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.

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.

Allergic esophagitis in children: a clinicopathological entity.

Infiltration of esophageal epithelium by eosinophils is seen in reflux esophagitis and allergic gastroenteritis. This study was performed to identify differences between patients with acid reflux esophagitis and those with non-acid reflux, possibly allergic, esophagitis. Intraepithelial eosinophils were demonstrated in posttherapy esophageal biopsy specimens in 28 children treated for gastroesophageal reflux disease (GERD). These patients were divided into three groups based on their response to treatment and the results of esophageal pH probe monitoring. Eleven patients (Group A) had incomplete clinical response and normal pH probe monitoring results. Ten patients (Group B) had incomplete response but did not have pH probe monitoring. These two groups formed the index population. Seven patients (Group C) had clinical improvement with GERD therapy and abnormal pH probe monitoring characteristic of GERD; they constituted the control population. Clinical, laboratory, and pathologic features were evaluated to detect differences between index and control populations. Dysphagia, food impaction, failure to thrive, peripheral eosinophilia, and abnormal allergen skin test results were detected only in Group A and B patients. Biopsy specimens of the distal 9 cm of the esophagus, after GERD therapy, contained larger numbers of eosinophils in Groups A and B than in Group C as shown on high-power fields (HPF) (A: 31/HPF +/- 19.5; B: 28/HPF +/-23.7; versus C: 5/HPF +/-6.7; p = 0.009). Eosinophil aggregates were identified only in Groups A and B (p = 0.07). Eosinophils located preferentially in the superficial layers of the squamous epithelium were noted only in Groups A and B (p = 0.02). Group A and B patients demonstrated clinical improvement when given antiallergic therapy. The authors identified a group of pediatric patients characterized by an allergic history, lack of adequate response to GERD therapy, normal esophageal pH probe monitoring results, and large numbers of eosinophils in esophageal biopsy specimens obtained after GERD treatment. On the basis of these features, the authors propose that these patients represent examples of allergic esophagitis.

Mitochondrial neurogastrointestinal encephalomyopathy: diagnosis by rectal biopsy.

A 14-year-old girl with the mitochondrial neurogastrointestinal encephalopathy syndrome had an 8-year history of intestinal pseudoobstruction with abdominal pain, persistent vomiting, gastric and duodenal dilatation, and duodenal diverticulosis. The child appeared chronically malnourished and had severe growth failure. Multisystem involvement was evident with the presence of ptosis, external ophthalmoplegia, muscle wasting, peripheral neuropathy, and diffuse white matter disease seen on magnetic resonance imaging. Lactic acidosis and increased cerebrospinal fluid protein were observed. Mitochondrial enzyme analysis of fresh-frozen skeletal muscle revealed a respiratory chain defect. Molecular genetic studies showed multiple mitochondrial DNA deletions. Pathologic findings in the intestine included atrophy of the external layer of the muscularis propria and an increased number of abnormal-appearing mitochondria in ganglion and smooth-muscle cells. Microvesicular steatosis was observed in liver, skeletal, and gastrointestinal smooth muscle, and Schwann cells of peripheral nerve. Brightly eosinophilic inclusions in the cytoplasm of gastrointestinal ganglion cells were visible by light microscopy, which were confirmed to be megamitochondria by ultrastructural studies. This is the first report of abnormal mitochondria observed in intestinal ganglion and smooth-muscle cells in this syndrome.

Lymphocytes bearing the gamma delta T-cell receptor in normal human intestine and celiac disease.

