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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.12.045 Byline: Wensheng Wei (1), Quan Lu (1), G. Jilani Chaudry (3)(4), Stephen H. Leppla (3), Stanley N. Cohen (1)(2) Abstract: Toxins produced by Bacillus anthracis and other microbial pathogens require functions of host cell genes to yield toxic effects. Here we show that low density lipoprotein receptor-related protein 6 (LRP6), previously known to be a coreceptor for the Wnt signaling pathway, is required for anthrax toxin lethality in mammalian cells. Downregulation of LRP6 or coexpression of a truncated LRP6 dominant-negative peptide inhibited cellular uptake of complexes containing the protective antigen (PA) carrier of anthrax toxin moieties and protected targeted cells from death, as did antibodies against epitopes in the LRP6 extracellular domain. Fluorescence microscopy and biochemical analyses showed that LRP6 enables toxin internalization by interacting at the cell surface with PA receptors TEM8/ATR and/or CMG2 to form a multicomponent complex that enters cells upon PA binding. Our results, which reveal a previously unsuspected biological role for LRP6, identify LRP6 as a potential target for countermeasures against anthrax toxin lethality. Author Affiliation: (1) Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA (2) Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA (3) Microbial Pathogenesis Section, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA (4) Present address: Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249, USA Article History: Received 7 June 2005; Revised 18 November 2005; Accepted 20 December 2005 Article Note: (miscellaneous) Published: March 23, 2006

The human homolog TSG101 has been isolated and mapped to chromosome 11, bands 15.1-15.2, a region showing loss of heterozygosity in several human malignancies, especially breast cancers. The homolog was observed to mutate at high frequency in human breast cancer. No TSG101 defects were observed in matched normal breast tissue from breast cancer patients. Results indicate that defects in TSG101 occur during breast cancer tumorigenesis and/or progression.

The spontaneous cell proliferation of cancerous tissue is caused by the abnormal regulation of stathmin due to the effects of the tsg101 gene. This process was investigated by isolating tsg101 using antisense codons of ribonucleic acid. tsg101 was cloned in a petri dish and was inoculated in lab rats. The resulting tumor outgrowths showed that tsg101 triggers a faulty metabolic reaction that abnormally increases stathmin causing uncontrolled cell differentiation. The elimination of the transactivating promoter gene was effective in reversing tumor genesis.

Polyadenylation at the 3' end of RNA made in prokaryotic cells is involved in regulating the decay of mRNA, similar to the process in eukaryotic cells. Studies of E. coli show that cells with normal pcnB gene undergo RNA decay initiated by ribonuclease E. In cells with mutant pcnB, however, RNA degradation is retarded.

A demonstration that low density lipoprotein receptor related protein 6 (LRP6), known to be a coreceptor for the Wnt signaling pathway, is required for anthrax toxin lethality in mammalian cells is presented. The results reported indicate that the LRP6 protein, which was known principally as a mediator of the Wnt signaling pathway, has a hitherto unsuspected role in the delivery of anthrax toxins into cells.

Research demonstrates that the 17.4 kilodalton regulator of ribonuclease activity A, RraA, binds to ribonuclease E and inhibits the latter's endonucleolytic cleavages. Data indicate that RraA abundance circumvents an autoregulatory mechanism that maintains the cellular concentration of ribonuclease E leading to a genome-wide accumulation of ribonuclease E-targeted transcripts.

Abstract Objective This post-hoc, pooled analysis of Phase 3 studies of tofacitinib examined the safety of tofacitinib 5 and 10 mg twice daily (BID) when used as monotherapy versus combination therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis (RA). Methods Pooled data from six double-blind, randomized controlled Phase 3 studies of tofacitinib 5 and 10 mg BID in patients with RA were analyzed for safety and stratified by administration as monotherapy (ORAL Solo: NCT00814307 and ORAL Start: NCT01039688) or in combination with csDMARDs (ORAL Sync: NCT00856544, ORAL Standard: NCT00853385, ORAL Scan: NCT00847613, and ORAL Step: NCT00960440), and by glucocorticoid use at baseline. Safety assessments included incidence rates (IRs) for serious adverse events (SAEs), discontinuations due to AEs, serious infection events, and herpes zoster (HZ), and were evaluated throughout the duration of the Phase 3 studies. Results In total, 3881 patients were included in the safety analysis (monotherapy studies: n = 1380; combination therapy studies: n = 2501). IRs for selected AEs of interest were generally numerically lower in patients who received tofacitinib 5 and 10 mg BID as monotherapy than as combination therapy (SAEs: IR [range] 6.21–6.72 versus IR 10.17–13.46; discontinuations due to AEs: IR 5.53–6.18 versus IR 10.80–11.01; serious infections: IR 1.57–1.66 versus IR 3.39–3.56; HZ: IR 1.95–2.93 versus IR 4.37–4.99, respectively), irrespective of tofacitinib dose or glucocorticoid use. There were too few patients and events within the placebo group to fully evaluate effect between combination therapy and monotherapy. Conclusions Safety profiles were generally similar between patients receiving monotherapy and combination therapy; however, selected safety events of interest, including HZ and serious infections, showed lower IRs with non-overlapping 95% confidence intervals for tofacitinib all monotherapy versus combination therapy. Tofacitinib monotherapy may, therefore, have fewer safety events compared with combination therapy, and have a favorable risk-benefit profile in patients with active RA who are intolerant to csDMARDs. [ABSTRACT FROM AUTHOR]

