The Pathogenesis of Extraintestinal Manifestations: Implications for IBD Research, Diagnosis, and Therapy.

This article reports on the sixth scientific workshop of the European Crohn's and Colitis Organisation [ECCO] on the pathogenesis of extraintestinal manifestations [EIMs] in inflammatory bowel disease [IBD]. This paper has been drafted by 15 ECCO members and 6 external experts [in rheumatology, dermatology, ophthalmology, and immunology] from 10 European countries and the USA. Within the workshop, contributors formed subgroups to address specific areas. Following a comprehensive literature search, the supporting text was finalized under the leadership of the heads of the working groups before being integrated by the group consensus leaders.

A multi-centre audit of excess steroid use in 1176 patients with inflammatory bowel disease.

BACKGROUND: Corticosteroids are central to inducing remission in inflammatory bowel disease (IBD) but are ineffective maintenance agents. AIM: To benchmark steroid usage in British outpatients and assess factors associated with excess exposure. METHODS: We recorded steroid use in unselected IBD outpatients. Cases meeting criteria for steroid dependency or excess were blind peer reviewed to determine whether steroid prescriptions were avoidable. Associations between steroid use and patient/institutional factors were analysed. RESULTS: Of 1176 patients, 30% received steroids in the prior 12 months. 14.9% had steroid dependency or excess, which was more common in moderate/severe ulcerative colitis (UC) than Crohn's disease (CD) (42.6% vs 28.1%; P = .027). Steroid dependency or excess was deemed avoidable in 49.1%. The annual incidence of inappropriate steroid excess was 7.1%. Mixed-effects logistic regression analysis revealed independent predictors of inappropriate steroid excess. The odds ratio (OR, 95%CI) for moderate/severe compared to mild/quiescent disease activity was 4.59 (1.53-20.64) for UC and 4.60 (2.21-12.00) for CD. In CD, lower rates of inappropriate steroid excess were found in centres with an IBD multi-disciplinary team (OR 0.62 [0.46-0.91]), whilst dedicated IBD clinics protected against inappropriate steroid excess in UC (OR 0.64, 95% CI 0.21-0.94). The total number of GI trainees was associated with rates of inappropriate steroid excess. CONCLUSIONS: Steroid dependency or excess occurred in 14.9% of British IBD patients (in 7.1% potentially avoidable). We demonstrated positive effects of service configurations (IBD multi-disciplinary team, dedicated IBD clinics). Routine recording of steroid dependency or excess is feasible and should be considered a quality metric.

Assessing DNA methylation in the developing human intestinal epithelium: potential link to inflammatory bowel disease.

DNA methylation is one of the major epigenetic mechanisms implicated in regulating cellular development and cell-type-specific gene expression. Here we performed simultaneous genome-wide DNA methylation and gene expression analysis on purified intestinal epithelial cells derived from human fetal gut, healthy pediatric biopsies, and children newly diagnosed with inflammatory bowel disease (IBD). Results were validated using pyrosequencing, real-time PCR, and immunostaining. The functional impact of DNA methylation changes on gene expression was assessed by employing in-vitro assays in intestinal cell lines. DNA methylation analyses allowed identification of 214 genes for which expression is regulated via DNA methylation, i.e. regulatory differentially methylated regions (rDMRs). Pathway and functional analysis of rDMRs suggested a critical role for DNA methylation in regulating gene expression and functional development of the human intestinal epithelium. Moreover, analysis performed on intestinal epithelium of children newly diagnosed with IBD revealed alterations in DNA methylation within genomic loci, which were found to overlap significantly with those undergoing methylation changes during intestinal development. Our study provides novel insights into the physiological role of DNA methylation in regulating functional maturation of the human intestinal epithelium. Moreover, we provide data linking developmentally acquired alterations in the DNA methylation profile to changes seen in pediatric IBD.

Consistent patterns of expression of HLA class I free heavy chains in healthy individuals and raised expression in spondyloarthropathy patients point to physiological and pathological roles.