Monoclonal antibodies to T-cell receptors were used to investigate the prevalence of the two distinct T-cell subpopulations (TCR alpha beta+ and TCR gamma delta+ cells) in the intestinal mucosa of children with celiac disease (gluten-sensitive enteropathy) as compared with normal intestinal mucosa. TCR gamma delta+ cells were rarely identified in the epithelium of human fetal or normal postnatal intestine and few were present in the lamina propria, whereas the number of distribution of TCR alpha beta+ cells closely resembled that of CD3+ cells. Compared with normal intestine, a significant increase in the number of CD3+, CD8+, TCR alpha beta+, and TCR gamma delta+ intraepithelial lymphocytes was present in celiac disease. Although the mucosal TCR gamma delta+ cells were less numerous than TCR alpha beta+ cells in celiac disease, there was a marked increase in the number of TCR gamma delta+ cells as compared with controls. The ligand recognized by the gamma delta T-cell receptor and the function of these cells have not been determined; however, these findings suggest a possible role for TCR gamma delta+ lymphocytes in mucosal immune responses and tissue injury as seen in celiac disease.

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.

Pediatric endoscopy.

The emergence of pediatric gastroenterology as a subspecialty and improved design and widespread distribution of small diameter endoscopes have combined to foster dramatic expansion in the practice of pediatric endoscopy over the past three decades. Endoscopic evaluation and treatment of gastrointestinal disease in children has led to new diagnoses and provided exciting opportunities for nonsurgical treatment. This article will focus on important pediatric applications, highlight differences with adult practice, and anticipate future research and development of pediatric endoscopy.

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.

Marine radioactivity assessment of Mururoa and Fangataufa atolls.

The International Atomic Energy Agency (IAEA) carried out an international project. 'The Study of the Radiological Situation at the Atolls of Mururoa and Fangataufa' with the aim of assessing the present and future radiological situation at the atolls and making recommendations for either monitoring or remedial actions if they are deemed necessary. The paper concentrates on marine radioactivity aspects and gives an estimation of present radionuclide concentrations in water, sediment and biota of the Mururoa and Fangataufa lagoons and the surrounding ocean. The dominant radionuclide in both lagoons is Pu in sediments (the total inventory is approximately 30 TBq). A decline in radionuclide concentrations has been observed in recent years in lagoon water, with the exception of 3H and 90Sr, for which a contribution from underground sources is to be expected. Radionuclide concentrations in biota from the lagoons and the surrounding ocean are low and consistent with previous measurements. The observed radionuclide concentrations in both lagoons imply that no radiological risk exists for hypothetical inhabitants of Mururoa and Fangataufa Atolls.

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.

What makes oncology nursing special? Walking the road together.

PURPOSE: To identify the factors that influence oncology nurses' decisions to enter nursing and specialize in oncology and to describe the role dimensions of oncology nursing practice. DESIGN: Multi-institutional, descriptive, qualitative. SETTING: Six sites in different regions of the United States; rural and urban cancer and noncancer centers. SAMPLE: 38 oncology nurses (mean age = 35 years; average time in nursing = 10 years and in oncology = 7 years; 47% bachelor's degree in nursing, 29% diploma, 13% associate degree in nursing, and 11% master's prepared). METHODS: Phenomenological; content analysis of interviews. MAIN RESEARCH VARIABLES: Life events, career decision-making, personal and professional rewards, role dimensions of practice, caring behaviors. FINDINGS: Nurses said that their decisions to specialize in oncology were based on family experiences with cancer, the challenges of administering sophisticated cancer therapies, and influential role models. They reported that professional rewards are derived from valuing each patients as a 'whole person' and providing family-centered care. Nurses find that personal rewards and career survivorship are embedded in several ongoing discoveries: work offers a unique laboratory for learning about life in general, distancing maneuvers are necessary for self-preservation, and the fuzzy boundary between work and personal life must be constantly renegotiated. CONCLUSIONS: Oncology nurses find the best in the worst of situations, live fully the cancer experience by embracing their patients' heartaches and triumphs, share a collective sense of pride in their specialty, and report a high level of job satisfaction. IMPLICATIONS FOR NURSING PRACTICE: Caring for the dying person with cancer is the most difficult aspect of oncology nursing practice and being with--being present in the moment, no matter what the outcome--is the most rewarding and ubiquitous caring behavior of oncology nurses.