Background and Aims Data on colon capsule endoscopy (CCE) in evaluating the small bowel and colon concurrently are rare. This study aimed to evaluate the accuracy of CCE in assessing disease activity of the small bowel and colon in pediatric Crohn’s disease (CD) by comparison with magnetic resonance enterography (MRE), small-intestine contrast US (SICUS), and ileocolonoscopy. Methods We prospectively enrolled 40 consecutive patients (22 male, 18 female, mean age 13.1 ± 3.1 years) with CD of the small bowel and colon. All underwent SICUS, MRE, CCE, and ileocolonoscopy sequentially over 5 days. All investigators were blinded to patient history and test results. Patients were classified as active or inactive for the small bowel and the colon according to specific criteria for each tool (simple endoscopic score for CD, Lewis score, US and magnetic resonance parameters of activity). For colon mucosa evaluation, ileocolonoscopy was the comparator. For the small bowel, a consensus panel was convened. Results Sensitivity of CCE to detect colon inflammation was 89%, and specificity was 100%. The positive predictive value (PPV) and negative predictive value (NPV) of CCE for colon inflammation were 100% and 91%, respectively. In the small bowel, CCE showed 90% sensitivity, 94% specificity, with PPV and NPV of 95% and 90%, respectively. Accuracy parameters for SICUS (sensitivity 90%, specificity 83%) and MRE (sensitivity 85%, specificity 89%) were lower than those for CCE. No serious adverse events related to the CCE procedure or preparation were reported. Conclusions CCE is of great usefulness in evaluating both small bowel and colon mucosa in pediatric CD. This single, noninvasive tool makes it possible to evaluate the small-bowel and the colon concurrently with high diagnostic accuracy. Future multicenter studies need to define the role of CCE in the routine management of pediatric patients with CD. (Clinical trial registration number: NCT02199626.) [ABSTRACT FROM AUTHOR]

Summary The relationship between the host and its microbiota is challenging to understand because both microbial communities and their environments are highly variable. We have developed a set of techniques based on population dynamics and information theory to address this challenge. These methods identify additional bacterial taxa associated with pediatric Crohn disease and can detect significant changes in microbial communities with fewer samples than previous statistical approaches required. We have also substantially improved the accuracy of the diagnosis based on the microbiota from stool samples, and we found that the ecological niche of a microbe predicts its role in Crohn disease. Bacteria typically residing in the lumen of healthy individuals decrease in disease, whereas bacteria typically residing on the mucosa of healthy individuals increase in disease. Our results also show that the associations with Crohn disease are evolutionarily conserved and provide a mutual information-based method to depict dysbiosis. [ABSTRACT FROM AUTHOR]

Background This prospective single-centre study aims to evaluate a new diagnostic algorithm using capsule endoscopy, colon capsule endoscopy and single-balloon enteroscopy in the work-up of obscure gastrointestinal bleeding in children. Methods The usefulness of a new diagnostic algorithm was assessed comparing the clinically relevant findings revealed by each technique, and evaluating the clinical outcomes during the follow-up. Results A total of 22 paediatric patients were evaluated (14 male; mean age 12.5 years ± 3.9). Capsule endoscopies were positive in 14 (63.6%), suspicious in 5 (22.7%) and negative in 3 (13.6%). A second look with colon capsule identified new lesions in 2/3 (67%) of previous negative cases. Enteroscopies were able to reach the positive and suspicious findings in all but 2, in which an intraoperative enteroscopy was needed. This combined approach showed positive findings in 21/22 of cases with a diagnostic yield of 95%. Eighteen patients (82%) had a complete resolution after therapy. One patient resolved his symptoms spontaneously. Despite diagnosis, in three patients (13.6%) the gastrointestinal bleeding was not resolved after therapy. Conclusion This algorithm achieves optimal levels of diagnostic yield (95%) and therapeutic outcome (82%). This approach deserves to be studied in a larger multicentre cohort of patients and for a longer follow-up period. [ABSTRACT FROM AUTHOR]

