in diagnosis is common. We report a case and review the literature describing the typical features that should alert pediatricians to the diagnosis. We also describe a novel management strategy for providing symptomatic relief.

Laparoscopic and thoracoscopic esophagomyotomy for children with achalasia.

BACKGROUND: Minimally invasive esophagomyotomy, consisting of a laparoscopic or thoracoscopic approach, has become a preferred surgical treatment for adults with achalasia. This multicenter study reports on the clinical status of children who have undergone minimally invasive esophagomyotomy for achalasia. METHODS: Symptomatology for achalasia was assessed in 22 pediatric patients who underwent minimally invasive esophagomyotomy for achalasia between 1995 and 2000. All patients were evaluated for duration of hospitalization, postoperative resumption of feeds, postoperative complications, and symptomatic relief. Participants were assigned pre-and postoperative symptom severity scores ranging from 0 (no symptoms) to 3 (severe). RESULTS: The median age of the 10 females and 12 males at time of surgery was 11.3 years +/- 3.4 (standard deviation). Transabdominal laparoscopic esophagomyotomy with fundoplication was performed in 18 patients, and thoracoscopic esophagomyotomy without fundoplication was performed in 4. Two patients required conversion from transabdominal laparoscopic esophagomyotomy to open esophagomyotomy because of intraoperative esophageal perforation. The mean duration of postsurgical follow-up was 17 +/- 16 (standard deviation) months (range, 1-54 months). Mean duration of hospitalization (days +/- standard error or mean) was less for transabdominal laparoscopic esophagomyotomy than for converted open esophagomyotomy (2.7 +/- 0.3 vs. 9.0 +/- 3.0 days; P < 0.05) or for thoracoscopic esophagomyotomy (4.8 +/- 1.7 days; P = not significant). Mean time to resumption of soft feedings (days +/- standard error or mean) occurred sooner after transabdominal laparoscopic esophagomyotomy than after converted open esophagomyotomy (2.0 +/- 0.2 vs. 5.5 +/- 0.5 days; P < 0.001) or after thoracoscopic esophagomyotomy (4.0 +/- 1.3 days; P = not significant). Patients experienced significant pre-to postoperative improvement in mean severity score with regard to dysphagia (2.6 vs. 0.4; P < 0.001) and regurgitation (1.7 vs. 0.2; P < 0.001). CONCLUSIONS: Minimally invasive esophagomyotomy can provide excellent symptomatic relief from dysphagia and regurgitation for children with achalasia.

Visceral vascular anomalies.

Gastrointestinal endoscopy is an essential modality often used for initial diagnostic assessment and staging of visceral vascular anomalies, especially when bleeding is the presenting symptom. Some lesions have a pathognomonic appearance on endoscopy. Others are less clearly identifiable and require a multidisciplinary assessment, including histopathology, for a correct diagnosis. Proper application of nomenclature is crucial to prevent the institution of improper therapies. Advanced endoscopic methods, including endosonography and various hemostatic techniques, are useful to evaluate the depth and character of gastrointestinal wall involvement and to provide minimally invasive treatment when appropriate.

Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas.

Both Gliadel wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] and temozolomide (TEMO) have been shown in independent studies to prolong survival of patients with recurrent malignant glioma following surgery and radiotherapy. On the basis of preclinical evidence of synergism between Gliadel wafers and TEMO, a phase I study was designed to evaluate the toxicity of combining these 2 agents in the treatment of patients with recurrent supratentorial malignant glioma. All patients had surgical resection of the tumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in the surgical cavity following resection. Two weeks after surgery, TEMO was given orally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2, respectively. Patients were assessed for toxicity 4 weeks after start of the first course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease or response after the first cycle of TEMO were allowed to continue treatment at the same dose every 4 weeks for 12 cycles or until disease progression or unacceptable toxicity. Ten patients with a median age of 47 years (range, 22-66 years) were enrolled in this study. There were 7 patients with glioblastoma multiforme and 3 patients with anaplastic astrocytoma. Three patients were treated with TEMO at the first dose level of 100 mg/m2, 4 at the second dose level of 150 mg/m2, and 3 at the third dose level of 200 mg/m2. The 10 patients received a median of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadel wafers. The treatment was well tolerated, with only 1 patient suffering grade III thrombocytopenia at the highest dose level. Two patients at each dose level had no evidence of disease progression after treatment. Four patients suffered progressive disease on therapy. Our study demonstrates that TEMO can be given safely after placement of Gliadel (3.85%) wafers. The recommended dosage for TEMO for a phase II study of this combination is 200 mg/m2 per day for 5 days.