Cutaneous reactions associated with alpha interferon therapy.

Although flu-like symptoms are the most common side effect associated with alpha interferon therapy, cutaneous reactions also can occur and present a management challenge for oncology nurses. Cutaneous reactions reported in the literature include generalized effects and localized reactions. Alopecia appears to be the most common generalized cutaneous reaction reported, followed by transient and mild generalized rash-like reactions. Localized manifestations include injection-site reactions, induration, or necrosis. Armed with knowledge about interferon-associated cutaneous reactions, oncology nurses can identify these reactions early and promptly implement appropriate interventions.

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."

Advances in the treatment of hepatitis C: combination antiviral therapy with interferon alfa-2b and ribavirin.

PURPOSE: To provide nurse practitioners with the information to manage patients with chronic hepatitis C (HCV) receiving a new combination drug therapy containing ribavirin and interferon alfa-2b. DATA SOURCES: Reviews of clinical trial results including large multicenter trials, Centers for Disease Control and Prevention documents, data from the drug manufacturer. CONCLUSION: This new therapy offers the potential for HCV remission or complete cure of the HCV infection. Although virologic responses are markedly improved with combination therapy, the side effects associated with combination therapy warrant regular patient monitoring, management, and medical intervention when clinically indicated. IMPLICATIONS FOR PRACTICE: Combination therapy does not significantly worsen the side effects associated with mono-therapy, which are predictable, manageable, and reversible. However, proper patient education, symptom management, vigilance for serious side effects, and monitoring of hematologic parameters are critical to patient outcome.

The pioneer spirit in first assisting.

Unless RNs are willing to accept this responsibility, less trained people will be more than happy to do so. We have given away many of our technical skills in the past, such as allowing technicians to become firmly entrenched in the scrub role. I hope we don't let this opportunity slip through our hands because we have lost the pioneering spirit of our nursing heritage. Thirty years ago, the issue was whether or not nurses could take blood pressures. More recently, it has been whether nurses could use the defibrillator. Now both are accepted without a thought. Those of us who have chosen to expand our practice must be patient with our colleagues who have not had an opportunity to work through both sides of the issue, and encourage them to do so. There will be those who choose not to function in this role, and I believe that first assisting is not for everyone. But in order to have a choice, the option must be there.

Surgical treatment of familial polyposis. The ileal reservoir/anal pull-through.

The success of the procedure is evaluated by the number of bowel movements the patient has in a 24-hour period. Nine or more in 24 hours is considered poor; the average postoperative patient has five to six. As the patient's functional results improve, he is generally more at ease in social and work environments. He can govern his own routine to a great extent, rather than being tied to the bathroom. Usually, the patient can return to work in about four weeks after the ileostomy takedown. Generally, these patients seem to be satisfied with the results of their surgery. One study noted that 92% of the patients studied stated they would not hesitate to have the same operation again if faced with the same options. For the first few months postoperatively, Billy was somewhat apprehensive that he would have an "accident." He did not report any, though. He also did not leak any stools, even at night. Now, more than a year after the surgery, Billy has about four to six bowel movements a day and continues to take psyllium hydrophilic mucilloid daily. He has occasional mild irritation of the perianal skin. He has also gained 15 pounds. Billy returned to college to complete his senior year six months postoperatively. He took a full course load and planned to graduate in August 1987 with a degree in computer science. He reported that, "I'm doing very well. I just forget I had surgery."

Postoperative education that works.

Perioperative nurses have acquired greater responsibility for patients' and family members' postoperative education. Recent nursing research indicates that patients may not be getting specific information about dealing with the everyday practical matters they encounter while recovering at home from their surgical procedures. This article addresses some of these issues (e.g., food, sex, driving, bathing, wound care, return to work, limits on activities). The authors answer questions most often asked by patients and their family members.