Capsule endoscopy (CE) usage and research in pediatrics is in its infancy but is growing. The possibility of avoiding ionizing radiation, deep sedation, and general anesthesia makes CE an appealing tool for diagnosis and disease state monitoring in luminal pediatric gastrointestinal disorders. As such, clinical use is expanding, but research has lagged behind, focusing on inflammatory bowel diseases (IBD) and polyposis syndromes. Food and Drug Administration approval in 2009 for children 2 years of age and older has resulted from the broader application of CE. In turn, this acceptability has fostered use in infants as young as 8 months (and 7.9 kg in weight). With these age differences (within the pediatric population and in comparison with adults), the indications have changed, with continued emphasis on not only patients with IBD but also in younger children who have a lower incidence of IBD, with more concern regarding occult bleeding and additional small bowel disorders, including graft-vs-host disease, Henoch-Schönlein purpura, cystic fibrosis, and lymphangiectasia. The ability to swallow or place the capsule remains a concern, but retention parallels adult indications rather than age. To date, esophageal capsules have been used primarily for the evaluation of varices, although the colon capsule has been used to further understand IBD in both the small bowel and the large bowel. With this varied and expanded use has come comparisons with other diagnostic modalities, attempts to integrate CE with these modalities into effective and cost-effective clinically assessed algorithms, and a plea for further research and the funding to make that possible. [ABSTRACT FROM AUTHOR]

Background & Aims: Evaluation of the small intestine for inflammation has traditionally relied on small-bowel follow-through (SBFT), but multiple studies have demonstrated its low diagnostic accuracy. Capsule endoscopy (CE) transmits high-quality images of the small intestinal mucosa; it can be used to visualize the entire length of the small bowel and much of the mucosa. We compared the diagnostic yields of CE vs SBFT in a prospective study of patients with suspected small-bowel Crohn’s disease. Methods: Eighty patients with signs and/or symptoms of small-bowel Crohn’s disease (age, 10–65 years) underwent CE, followed by SBFT and ileocolonoscopy. Readers were blinded to other test results. The primary outcome was the diagnostic yield for inflammatory lesions found with CE before ileocolonoscopy compared with SBFT and ileocolonoscopy. A secondary outcome was the incremental diagnostic yield of CE compared with ileocolonoscopy and CE compared with SBFT. Results: The combination of CE and ileocolonoscopy detected 107 of 110 inflammatory lesions (97.3%), whereas the combination of SBFT and ileocolonoscopy detected only 63 lesions (57.3%) (P < .001). The diagnostic yield of CE compared with ileocolonoscopy was not different (P = .09). The diagnostic yield was higher for CE than for SBFT (P < .001). Of the 80 patients with suspected Crohn’s disease, 25 (31.3%) had the diagnosis confirmed. Eleven were diagnosed by CE findings alone and 5 by ileocolonoscopy findings alone. In the remaining 9 patients, diagnostic findings were identified by at least 2 of the 3 modalities. No diagnoses were made on the basis of SBFT findings alone. Conclusions: CE was better than SBFT and equivalent to ileocolonoscopy in detecting small-bowel inflammation. Although ileocolonoscopy remains the initial diagnostic test of choice, CE is safe and can establish the diagnosis of Crohn’s disease in patients when ileocolonoscopy results are negative or the terminal ileum cannot be evaluated. ClinicalTrials.gov Number: NCT00487396. [Copyright &y& Elsevier]

Abstract: This first decade of capsule endoscopy (CE) has expanded our knowledge of small bowel disorders, pointed the way to lesions that could not be appreciated clinically or radiologically, and helped to target and monitor therapy. Although insurance companies have often dictated that upper and lower endoscopy and sometimes even radiographic procedures precede CE, in many instances, it makes more clinical sense to reverse that paradigm, and instead screen the gastrointestinal tract using a less invasive, less expensive, anesthesia-free, radiation-free miniaturized camera that can assist diagnosis and management. Although retention and incomplete visualization of the intestine still limit the full effectiveness of CE, further studies and development promise to expand CE''s utility throughout the gastrointestinal tract for a variety of indications. [Copyright &y& Elsevier]

