John F. Valentine

Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn's disease

BACKGROUND Crohns disease, a form of inflammatory bowel disease, resembles some aspects of tuberculosis, leprosy, and paratuberculosis. The role of Mycobacterium avium subspecies paratuberculosis (MAP) in Crohns disease is controversial. METHODS We tested for MAP by PCR and culture in buffy coat preparations from 28 individuals with Crohns disease, nine with ulcerative colitis, and 15 without inflammatory bowel disease. FINDINGS MAP DNA in uncultured buffy coats was identified by PCR in 13 (46%) individuals with Crohns disease, four (45%) with ulcerative colitis, and three (20%) without inflammatory bowel disease. Viable MAP was cultured from the blood of 14 (50%) patients with Crohns disease, two (22%) with ulcerative colitis, and none of the individuals without inflammatory bowel disease. Current use of immunosuppressive medication did not correlate with a positive MAP culture. Sequencing of PCR products from MAP cultures confirmed the presence of the MAP-specific IS900 fragment. Among 11 MAP isolates assessed, we identified nine strains that were not identical. INTERPRETATION We detected viable MAP in peripheral blood in a higher proportion of individuals with Crohns disease than in controls. These data contribute to the evidence that MAP might be a cause of Crohns disease.

Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease.

BACKGROUND & AIMS Some women with inflammatory bowel disease require therapy with tumor necrosis factor (TNF) antagonists during pregnancy. It is not clear whether these drugs are transferred to the fetus via the placenta and then cleared, or whether structurally different TNF antagonists have different rates of transfer. METHODS We studied 31 pregnant women with inflammatory bowel disease receiving infliximab (IFX, n = 11), adalimumab (ADA, n = 10), or certolizumab (CZP, n = 10). Serum concentrations of the drugs were measured at birth in the mother, infant, and in cord blood, and then monthly in the infant until the drugs were undetectable. Drug concentrations in the cord and the infant at birth were compared with those of the mother. RESULTS Concentrations of IFX and ADA, but not CZP, were higher in infants at birth and their cords than in their mothers. The levels of CZP in infants and their cords were less than 2 μg/mL. The median level of IFX in the cord was 160% that of the mother, the median level of ADA in the cord was 153% that of the mother, and the median level of CZP in the cord was 3.9% that of the mother. IFX and ADA could be detected in the infants for as long as 6 months. No congenital anomalies or serious complications were reported. CONCLUSIONS The TNF antagonists IFX and ADA are transferred across the placenta and can be detected in infants at birth; the drugs were detected in infants up to 6 months after birth. CZP has the lowest level of placental transfer, based on levels measured in cords and infants at birth, of the drugs tested.

Infliximab for treatment of pyoderma gangrenosum associated with inflammatory Bowel disease

OBJECTIVES:Pyoderma gangrenosum is an immune-mediated inflammatory condition characterized by ulcerative skin lesions affecting 1–2% of patients with inflammatory bowel disease (IBD). Treatment includes wound care, antibiotics, corticosteroids, and immunomodulators. However, response to therapy varies, and many patients with pyoderma gangrenosum have disease that is refractory to these agents. The aim of this study was to assess the response of medically refractory pyoderma gangrenosum to infliximab.METHODS:This was a multicenter retrospective study of patients with IBD and medically refractory pyoderma gangrenosum treated with infliximab. Data collected included the following: baseline demographics; duration of IBD; history of bowel resection; duration of skin lesions; number, size, and location of pyoderma gangrenosum lesions; prior medications; dose and number of infliximab infusions; bowel activity before and after infliximab; pyoderma gangrenosum activity before and after infliximab therapy; time to response and time to healing of pyoderma gangrenosum lesions; recurrence of pyoderma gangrenosum after infliximab; corticosteroid taper; and adverse reactions to infliximab.RESULTS:There were 13 patients with moderate to severe pyoderma gangrenosum and IBD treated with infliximab. All patients demonstrated complete healing of the skin lesions. Three patients had a complete response to induction infliximab therapy and did not require additional treatment. Ten patients responded to induction infliximab and have maintained pyoderma gangrenosum healing with infusions every 4–12 wk. All patients receiving corticosteroids were able to discontinue them completely after institution of infliximab treatment. Infliximab was well tolerated; the only treatment-related adverse events were sunburn in one patient and an infusion reaction in another.CONCLUSION:Infliximab is a safe and effective treatment for IBD-associated pyoderma gangrenosum.