OBJECTIVES: Major histocompatibility complex class I (MHC-I) proteins exist at the cell surface in antigen presenting forms and as beta2m-independent free heavy chains (FHCs). FHCs have been implicated in spondyloarthritis, but little is known about their expression in healthy individuals. We studied FHC expression on various human cell types, comparing spondyloarthropathy patients with healthy and rheumatoid arthritis (RA) patient controls. METHODS: MHC-I expression was analysed by flow cytometry. FHC levels were normalized for overall MHC-I to generate a relative expression level. Relative FHC levels were analysed for peripheral blood and trophoblast samples from healthy volunteers, RA and spondyloarthropathy patients. Macrophages and dendritic cells were cultured in vitro to analyse changes following activation. Peripheral blood leucocytes from patients with ankylosing spondylitis (AS) and RA were treated with inflammatory stimuli and subsequent alterations in their relative FHC levels were analysed. RESULTS: We found consistent patterns of differential relative FHC expression across lymphocyte subpopulations and particularly high expression on extravillous trophoblast. FHCs were present at higher levels in a reactive arthritis (ReA) population than in healthy controls and RA patients; differences not merely due to the presence of Human Leucocyte Antigen (HLA) B27. Treatment of leucocytes from arthritic patients with bacterial lipopolysaccharide resulted in significant up-regulation of FHC compared with an HLA B27+ control population. CONCLUSIONS: Our findings define normal levels and tissue expression of FHCs, and support the hypothesis that disregulation of heavy chain expression may play a pathogenic role in spondyloarthropathy.

The benefits and risks of over-the-counter availability of levonorgestrel emergency contraception.

Removing the prescription requirement for Plan B will help ensure that the product plays a larger role nationally in the reduction of unintended pregnancy and abortion-important public health goals. Over-the-counter (OTC) sale of Plan B should present no serious safety issues. OTC consumers are able to understand and follow the instructions for proper use of Plan B. Efficacy of the OTC product is likely to be the same as, or better than, the prescription product, given more timely access to treatment. Based on the results of a growing body of literature and foreign marketing experience, the risk of unintended health consequences also appears to be minimal. There is no evidence to suggest that American women will abuse Plan B as an OTC product.

Leukocyte receptor complex-encoded immunomodulatory receptors show differing specificity for alternative HLA-B27 structures.

We studied recognition of the disease-associated HLA-B27 allele by immunomodulatory receptors encoded within the leukocyte receptor complex. HLA class I are ligands for members of the killer Ig receptor (KIR) and Ig-like transcript (ILT)/LIR/LILR families (the new LILR nomenclature is described at www. gene.ucl.ac.uk/nomenclature/genefamily/lilr.html). Members of these families bound HLA-B27 in both classical and beta(2) microglobulin-independent forms. Classical complexes bound ILT2, ILT4, and LIR6 transfectants but not ILT1, ILT3, or ILT5. A free H chain form of HLA-B27 bound ILT4 and LIR6. Both forms of HLA-B27 bound KIR3DL1 transfectants. HLA-B27 free H chain bound CD14(+) cells in PBL from healthy controls, consistent with ILT4 expression on monocytes. Alternative recognition of different forms of HLA-B27 by KIR or ILT could influence their immunomodulatory function and may imply a role in inflammatory disease.

Postponing sexual intercourse among urban junior high school students-a randomized controlled evaluation.

PURPOSE: To describe a randomized, controlled evaluation of a school-based intervention to delay sexual intercourse among urban junior high school students. METHODS: Six Washington, D.C., junior high schools were randomly assigned to the intervention or nonintervention control condition for an educational program. During the first school year, seventh graders (n = 582) from the six schools obtained written parental consent to participate. Three health professionals (one per intervention school) implemented the program, which consisted of reproductive health classes, the Postponing Sexual Involvement Curriculum, health risk screening, and "booster" educational activities during the following (eighth grade) school year. Cross-sectional surveys were administered at baseline, the end of the seventh grade, and the beginning and end of the eighth grade. Intervention and control group differences in virginity, attitudes toward delayed sex and childbearing, and sexual knowledge and behavior were assessed at all four time points. RESULTS: At baseline, 44% of the seventh grade males and 81% of the seventh grade females reported being virgins. At the end of the seventh grade (first follow-up), after controlling for baseline study group differences, intervention-group females were more likely to report virginity, self-efficacy to refuse sex with a boyfriend, and the intention to avoid sexual involvement during the following 6 months. At the end of the eighth grade, significantly more intervention- than control-group females reported virginity, birth control use at last intercourse (for nonvirgins), and knowledge of adolescent reproductive health and confidentiality rights. No changes in virginity, self-efficacy to refuse sex, or sexual intent for the next 6 months were observed among male participants at any time during the study. However, on all three follow-up surveys, intervention-group males scored significantly higher than their control-group counterparts in knowledge of birth control method efficacy. No change in attitudes toward abstinence was observed for either gender at any follow-up point. CONCLUSIONS: Gender differences in baseline sexual activity rates and in various study outcomes suggest a possible need for separate, gender-specific intervention activities that can adequately address the social and cognitive needs of both sexes.