Background & Aims: To further our understanding of capsule endoscopy (CE) in children, we systematically compiled data on indications and outcomes and evaluated the effectiveness of CE on patient management using meta-analyses. Methods: We searched the Medline and PubMed databases (January 2001–May 2010) for English language citations of use of CE in patients ≤18 years old. Duplicate reports and those that included 5 patients or fewer were removed. We analyzed data from 15 source documents with 740 CE procedures in 723 patients. Results: Suspicion or evaluation of inflammatory bowel diseases was the most common indication for CE (54%: 34% for patients suspected to have Crohn''s disease [CD], 16% for patients known to have CD, 1% for patients with ulcerative colitis, and 3% for patients with indeterminate colitis). Completion and retention rates were 86.2% (95% confidence interval [CI], 81.5–90.3) and 2.6% (95% CI, 1.5–4.0), respectively. Retention rates for children that underwent gastric (0.5%) or small bowel (1.9%) CE were similar to those of adults, by indication. For CE, 65.4% of procedures resulted in positive findings (95% CI, 54.8–75.2). Where reported, 69.4% of CE examinations (95% CI, 46.9–87.9) resulted in a new diagnosis and 68.3% (95% CI, 43.6–88.5) led to change in therapy. Conclusions: The relative frequency of CE indications varies among pediatric and adult patients. In pediatric patients, CE is used primarily to evaluate patients with CD — to aid in diagnosis, monitor disease severity, and assist patient management. Retention rates appear to be related to indication, rather than patient age; capsule retention is relatively infrequent for adults and children. [Copyright &y& Elsevier]

Background & Aims: Hepatic encephalopathy, a spectrum of neuropsychiatric abnormalities that can occur in patients with liver dysfunction, negatively affects driving performance, but no study has examined legal ramifications. We studied state requirements for reporting hepatic encephalopathy and investigated whether lawsuits have been completed against physicians or patients for motor vehicle accidents that were related to hepatic encephalopathy. Methods: We contacted motor vehicle departments from all 50 states and examined motor vehicle codes and legal databases to search for hepatic encephalopathy–related lawsuits. Results: Definitions of a medically impaired driver varied considerably. No state specifically mentioned hepatic encephalopathy or patients with advanced liver disease. Only 6 (12%) of the states had mandatory reporting laws for drivers who have medical impairment, and 25 of the remaining 44 states (57%) provided legal immunity to physicians for reporting such patients. The legal databases did not contain any cases against physicians for failure to warn against driving or diagnose hepatic encephalopathy that resulted in an accident. There were no lawsuits identified against an encephalopathic patient for causing a motor vehicle accident. Conclusions: Only 6 states require physicians to report drivers with medical impairments. Hepatic encephalopathy is not specifically addressed in any state vehicle code. There are no completed lawsuits against physicians or patients for motor vehicle accidents associated with driving impairment from hepatic encephalopathy. In the absence of definitive laws, the onus of responsibility for identifying potentially hazardous drivers might still lie with the physician; physicians should carefully evaluate patients for driving abilities. [ABSTRACT FROM AUTHOR]

Background: Secondary stroke prevention guidelines recommend antithrombotic agents such as over-the-counter aspirin, prescription antiplatelet agents, or anticoagulant agents. Purpose: The study was designed to measure whether use of outpatient antithrombotic agents is increasing among stroke survivors. Methods: The sample consisted of 4168 people who self-reported cerebrovascular disease and who participated in the Medical Expenditure Panel Survey, an annual representative sample of the U.S., during the years 2000–2006. Use of antithrombotic agents was calculated from face-to-face interviews about the use of aspirin and from pharmacies about the use of prescription medications. Cochran–Armitage tests were used to detect temporal trends and multivariate models to identify predictors of use of antithrombotic agents. Results: Pooling results across the 7 years, it was found that 57% were taking aspirin, 66% were using any antiplatelet agent, and 75% were using any antithrombotic agent. After excluding people who said aspirin was unsafe, 81% were using any antithrombotic agent. During the study period, use of prescription antiplatelet agents increased (p<0.001) but there was no temporal change in use of antithrombotic agents overall. In multivariate models, being aged >65 years, male gender, non-Hispanic ethnicity, having a usual source of care, and poor or fair health status were associated with use of an antithrombotic agent (p<0.05). Conclusions: Although a high percentage of stroke survivors appear to use an antithrombotic agent, further research should investigate whether and how to improve care among the remaining 20% of stroke survivors, particularly among younger, female, and Hispanic patients. [Copyright &y& Elsevier]

The article presents the origin of growth factors such as nerve growth factor (NGF) and epidermal growth factor (EGF). The author explains that the original neuroembryological experiments started in the laboratories of Drs. Viktor Hamburger and Rita Levi-Montalcini. Then, the author got involved in the experiment and decided to examine some of the metabolic effects of EGF on epidermal cultures. Pedro Cuatrecasas discovered that EGF can stimulate the growth of human fibroblasts when cultured.