The mutagenic potential of acetonitrile in the bone marrow and peripheral blood of the mouse.

Acetonitrile was tested for its ability to induce clastogenic or aneugenic effects through the induction of micronucleated polychromatic erythrocytes (MNPCE) in mouse bone marrow and peripheral blood. Groups of NMRI mice, five males and five females, were administered a single i.p. dose of acetonitrile, corresponding to the maximum tolerated dose (MTD), 100 or 125 mg/kg body wt for males and females, respectively. Bone marrow was sampled at 18, 24 or 36 h after treatment, while peripheral blood was sampled before and 24, 48, 72 and 96 h after treatment. Positive controls were administered cyclophosphamide (65 mg/kg i.p.). Acetonitrile did not increase the incidence of MNPCE in either bone marrow or peripheral blood in male mice or in peripheral blood in females. A small, but statistically significant (P: < 0.05), increase was observed in female bone marrow 36 h after administration, but since this was within the range of the control data it is not considered to be of biological significance. Cyclophosphamide increased the incidence of MNPCE in bone marrow and peripheral blood of both sexes. It is concluded that acetonitrile is neither clastogenic nor aneugenic in the bone marrow of the mouse at the MTD.

Erythroid Kruppel-like factor (EKLF) coordinates erythroid cell proliferation and hemoglobinization in cell lines derived from EKLF null mice.

Erythroid Kruppel-like factor (EKLF) is a transcription factor of the C2H2 zinc-finger class that is essential for definitive erythropoiesis. We generated immortal erythroid cell lines from EKLF(-/-) fetal liver progenitor cells that harbor a single copy of the entire human beta-globin locus and then reintroduced EKLF as a tamoxifen-inducible, EKLF-mutant estrogen receptor (EKLF-ER) fusion protein. Addition of tamoxifen resulted in enhanced differentiation and hemoglobinization, coupled with reduced proliferation. Human beta-globin gene expression increased significantly, whereas gamma-globin transcripts remained elevated at levels close to endogenous mouse alpha-globin transcript levels. We conclude that EKLF plays a role in regulation of the cell cycle and hemoglobinization in addition to its role in beta-globin gene expression. The cell lines we used will facilitate structural and functional analyses of EKLF in these processes and provide useful tools for the elucidation of nonglobin EKLF target genes.

First person account: schizophrenia, medication, and outpatient commitment.

The article that follows is part of the Schizophrenia Bulletin's ongoing First Person Account series. We hope that mental health professionals-the Bulletin's primary audience--will take this opportunity to learn about the issues and difficulties confronted by consumers of mental health care. In addition, we hope that these accounts will give patients and families a better sense of not being alone in confronting the problems that can be anticipated by persons with serious emotional difficulties. We welcome other contributions from patients, ex-patients, or family members. Our major editorial requirement is that such contributions be clearly written and organized, and that a novel or unique aspect of schizophrenia be described, with special emphasis on points that will be important for professionals. Clinicians who see articulate patients with experiences they believe should be shared might encourage these patients to submit their articles to Schizophrenia Bulletin, First Person Accounts, EEI Communications, 66 Canal Center Plaza, Suite 200, Alexandria, VA 22314.-The Editors.

Marriage and mental illness.

I have not read anything regarding persons who marry while living with serious, persistent mental illness. I married in the 1960s when persistent mental illness was considered a "nervous breakdown" and not an ongoing disease. With this article, I want to educate and explore thought in other persons who might share the same problems I experienced. I want to give a voice to the isolation I felt while married, coping with my illness. I felt so different from other married women with my closeted illness. I have two beautiful daughters who suffered a tragedy in their young lives when I became ill, yet our love seems to have survived and our relationship each day grows. With this article I want to give a voice to one marriage and mental illness. I want someone who reads this to say, "Yes, I feel like that; I know I'm not alone."