Emergency contraception: advance provision in a young, high-risk clinic population.

OBJECTIVE: To assess whether advance provision of emergency contraception increases its use and whether it has secondary effects on regular contraceptive use. METHODS: We conducted a controlled trial of female clients, aged 16-24 years, who attended a publicly funded family planning clinic. Women were systematically assigned to receive an advance provision of emergency contraception and education (treatment) or education only (control). Among 263 participants enrolled (133 treatment, 130 control), follow-up was completed in 213 (111 treatment, 102 control). The main outcome measures were emergency contraception knowledge and use, frequency of unprotected sex, and pattern of contraceptive use in the past 4 months. RESULTS: Participants were aware of emergency contraception at follow-up, but the treatment group was three times as likely to use it (P =.006). Although the treatment group did not report higher frequencies of unprotected sex than the control group, women in the treatment group (28%) were more likely than those in the control group (17%) to report using less effective contraception at follow-up compared with enrollment (P =.05). The proportion of women in both groups who reported consistent pill use increased from enrollment to follow-up (34% versus 45%); however, the control group (58%) was more likely than the treatment group (32%) to report consistent pill use at follow-up (P =.03). CONCLUSION: Use of emergency contraception was increased by providing it in advance, but not by education alone. Changes to less effective contraceptive methods and patterns of pill use were potentially negative effects that need to be explored in relation to observed benefits.

Sociodemographic correlates of virginity in seventh-grade black and Latino students.

PURPOSE: To examine rates of virginity in seventh-grade black and Latino students and assess the extent to which various sociodemographic factors are correlated with virginity. METHODS: A total of 523 seventh-grade students from five junior high schools and one middle school in the District of Columbia completed an anonymous self-administered questionnaire. Students responded to questions about age at first intercourse, demographics, grades, educational expectations, and risk behaviors. Multivariate analysis was used to determine the independent strength of the association of these variables with virginity. RESULTS: Eighty-one percent of girls and 44% of boys reported never having had sexual intercourse, i.e., being virgins. Black and Latino students were equally as likely to report being virgins. Younger age and absence of other risk behaviors, including smoking and alcohol use, were associated with virginity for males and females. For boys, reporting high academic achievement and living with both parents was significantly correlated with virginity and appeared to be protective. CONCLUSIONS: Although prevalent particularly in seventh-grade black and Latino boys, sexual activity was clearly associated with other risk behaviors in both boys and girls. Sociodemographic correlates of virginity were gender-specific. School-based efforts to delay the onset of initiation of sexual activity in high-risk populations should be targeted at boys 12 years and younger with interventions which are gender-specific. This study underscores a need to examine correlates of virginity to generate practical approaches to prevention of early sexual activity.

Influence of provider characteristics and insurance status on maternal serum alpha-fetoprotein screening.

BACKGROUND: The maternal serum alpha-fetoprotein test (MSAFP) was developed to screen for neural tube defects. Little is known about the adoption of the MSAFP test. This study examines the effect of provider specialty and geographic location and patient insurance status on MSAFP test use in Washington State. METHODS: We conducted a retrospective cohort study of MSAFP use in low-risk obstetric patients of five provider groups. MSAFP use was examined for Medicaid and privately insured patients, as well as for the patients of the five provider types. RESULTS: Patients of urban and rural obstetrician-gynecologists were most likely to have MSAFP testing (80.4 percent and 77.0 percent, respectively); patients of urban certified nurse midwives and rural family physicians were least likely to have MSAFP testing (64.2 percent and 62.2 percent, respectively). Patients of certified nurse midwives were more likely to decline MSAFP testing when offered (26.1 percent). Medicaid-insured women were significantly less likely to have MSAFP testing than privately insured women (60.5 percent versus 79.1 percent, P < or = 0.05). CONCLUSIONS: Providers and patients did not uniformly use MSAFP screening. Efforts should be made to ensure that all patients are adequately informed of screening tests for neural tube defects.