Background & Aims: Few epidemiologic investigations characterize inflammatory bowel disease (IBD) in non-Caucasian children. Our study compared IBD characteristics between African Americans and non–African Americans enrolled in a multicenter pediatric IBD registry with endoscopic- and pathology-based diagnosis. Methods: The study retrieved data entered from January 2000 to October 2003 on children 1 to 17 years old, inclusive, followed by a consortium of academic and community US pediatric gastroenterology practices. Analyses examined racial/ethnic differences by comparing the proportions of African Americans and non–African Americans in the following categories: each diagnostic disease classification (any IBD, Crohn''s disease, ulcerative colitis, indeterminate colitis); age group (<6 y, 6–12 y, or >12 y) at diagnosis or symptom onset; presence of extraintestinal manifestations, Z-scores for height and weight, immunomodulatory therapy, anatomic disease location, and abnormal hemoglobin, albumin, or sedimentation rate at diagnosis. Results: A total of 1406 patients had complete data, 138 (10%) of whom were African American. African Americans more often were older than 12 years of age at diagnosis (52% vs 37%; odds ratio [OR], 1.82; 95% confidence interval [95% CI], 1.28–2.59) and symptom onset (46% vs 30%; OR, 1.99; 95% CI, 1.40–2.84); had Crohn''s disease (78% vs 59%; OR, 2.36; 95% CI, 1.56–3.58); and had a low hemoglobin level at diagnosis (39% vs 17%; OR, 3.15; 95% CI, 1.92–5.17). Conclusions: IBD in African American children and adolescents presents more commonly with Crohn''s disease and at older ages compared with non–African Americans. Racial/ethnic differences in the epidemiology of IBD, particularly Crohn''s disease, among American youths require further investigation. [Copyright &y& Elsevier]

Objective: To investigate the effect of human growth hormone (GH) injections on growth velocity in growth-impaired children with Crohn''s disease (CD). Study design: Ten children and adolescents (mean age, 12.6 ± 4.5 years; 6 males) with CD and poor height growth were treated with open-label recombinant GH, 0.043 mg/kg/day administered via subcutaneous injection, for 1 year. Patients were retrospectively matched with untreated patients (3 comparisons per case) by race, age, sex, and baseline height. Primary endpoint was height velocity; secondary endpoints were disease activity, body composition, and bone density determined by dual-energy x-ray absorptiometry scan. Results: Mean height velocity increased by 5.33 ± 3.40 (mean ± standard deviation) cm/year in the GH-treated patients during the year of GH treatment, compared with 0.96 ± 3.52 cm/year in the comparison group (P = .03). Height z-score increased by 0.76 ± 0.38 in the treated group, compared with 0.16 ± 0.40 in the comparison group (P < .01), and weight z-score increased by 0.81 ± 0.89 in the treated group, compared with 0.00 ± 0.57 in the comparison group (P < .01). Bone density revealed an increase of 0.31 ± 0.33 in the lumbar spine z-score (P = .03 vs baseline). Conclusions: GH treatment increases height velocity and may enhance bone mineralization in children with CD. A randomized controlled trial in a large cohort of children is needed to evaluate the ultimate impact of GH treatment. [Copyright &y& Elsevier]

Objective: This study sought to determine if calcified carotid artery atheromas (CCAA) imaged on panoramic radiographs portend an adverse vascular event. Study design: Medical records of 46 males (mean age 66) with a CCAA (Group 1) were reviewed for preimaging vascular risks and for cerebrovascular events subsequent to the radiograph. Matched controls (age, gender, ethnicity, and vascular risks) treated at the same hospital but never radiographed were identified (Group 2) and matched to their cohort. The medical records of Group 2 individuals were re-reviewed for development of vascular events occurring after the date of their cohort’s radiograph. Results: Twenty adverse vascular events (myocardial infarct, stroke, revascularization procedure, transient ischemic attack, angina requiring hospitalization) occurred in twelve Group 1 patients and 6 events occurred in five Group 2 patients (P = 0.006). Conclusion: The incidental finding of a CCAA portends significant risk of a future, adverse vascular event. [Copyright &y& Elsevier]

Background & Aims: The REACH study evaluated the safety and efficacy of infliximab in children with moderately to severely active Crohn’s disease. Methods: Patients (n = 112) with a Pediatric Crohn’s Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6. Patients responding to treatment at week 10 were randomized to infliximab 5 mg/kg every 8 or 12 weeks through week 46. A concurrent immunomodulator was required. Clinical response (decrease from baseline in the PCDAI score ≥15 points; total score ≤30) and clinical remission (PCDAI score ≤10 points) were evaluated at weeks 10, 30, and 54. Results: At week 10, 99 of 112 (88.4%) patients responded to infliximab (95% confidence interval: [82.5%, 94.3%]) and 66 of 112 (58.9%) patients achieved clinical remission (95% confidence interval: [49.8%, 68.0%]). At week 54, 33 of 52 (63.5%) and 29 of 52 (55.8%) patients receiving infliximab every 8 weeks did not require dose adjustment and were in clinical response and clinical remission, respectively, compared with 17 of 51 (33.3%) and 12 of 51 (23.5%) patients receiving treatment every 12 weeks (P = .002 and P < .001, respectively). Conclusions: Pediatric patients responding to an induction regimen of infliximab were more likely to be in clinical response and remission at week 54 without dose adjustment when their maintenance therapy was given every 8 weeks rather than every 12 weeks. Allowing for dose intensification in the case of relapse, remission rates, but not response rates, at week 54 were superior with every 8-week dosing compared with every 12-week dosing. [Copyright &y& Elsevier]