Combination Interferon alfa-2b/ribavirin therapy for the treatment of hepatitis C: nursing implications.

An effective new therapeutic option consisting of Intron A (Interferon alfa-2b, recombinant; Schering Corporation, Kenilworth, NJ) Injection and Rebetol (Ribavirin, USP) Capsules is now available for the initial therapy of patients with hepatitis C and for patients who had previously responded to alpha interferon but subsequently relapsed. The combination of recombinant interferon alfa-2b/ribavirin therapy increases hepatitis C viral clearance 10-fold in hepatitis C relapse patients and almost threefold in previously untreated patients compared with alpha interferon monotherapy. There is no synergistic toxicity apparent with the two-drug combination. Ribavirin does not significantly worsen the side effects associated with interferon alfa-2b, which are predictable, manageable, and reversible. The major side effects of combination therapy include flulike symptoms, neutropenia, psychiatric disorders, and anemia; however, these side effects are well known and can be managed with dose modifications and nursing intervention. The assistance of nurses in patient education, in side effect management, in hematologic parameter monitoring, and in medication dosing and administration is crucial to maximizing patient compliance and therapy outcome.

The pioneer spirit in perioperative advanced practice--two practice examples.

Perioperative nurses have options in advanced practice instead of leaving the acute care setting. One of the newest advanced practice roles is the acute care nurse practitioner (ACNP). This role may be ideal for perioperative nurses who want to remain in perioperative practice and grow clinically by pursuing advanced practice. This article presents two collaborative practice examples for the ACNP in the perioperative setting. The authors describe new frontiers in advanced perioperative practice and analyze the emerging advanced practice role of the ACNP. This challenging and exciting role is well suited to perioperative practice in a general and trauma surgery practice. The academic preparation, certification, and credentialing necessary to practice as an ACNP are explained.

Applying the health care industry representative statement to your setting. Association of periOperative Registered Nurses.

AORN values the role our industry partners play in the care of our patients. Table 3 is an example of a policy on the health care representative in the OR. This article is meant to assist perioperative nurses in writing policies that enhance the role of the health care industry representative in the OR, promote collegial relationships with an important player on the team, and preserve patient safety and privacy.

Endorectal pull-through abates gastrointestinal hemorrhage from colorectal venous malformations.

BACKGROUND/PURPOSE: Lower intestinal venous malformations are rare anomalies resulting from errors in vascular morphogenesis. These lesions may cause significant chronic and acute gastrointestinal hemorrhage. Venous malformations are unresponsive to angiogenesis inhibitors. Although these anomalies generally are incompletely resectable because of diffuse pelvic and mesenteric involvement, the authors sought to abate bleeding by excluding the lesion from the gastrointestinal lumen. METHODS: Three patients with circumferential transmural venous malformations of the colorectum, pelvis, and mesentery were identified. Imaging findings were similar among the patients and included circumferential septated bright signal on T2-weighted magnetic resonance imaging (MRI) contrast enhancement, and multiple phleboliths, seen best on computed tomography (CT). The lesion extended from the anus to the splenic flexure in 2 patients and throughout the entire colorectum in the other. Each had daily hematochezia for many years and required transfusions and chronic iron therapy. Although bleeding began in childhood in each patient, no therapy was successful until ages 7, 24, and 45. Colectomy, anorectal mucosectomy (through the pelvic venous malformation), and endorectal pull-through and anastomosis was performed (coloanal in 2 and ileoanal in 1). RESULTS: Bleeding essentially has been eradicated in all 3 patients with 10- to 57-month follow-up. One patient received a 3-unit transfusion intraoperatively, and the other 2 received none. The most recent patient to undergo surgery, who has residual venous malformation in the remaining 1 cm of anal mucosa, has some mild difficulty with fecal control if her diet results in loose stool. CONCLUSION: Colectomy with mucosectomy and endorectal pull-through should be considered for diffuse venous malformations of the colorectum before the development of large transfusion requirements.