The primacy of top-down effects in shallow benthic ecosystems

Individual scientists, scientific organizations, and government agencies have all concluded that eutrophication is among the most detrimental of all human activities in coastal ecosystems; very large amounts of funding have been earmarked to study the negative consequences of nutrient pollution. Most studies of eutrophication have been conducted long after the numbers and diversity of larger marine consumers were dramatically reduced by centuries of intense harvesting. It is now understood that these once abundant predators played pivotal roles in regulating ecosystem structure and function, and that the widespread overharvesting of large consumers can trigger indirect effects that alter species compositions in ways that are very similar to those reported to result from eutrophication. All of this suggests that we should reevaluate whether the many negative effects attributed to eutrophication are actually a result of nutrient additions or whether they may be the result of the indirect effects of dramatically altered coastal food webs. In this essay, we review experimental assessments of the degree to which changes in consumer abundances have indirectly altered the structure of benthic ecosystems in coastal waters, and on the relative importance of top-down and bottom-up effects on coral reefs, rocky shores, and seagrass meadows. We find that the evidence clearly indicates that indirect consumer effects are the primary drivers of coastal benthic ecosystem structure and function.

Efficacy and safety of endoscopic balloon dilation of symptomatic upper and lower gastrointestinal Crohn's disease strictures.

Goals: To evaluate efficacy and safety of endoscopic balloon dilation with or without intralesional steroid injection, of symptomatic upper gastrointestinal (UGI) and lower gastrointestinal (LGI) Crohns disease (CD) strictures. Background: Patients with CD commonly develop obstructive symptoms secondary to gastrointestinal strictures. When these do not resolve with medical management, surgery is usually the only alternative. Limited data are available on the safety and efficacy of endoscopic through-the-scope (TTS) balloon dilation of CD strictures. Study: We performed a retrospective review of TTS balloon dilations done on CD-related UGI and LGI strictures. Postdilation intralesional steroid injections were done at the discretion of the endoscopist. Stricture was defined as luminal stenosis <10 mm in diameter, through which a scope could not be passed. Technical success was defined as the ability of the scope to traverse the stricture postdilation. Long-term success rate was claimed if a patient remained asymptomatic and did not require surgery or further endoscopic dilation. Results: Over 4 years, we performed 29 stricture dilations on 17 patients (10 female, 7 male) with 20 strictures. The mean follow-up period was 18.8 months (range, 5-50 months). Stricture locations were as follows: rectal, 5; sigmoid colon, 2; colo-colonic anastomosis, 3; ileocolonic anastomosis, 4; ileum, 1; descending colon, 1; cecum, 1; and distal duodenal bulb, 3 patients. Technical success was achieved in 28 of 29 stricture dilations (96.5%). Ten strictures (34.5%) were dilated to <15 mm and 19 (65.5%) to ≥15 mm diameter. Long-term success rate in the <15 mm group was 70%, and in ≥15 mm group was 68.4%. Four quadrant steroid injections were done on 11 strictures. The recurrence rate in this group was 10% and that in the nonsteroid group was 31.3%. The overall long-term success rate was 76.5% by intent-to-treat analysis. Three perforations occurred (all colonic) during 29 stricture dilations, a complication rate of 10% with no mortalities. Conclusion: We report the first series of TTS balloon dilations with or without intralesional steroid injection, of both primary and anastomotic UGI and LGI strictures in CD patients. Long-term success was achieved in 76.5% patients with a complication rate of 10%. This mode of therapy appears safe and effective and can be considered as an alternative to surgery in selected patients with medically refractory CD-associated GI strictures. Success rates were better in patients who received four quadrant steroid injections. No difference was seen in stricture recurrence rate or complications based on diameter of TTS balloon used.

Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial.

Background: An uncontrolled pilot study demonstrated that daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), might be effective for the treatment of active ulcerative colitis. Methods: A randomised, double blind, placebo controlled trial was conducted to evaluate the efficacy of daclizumab induction therapy in patients with active ulcerative colitis. A total of 159 patients with moderate ulcerative colitis were randomised to receive induction therapy with daclizumab 1 mg/kg intravenously at weeks 0 and 4, or 2 mg/kg intravenously at weeks 0, 2, 4, and 6, or placebo. The primary end point was induction of remission at week 8. Remission was defined as a Mayo score of 0 on both endoscopy and rectal bleeding components and a score of 0 or 1 on stool frequency and physician’s global assessment components. Response was defined as a decrease from baseline in the Mayo score of at least 3 points. Results: Two per cent of patients receiving daclizumab 1 mg/kg (p = 0.11 v placebo) and 7% of patients receiving 2 mg/kg (p = 0.73) were in remission at week 8, compared with 10% of those who received placebo. Response occurred at week 8 in 25% of patients receiving daclizumab 1 mg/kg (p = 0.04) and in 33% of patients receiving 2 mg/kg (p = 0.30) versus 44% of those receiving placebo. Daclizumab was well tolerated. The most frequently reported adverse events in daclizumab treated patients compared with placebo treated patients were nasopharyngitis (14.6%) and pyrexia (10.7%). Conclusion: Patients with moderate ulcerative colitis who are treated with daclizumab are not more likely to be in remission or response at eight weeks than patients treated with placebo.