Background & Aims: The cumulative incidence of surgery ranges from 40%–70% at 10 years from the time of diagnosis of Crohn’s disease in adults. We retrospectively determined the cumulative incidence of and risk factors for surgery (intestinal resection) in pediatric patients with Crohn’s disease. Methods: Uniform data from 989 consecutive Crohn’s disease patients (age 0–17 years at diagnosis), collected from 6 different pediatric centers between January 2000 and November 2003 and stored in the Pediatric IBD Consortium Registry, were analyzed. Results: Median follow-up time was 2.8 years (range, 1 day to 16.7 years). One hundred twenty-eight patients underwent surgery. Kaplan–Meier survival estimates of the cumulative incidence of surgery were 17% at 5 years and 28% at 10 years from the diagnosis of inflammatory bowel disease. Univariate Cox proportional hazards models showed leukocytosis (2.85 [hazard ratio]; P = .02), hypoalbuminemia (3.41; P = .05), and anti-Saccharomyces cerevisiae antibody (ASCA) positivity (3.43; P = .05) were associated with increased risk for surgery. Multivariate Cox models showed female gender (1.49; P = .03), initial diagnosis of ulcerative colitis (3.63; P < .0001), poor growth at presentation (2.16; P = .007), and abscess (1.90; P = .009), fistula (2.30; P = .0005), or stricture (3.41; P < .0001) development were associated with increased risk for surgery. Age 3–5 years (0.26; P = .01) or 6–12 years (0.62; P = .01) at diagnosis, fever at presentation (0.50; P = .03), and treatment with infliximab (0.36; P = .0005) or 5-aminosalicylic acid (0.44; P < .0001) were associated with decreased risk for surgery. Conclusions: Risk stratification during the course of Crohn’s disease in pediatric patients will help to guide therapy that may improve the natural history of disease and decrease the need for surgery. [Copyright &y& Elsevier]

Background: Moyamoya disease (MMD), or spontaneous occlusion of blood vessels in the circle of Willis, is a noninflammatory, nonatheromatous vasculopathy that often presents with ischemia or hemorrhage and has a tendency to affect young women. We discuss a case of a woman 7 days postpartum with new onset strokes, suspected initially to have benign angiopathy of the central nervous system (BACNS)/postpartum angiopathy versus primary CNS vasculitis. Cerebral angiography was suspicious for MMD and the patient underwent surgical revascularization. Objectives: To review the epidemiology, presentation, diagnosis, differential diagnosis, treatment, prognosis, and postpartum maternal outcomes of MMD. Methods: The authors reviewed the English-language literature published between 1996 and 2004 using Medline databases. Additional articles were obtained from references described in literature obtained by the primary search. Results: MMD is characterized by severe bilateral stenosis of the distal internal carotid arteries and their first branches, with prominent collateralization. Autoantibodies relating to endothelial cell dysfunction have been studied as possible pathogenetic mechanisms. The gold standard for diagnosing MMD is digital subtraction contrast angiography (DSA). MMD-related findings on imaging studies may, at times, be mistaken for those of vasculitis. A surgical approach may need to be considered. Despite treatment, the overall prognosis of MMD is worse in adults compared with children. Conclusion: Awareness of the specific features of MMD is crucial for clinical decision-making to avoid unnecessary exposure to aggressive immunosuppressive therapy. It is important for rheumatologists to consider MMD in the differential diagnosis of suspected CNS vasculitis. [Copyright &y& Elsevier]

Background: Although guidelines recommend control of risk factors for secondary stroke prevention, few studies examine the level of risk factor control achieved in a poststroke population. Methods: We examined medical records of 99 consecutive patients admitted for ischemic stroke or transient ischemic attack to the Department of Veterans Affairs (VA) West Los Angeles Healthcare Center who were still alive 1 year later. Values for blood pressure, low-density lipoprotein, hemoglobin A1c, and body mass index were collected from a time period of up to 6 months before admission and compared with a time period 6 to 13 months after admission. Results: For the entire sample, improvements in risk factor control were detected only in diastolic blood pressure (5 mm Hg) and hemoglobin A1c (0.9%) (P < .05). When analyzing just the subset of patients with suboptimal control before hospitalization, improvements were detected for systolic blood pressure (12 mm Hg), diastolic blood pressure (12 mm Hg), low-density lipoprotein (29 mg/dL), and hemoglobin A1c (1.4%) (all P < .01). However, a majority of patients with suboptimal control of systolic blood pressure, low-density lipoprotein, and body mass index before admission failed to achieve optimal control of that risk factor in the year after admission. Only 23 patients had all relevant risk factors measured in the VA system during the period after admission and had the final measurements of those risk factors in the optimal range. Conclusions: Although modest improvements were detected, there remains room for improvement in optimizing control of risk factors after a stroke. [Copyright &y& Elsevier]