Interspecialty differences in the obstetric care of low-risk women.

OBJECTIVES: This study examined differences among obstetricians, family physicians, and certified nurse-midwives in the patterns of obstetric care provided to low-risk patients. METHODS: For a random sample of Washington State obstetrician-gynecologists, family physicians, and certified nurse-midwives, records of a random sample of their low-risk patients beginning care between September 1, 1988, and August 31, 1989, were abstracted. RESULTS: Certified nurse-midwives were less likely to use continuous electronic fetal monitoring and had lower rates of labor induction or augmentation than physicians. Certified nurse-midwives also were less likely than physicians to use epidural anesthesia. The cesarean section rate for patients of certified nurse-midwives was 8.8% vs 13.6% for obstetricians and 15.1% for family physicians. Certified nurse-midwives used 12.2% fewer resources. There was little difference between the practice patterns of obstetricians and family physicians. CONCLUSIONS: The low-risk patients of certified nurse-midwives in Washington State received fewer obstetrical interventions than similar patients cared for by obstetrician-gynecologists or family physicians. These differences are associated with lower cesarean section rates and less resource use.

The risk of repeating low birth weight and the role of prenatal care.

OBJECTIVE: To estimate the influence of adequacy of prenatal care and other known risk factors on the risk of repeating low birth weight (LBW) (less than 2500 g). METHODS: This was a retrospective cohort study of women having two births in Washington state during 1984-1990, as recorded using linked birth certificate records. Logistic regression was used to control for maternal age, marital status, smoking, miscarriage, inter-pregnancy interval, and prenatal care. RESULTS: Compared to the reference group of women with normal-weight first births (at least 2500 g), women with LBW first births, either preterm or small for gestational age (SGA), were significantly more likely to have an LBW second birth. The estimated relative risk of repeating LBW in general was 7.0 (95% confidence interval 4.8-10.1). Smoking during the second pregnancy was a significant effect modifier. The risk estimates were not significantly affected by any of the other variables entered into the models, including adequate prenatal care. CONCLUSIONS: Prior delivery of a preterm or SGA LBW infant was the strongest predictor of LBW delivery in a subsequent pregnancy. Adequate prenatal care during the second pregnancy did not provide statistically significant protection against the risk of repeat LBW. The tendency for women to have repeat LBW deliveries despite adequate prenatal care indicates a need for a better understanding of the underlying pathophysiology of preterm and SGA delivery.

Do providers adhere to ACOG standards? The case of prenatal care.

OBJECTIVE: To examine the extent to which obstetric providers abide by prenatal practice guidelines published by ACOG. METHODS: The prenatal records were abstracted for low-risk patients initiating care with randomly selected urban obstetrician-gynecologists, rural obstetrician-gynecologists, urban family physicians, rural family physicians, and urban certified nurse-midwives in Washington state between September 1, 1988 and August 30, 1989. The prenatal care recorded in their medical charts was compared with the ACOG-recommended guidelines. RESULTS: Overall, providers of all five types adhered closely to the published standards. Certified nurse-midwives recorded a standard of practice that most closely matched that recommended by ACOG. Overall, there was less complete adherence in the recording of maternal height, fetal activity after 30 weeks' gestation, and fetal presentation at or after 36 weeks' gestation. Those laboratory tests that ACOG has recommended most recently (serum alpha-fetoprotein and diabetes screening) and those not recommended for routine use were ordered less often on average by providers. CONCLUSIONS: The cross-sectional nature of this study cannot demonstrate definitively that ACOG's guidelines have changed provider prenatal practices. However, these findings demonstrate that providers in varying specialties and geographic locations can adhere to a detailed set of clinical guidelines if they are appropriately disseminated and implemented.

Myeloid leukaemia and osteosarcoma in CBA/H mice given 224Ra.