The role of sea urchin grazing in regulating subtropical seagrass meadows: evidence from field manipulations in the northern Gulf of Mexico

Abstract Sea urchin herbivory has been demonstrated to limit kelp forest distributions but its role in influencing distribution of seagrass habitats is inadequately investigated. During two annual cycles, we manipulated sea urchins [ Lytechinus variegatus (Lamarck)] at densities ranging from 0 to 80 individuals/m 2 , and documented their seasonal impact on turtlegrass Thalassia testudinum Banks ex Konig meadows in St. Joseph Bay, Florida. Results from these experiments indicate that the lowest densities of sea urchins required to overgraze (i.e., completely defoliate) turtlegrass occur during winter (approximately 20 individuals/m 2 ) while higher densities (approximately 40 individuals/m 2 ) are required for overgrazing during summer and fall. Field censuses frequently encountered sea urchin densities sufficient for overgrazing. We conclude that sea urchin herbivory is important in regulating subtropical seagrass meadow biomass and size particularly where sea urchin densities exceed 20 individuals/m 2 .

Sea urchin herbivory: evidence for long-lasting effects in subtropical seagrass meadows

A 4-month enclosure experiment, using high (40/m2) sea urchin densities (Lytechinus variegatus) (Lamarck), examined the effects of urchin grazing during winter-spring in St. Joseph Bay, Florida. This was done to test a prediction generated in earlier grazing experiments that repeated sea urchin cropping during fall and winter would likely produce permanently unvegetated plots. Three treatments were replicated in this experiment: (1) continuous grazing; (2) intermittent grazing of one week/month; and (3) no grazing (control). In addition, predation potential on various sized urchins was assessed using tethering experiments, and urchin residence times were estimated by direct observation. Sea urchin grazing dramatically affected seagrass habitat structure for long periods of time (> 3.5 yr). Intermittent grazing produced significant reductions in aboveground plant biomass compared to controls, while continuous grazing produced apparently permanent loss of sea-grasses. The winter start of the experiments was important in producing the large grazing effects observed because low productivity during winter increases the probability that plants can exhaust stored rhizome reserves. Published productivity values of seagrasses and urchin feeding rates, combined with our field densities of resident urchins, suggest that most aboveground production at our study site is consumed by urchins. Tethering experiments showed that small urchins (< 30 mm test diameter) were consumed in significantly greater numbers than large urchins (31–60 mm test diameter) and that significantly more urchins were consumed on sand than in grass. We hypothesize that urchins and seagrasses can coexist because newly recruited urchins are consumed at high rates when seagrass density is lowered by large amounts of urchin grazing, which subsequently leads to lower urchin densities. This eventually allows seagrasses to recover to high densities, which results in increased urchin survival. This, in turn, leads to high rates of grazing and, once again, reduced seagrass density.

Prevention and treatment of osteoporosis in patients with inflammatory bowel disease

Osteopenia or osteoporosis is common in patients with inflammatory bowel disease. The use of corticosteroids contributes to the decline in bone loss; however, osteoporosis may develop in patients with inflammatory bowel disease independent of corticosteroid use. Risk factors for the development of low bone mass in patients with inflammatory bowel disease include the general risk factors for osteoporosis as well as additional factors such as the presence of chronic inflammation, use of corticosteroids and other pharmaceuticals, and nutritional deficiencies as the result of small bowel disease or small bowel resections. Despite the high prevalence, few patients are entered into prophylactic regimens to prevent corticosteroid-induced bone loss. The American College of Rheumatology has recently published recommendations for the prevention and treatment of corticosteroid-induced osteoporosis. In this article, we highlight the special risks for osteoporosis in patients with IBD and adapt the recommendations for prevention and treatment of osteoporosis to this clinical setting.

Spatial and diurnal distribution of invertebrate and fish fauna of a Zostera marina bed and nearby unvegetated sediments in Damariscotta River, Maine (USA)

Abstract Fish, epibenthos and macroinfauna were collected in a Zostera marina bed and nearby unvegetated sediments in the estuary of the Damariscotta River, on the mid-coast of Maine. Samples of epibenthic fauna and fish were collected at low tides both during day and night, and samples of infauna at low tides during the day. The mean density of Zostera shoots in the study area was 335 m −2 . Abundance and species number of fish were greater at night than during the day and greater in eelgrass beds ( Z. marina ) than in unvegetated habitats. Daytime fish collections were dominated by Atlantic silversides ( Medinia medinia ), while juvenile winter flounder ( Pseudopleuronectes americanus ) dominated night collections. Also Zostera -associated epifaunal abundances and number of species were significantly higher at night than during the day. Mysis stenolepis , Idotea balthica and Littorina obtusata were dominant species in the epifauna samples. Of the total of 37 invertebrate species encountered, only five occurred both in the infaunal and epifaunal samples. Nineteen different taxa were collected from the benthic core samples. The most abundant invertebrate infaunal taxa were sipunculids, the polychaete Nereis virens , and oligochaetes. Infaunal invertebrate abundances and species diversity were significantly higher in eelgrass beds than in unvegetated sediments. The abundance and number of species of benthic invertebrates were also positively correlated to seagrass biomass. Community diversity values ( H ′) were relatively low but fit well in the general pattern of decreasing diversity towards northern latitudes.