Abstract: Limited data exist on the safety of primary total hip arthroplasty (THA) and total knee arthroplasty (TKA) in cirrhotic patients. We retrospectively reviewed outcomes of these procedures in cirrhotic patients and matched controls. Significant adverse outcomes occurred in 20.7% (6 of 29) of cirrhotic patients compared with 3.23% (3 of 93) of controls. No significant differences were seen between the groups for elective TKA or THA. However, 80% (4 of 5) of the cirrhotic patients undergoing emergent THA secondary to fracture had major complications, with a 60% (3 of 5) mortality rate. There was a trend toward worse overall outcome in cirrhotic patients with more advanced liver disease. In conclusion, primary THA or TKA can be safely performed electively in Child''s A and B cirrhotic patients. However, emergent THA to repair fractures in cirrhotic patients is associated with significantly increased morbidity and mortality. [Copyright &y& Elsevier]

Practicing psychologists frequently are asked to provide services to individuals whose backgrounds may differ from their own. Education in multicultural issues increasingly is being considered an important component of doctoral training programs. This article discusses the results of a survey of behavioral doctoral students concerning their graduate training on gay, lesbian, and bisexual (GLB) issues. The results indicate that participants (a) have received minimal training in GLB issues, (b) feel inadequate in working with GLB individuals, and (c) express significantly more favorable attitudes toward gay men than a sample from the general population. Included are recommendations for improving training in sexual orientation issues in behavioral clinical psychology programs. [Copyright &y& Elsevier]

The aim of this paper is relatively limited and modest: to classify and discuss the various models which have been and could be used to signify the relevance of the Western crime control experience for the Third World. While the implicitly relevant literature-for example, on the anthropology of law or on the nature of development is vast and complex, the explicit literature on crime in the Third World is sparse and poor. Criminologists have either ignored the Third World completely or treated it in a most theoretically primitive fashion, while the general literature on development and colonialism is remarkably silent about crime. Current systems of crime and deviance control in Western industrialized societies, originated in those three great historical transformations which took place from the end of the eighteenth to the beginning of the nineteenth centuries, first, the development of a centralized state apparatus for the control of crime and the care of dependency, second, the increasing differentiation of the deviant and dependent into separate types, each with its own attendant body of "scientific" knowledge and accredited experts; and, finally, the increased segregation of deviants and dependents into "asylums," mental hospitals, prisons, reformatories and other such closed, purpose-built institutions for treatment, punishment and custody.

The direct-acting antiviral combination glecaprevir/pibrentasvir has been approved by the Food and Drug Administration for 8 weeks of treatment in treatment-naïve patients with hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis. We performed an integrated analysis of data from trials to evaluate the overall efficacy and safety of 8 weeks of glecaprevir/pibrentasvir in treatment-naïve patients without cirrhosis or with compensated cirrhosis. We pooled data from 8 phase 2 or phase 3 trials of treatment-naïve patients with HCV genotype 1 to 6 infections, without cirrhosis or with compensated cirrhosis, who received 8 weeks of glecaprevir/pibrentasvir. Of 1248 patients, 343 (27%) had cirrhosis. Most patients were white (80%) and had HCV genotype 1 infection (47%) or genotype 3 infection (22%); the median age was 54 years. Overall rates of sustained virologic response at post-treatment week 12 were 97.6% (1218 of 1248) in the intention to treat (ITT) and 99.3% (1218 of 1226) in the modified ITT populations. When we excluded patients with genotype 3 infections with compensated cirrhosis (consistent with the European label), rates of sustained virologic response at post-treatment week 12 were 97.6% in the ITT and 99.4% in the modified ITT populations. Eight virologic failures (7 in patients without cirrhosis and 1 in a patient with cirrhosis) occurred in the ITT population. Virologic failure was not associated with markers of advanced liver disease or populations of interest (current alcohol use, opioid substitution therapy, history of injection-drug use, and severe renal impairment). Treatment-emergent adverse events (AEs) occurred in 58% of patients. The most frequent AEs (>10%) were headache (12%) and fatigue (12%). Serious AEs and AEs that led to glecaprevir/pibrentasvir discontinuation were reported in 2% and less than 1% of patients, respectively. In a pooled analysis of data from 8 trials, we found that 8 weeks of treatment with glecaprevir/pibrentasvir is efficacious and well tolerated in treatment-naïve patients with HCV genotype 1 to 6 infections, with or without cirrhosis. [ABSTRACT FROM AUTHOR]