Four groups of 400 12-week-old CBA/H mice were injected i.p. with 69, 139, 280 and 550 Bqg-1 224Ra. A further group of 400 mice were injected i.p. with diluting solution only. The mice were then allowed unrestricted access to food and water until they died or were killed. 53 cases of myeloid leukaemia and 22 cases of osteosarcoma were confirmed in the 2000 mice injected, and for both tumour types direct relationships were shown to exist between the amount of 224Ra administered and the incidence of tumours. It is concluded that mouse is at a greater risk from myeloid leukaemia than from osteosarcoma in the region of administered 224Ra below that which causes a maximum yield of osteosarcoma. These results are discussed in the light of the present acceptance of osteosarcoma as the major risk to man from bone-seeking alpha-particle emitters.

Sterile flexor tenosynovitis of the hand: a report of three cases.

Three patients presented with classic signs and symptoms of acute bacterial tenosynovitis. In each instance, the inflammatory condition was found to be sterile. The patients had no other known systemic diseases associated with sterile inflammation. Two patients had digital sheath exploration. The third patient had diagnostic digital sheath aspiration. Hand elevation, rest, and prophylactic antibiotics resulted in complete resolution in all three patients. One digital sheath biopsy specimen submitted for electron microscopy showed no evidence of a viral etiology.

Double-pedicle transverse rectus abdominis myocutaneous flap for unilateral breast and chest-wall reconstruction.

Fifteen patients underwent unilateral breast and chest-wall reconstruction by a double-pedicle transverse rectus abdominis myocutaneous flap technique. Criteria for using both pedicles include (1) exceptionally large soft-tissue requirements, (2) prior abdominal operations compromising the vasculature to portions of the anterior abdominal wall, and (3) certain higher-risk patients with suspected microvascular pathology. Double pedicles allowed the transfer of the skin island as one unit or as two independent hemiellipses of tissue. Follow-up time ranges from 4 to 17 months. Complications included partial tissue loss in two patients, one abdominal flap seroma, and one patient with a hernia.

Biocompatibility of silicone implants.

Polydimethylsiloxane has been considered immunologically inert, and previous work seems to have established that the production of circulating antibodies does not occur in response to its implantation. We have investigated the possibility of a cellular immune response to implanted silicone. We have observed histologically that the cellular response to polydimethylsiloxane in sensitized guinea pigs is consistent with a cellular immune reaction. Further studies with EM and XES have demonstrated intracellular silicon in the Golgi apparatus, rough endoplasmic reticulum, and at both ends of cytoplasmic bridges between macrophages and lymphocytes. All of these findings fit with the hypothesis that the cells are processing a silicon-containing complex as an antigen. Finally, macrophage migration inhibition studies have shown evidence of a cellular immune phenomenon. Further studies are planned to characterize the nature of the sensitizing complex and to attempt to confirm the migration inhibition studies in vivo.

Occult duodenal perforation complicating cerebral infarction: new problems in diagnosis of Cushing's ulcer.

Cushing's ulcers of the duodenum are well known complications of neurosurgery, head trauma, and other causes of increased intracranial pressure. Perforation of Cushing's ulcer of the duodenum is infrequently described. That the use of high-dose corticosteroids for cerebrovascular infarct in an aphasic patient may obscure the symptomatology and physical findings of a perforated Cushing's ulcer has not been described to our knowledge. We report a patient with a large left hemispherical infarct and resultant aphasia who developed a perforated duodenal ulcer and extensive chemical peritonitis while receiving high dose corticosteroids for increased intracranial pressure. She was unable to register any complaints and the typical physical findings of perforated duodenal ulcer with chemical peritonitis were virtually absent. A high index of suspicion must be maintained for a perforated Cushing's duodenal ulcer in the patient receiving high dose dexamethasone despite the presence of nonspecific symptomatology and abdominal findings. Elevated serum gastrin levels, as in this patient, may also indicate the patients with increased intracranial pressure who are at greater risk for developing Cushing's ulcer.

Progression of thermal injury: a morphologic study.

The events that participate in the local pathophysiology of a burn would have not been completely described. This study defines the sequential morphologic changes following untreated partial-thickness burns. Guinea pigs received partial-thickness scald burns by 75 degrees C water immersion for 10 seconds. Skin samples were then obtained at 2, 8, 24, and 96 hours after the burn and examined by light and electron microscopy. A definite progression of the thermal injury was found, with maximum tissue destruction occurring 8 hours after the burn. At 24 hours after the burn, some improvement in the burn wound was noted, especially in the dermal microvasculature. At 96 hours, the damaged epidermis sloughed, exposing a dermis that contained areas resembling microabscesses.