Pan-enteric capsule endoscopy (PCE) is effective for assessment of small intestinal and colonic Crohn's disease (CD) in pediatric patients. We aimed to determine whether PCE can be used to monitor mucosal healing and deep remission, in a treat to target strategy for pediatric patients with CD. We performed a prospective study of 48 children with a diagnosis of CD at a tertiary care pediatric gastroenterology unit; 46 patients were included in the final analysis. Biomarker, imaging, and PCE analyses were performed at baseline and after 24 and 52 weeks. Small bowel and colonic mucosal healing were defined by Lewis scores <135 and simple endoscopic score for CD ≤1, respectively. Clinical remission was defined as defined as a pediatric CD activity index score <10 and biomarker-based remission based on normal levels of biomarkers; deep remission was defined as a combination of clinical remission, biomarker-based remission, and mucosal healing. Treatments were adjusted based on findings from PCE (imaging was considered only for patients with negative findings from PCE). Therapies were introduced, optimized, switched, or combined at the discretion of treating clinicians. The primary outcome was the ability of PCE to assess mucosal healing and deep remission at 3 timepoints and to guide a treat to target strategy. PCE detected inflammation in 34 patients (71%) at baseline, 22 patients (46%) at week 24, and 18 patients (39%) at week 52 (P for comparison among timepoints <.05). Findings from PCE led to a change in therapy for 34 patients (71%) at baseline and 11 patients (23%) at 24 weeks, whereas only 2 patients with negative results from PCE (4%) changed therapies based on findings from imaging. When the treat to target strategy was applied, proportions of patients with mucosal healing and deep remission increased from 21% at baseline, to 54% at week 24, to 58% at week 52 (P for comparison among timepoints <.05); 2 patients (4%) did not respond to treatment. In a prospective study of 48 children with CD, we found a treat to target strategy, based on findings from PCE, to significantly increase the proportions of patients with mucosal healing and deep remission. Clinical Trial.gov no: NCT03161886. [ABSTRACT FROM AUTHOR]

Purpose SBI-087 is a Small Modular Immunopharmaceutical Protein™(SMIP™) drug that binds to CD20 and has been reported to deplete B cells in murine/primate studies. The safety, tolerability and pharmacokinetic/pharmacodynamic properties of SBI-087 were evaluated in patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Methods Single-dose SBI-087 was evaluated in 2 Phase I, open-label, escalating-dose studies in patients with RA or SLE. The studies included 6 IV/4 SC escalating doses (RA) and 1 IV/4 SC escalating doses (SLE). Escalation was determined by tolerability/rate of B-cell depletion. Serum was collected for analyses of pharmacokinetic and pharmacodynamic (CD19 + B cells) properties and immunogenicity. Patients were followed until B-cell counts were normalized or stabilized. Safety, tolerability was evaluated from adverse events, physical examinations, vital sign measurements, ECG, and clinical laboratory results. Findings Sixty patients with RA (IV, 28; SC, 32) and 30 patients with SLE (6 per cohort) were enrolled. Mild to moderate infusion reactions occurred in several patients at the top doses in the RA study despite a pretreatment regimen of IV doses. Unanticipated reactions after SC administration of SBI-087 included fever, chills, and malaise, seen on the day of dosing in the lowest-dose cohorts in both studies. These events were abrogated in subsequent cohorts by a pre/postdose treatment regimen consisting of oral corticosteroids, acetaminophen, and an antihistamine. SBI-087 clearance (IV) ranged from 22 to 229 mL/h; volume of distribution at steady state ranged from 5 to 12 L. Apparent clearance (SC) ranged from 44.7 to 105 mL/h; volume of distribution ranged from 14.3 to 32.1 L. Overall, PK properties were similar at equivalent doses between IV/SC administrations in patients with RA/SLE. Mean t ½ (IV) ranged from 2.1 to 10.7 days (less at lower doses). SBI-087 concentration and B-cell depletion were generally dose proportional across IV and SC cohorts. However, the extent of B-cell depletion was less, and rate of repletion was faster, in patients with SLE versus RA. In both studies, B-cell repletion to baseline did not occur in the majority of patients by the end of the observation period. Overall, the prevalence and type of adverse events were similar to those seen with other anti-CD20–depleting agents. Implications In patients with mild RA/SLE, SBI-087 was well tolerated when administered intravenously or subcutaneously with pre- and posttreatment regimens. B-cell depletion is long lasting, and the duration and extent of depletion may be greater in RA compared with SLE. SBI-087 exhibited slow elimination and low distribution in both populations. Clinicaltrials.gov identifiers: NCT00641225 (RA) and NCT00714116 (SLE). [ABSTRACT FROM AUTHOR]