Local and systemic interleukin-18 and interleukin-18-binding protein in children with inflammatory bowel disease

BACKGROUND: Interleukin-18 (IL-18) is increased in the inflamed mucosa of patients with Crohn's disease (CD). The balance between this pleiotropic proinflammatory cytokine and its natural inhibitor, IL-18-binding protein (IL-18BP), may contribute to the pathogenesis of inflammatory bowel disease (IBD). METHODS: Serum and mucosal biopsies were collected from children with IBD, from children with celiac disease, and from controls. Biopsies were maintained in culture for 24 hours, and supernatant was collected. Serum and supernatant IL-18 and IL-18BPa concentrations were measured by immunoassay. Disease activity score (PCDAI) and standard serum inflammatory markers (albumin, platelets, ESR, and CRP) were recorded. RESULTS: Serum IL-18 was greater in children with CD (537 pg/mL) than in controls (335 pg/mL; P < 0.05) but not in children with ulcerative colitis (UC) or IBD type unclassified (IBDU). Mucosal IL-18 was greater in children with CD and UC/IBDU than in controls (P < 0.01). Serum IL-18BPa was increased in children with CD compared with that in controls (3.9 versus 2.6 ng/mL; P < 0.05), but was not elevated in children with UC/IBDU. Furthermore, calculated free-serum IL-18 was elevated in CD, but not UC/IBDU, compared with that in controls (P = 0.001). Total and free-serum IL-18 were elevated in severe CD relative to in mild/moderate disease. CONCLUSIONS: IL-18, produced in the colons of children with IBD, may contribute to local inflammatory changes. Systemic IL-18 level may be a useful indicator of gut inflammation. Furthermore, free IL-18 is greatly elevated in children with CD, suggesting that compensatory increases in IL-18BPa are insufficient. Further exploration of the role of this cytokine in the pathogenesis of IBD is now required.     

Poor results of drilling in early stages of juxta-articular osteonecrosis in 12 joints affected by Gaucher disease

Background and purpose Gaucher disease is heterogeneous. One of the most devastating complications is bone involvement, ranging from mild osteopenia to osteonecrosis, but no markers have been discovered to predict onset and/or progression. We describe our experience in a large referral center using drilling for juxta-articular osteonecrosis in young patients with Gaucher disease.Patients and methods We retrospectively reviewed medical data from all patients who were recommended to undergo drilling for osteonecrosis of juxta-articular bone of the femoral head, the humeral head, or upper tibia for acute osteonecrosis at a pre-collapse stage.Results 11 patients (mean age 34 years) underwent drilling of 12 joints with juxta-articular osteonecrosis; 3 (mean age 51 years) refused intervention. 9 joints that were drilled showed advancing joint degeneration within 0.5 to 4 years. 3 joints have undergone replacement. Of the 3 joints that did not undergo drilling, 2 have undergone replacement and 1 has collapsed with osteoarthritis.Interpretation We found equally poor outcome with and without drilling. Effective intervention can only be achieved by improving our understanding of bone physiology and pathophysiology in Gaucher disease.Gaucher disease is the most common lysosomal storage disease, and occurs in approximately 1 in 50,000 live births. It is more common in Ashkenazi Jews where it occurs in approximately 1 in 850 live births (Beutler and Grabowski 2001). There is accumulation of lipids due to deficient β-glucocerebrosidase, but neither enzyme activity nor other genetic or biochemical biomarkers can predict onset or severity of disease progression (Beutler and Grabowski 2001). One of the most devastating consequences of the disease is bone involvement, which affects most patients (Elstein et al. 1997). The underlying pathology of bone in Gaucher disease is unclear, but it is postulated to be secondary to bone marrow infiltration by lipid-laden macrophages, causing vascular occlusion or a local inflammatory reaction (Cox 2001). There are recognized risk factors for bone disease in Gaucher disease (Rodrigue et al. 1999) such as splenectomy (especially in childhood) and the presence of alleles that produce little or no enzyme. Bone involvement ranges in severity from discrete radiographic findings such as the Erlenmeyer flask deformity of the distal femur and the “herringbone” pattern of the humerus diaphysis, to osteopenia and osteonecrosis (Itzchaki et al. 2004).Enzyme replacement therapy (ERT) (Genzyme Corp., Cambridge, MA) improves the visceral and hematological features of the disease (Barton et al. 1991) as well as sense of well-being (Giraldo et al. 2005). Even so, the effect of ERT on bone remains controversial since there is not necessarily a correlation between radiological improvement (Poll et al. 2002) and clinical lack of deterioration (Elstein et al. 1996). ERT may eliminate bone crises if treatment is begun early (Charrow et al. 2007), but ERT does not appear to reverse existing osteonecrosis. To date, there are no definitive theories to explain the inadequate response of affected bone to ERT.Invasive interventions have been recommended for the pre-collapse stages of femoral osteonecrosis in otherwise healthy patients (Mont et al. 2006), to prolong time to replacement (McGory et al. 2007). Core decompression was used by Ficat (1983) with good results (79% success rate in patients with disease of stages I–II). When used in sickle cell anemia and compared to physical therapy, however, no additional benefit was noted (Neumayr et al. 2006). Yet, it is possible that the bone marrow may be impacted directly by decompression in sickle cell disease if attempted early in the progression to collapse (Hernigou et al. 2006).The cause of osteonecrosis in Gaucher disease may be in the marrow; thus, drilling of affected bones in Gaucher disease seems tenable. We report our experience using drilling for joint osteonecrosis in patients with Gaucher disease.     

Monotherapy of lamotrigine versus carbamazepine in patients with poststroke seizure

OBJECTIVES: The incidence of seizures is known to be high in the elderly. The most common cause of an unprovoked seizure in the elderly population is stroke. These patients require effective and well-tolerated antiepileptic treatment because they frequently experience other medical conditions and use other medications that can interact with the antiepileptic treatment. The aim of the study was to analyze the tolerability and efficacy of lamotrigine (LTG) versus sustained-release carbamazepine (CBZ) treatment in newly diagnosed symptomatic poststroke seizure. METHODS: Sixty-four patients with a first post episode of seizures were randomized in a 1:1 ratio to either LTG or CBZ treatment and were followed up prospectively for up to 12 months for efficacy and tolerability of the drugs. RESULTS: More patients in the LTG group were seizure-free (72%) versus those in the CBZ group (44%; P = 0.06), but the numbers did not reach statistical significance because of a relative small number of study patients. The number of patients who withdraw from the study because of adverse events was statistically significantly less in the LTG group (3%) compared with the CBZ group (31%; P = 0.02). CONCLUSIONS: The LTG treatment in poststroke seizures versus CBZ treatment is a relatively better-tolerated drug and can be acceptable as initial treatment in this specific group of patients.     

Incidence and risk factors for surgical infection after total knee replacement

Surgical site infection (SSI) after total knee replacement (TKR) is a devastating complication. We performed a retrospective study of all consecutive TKRs performed during a 2-y period. Surgical site infection (SSI) was defined by standard criteria. All patients were examined 1 y following surgery. Of 180 patients undergoing TKR, 10 (5.6%) developed a superficial (3, 1.7%) or deep (7, 3.9%) SSI. Two independent risk factors for SSI were detected: left knees became infected more often (9/ 92, 9.8%) than right knees (1/88, 1.1%) (Relative Risk 6.7 +/- 95% CI 1.7-26.8); and 7/72 (9.7%) patients receiving a type-1 prosthesis developed infection versus 3/104 (3.1%) receiving a type-2 prosthesis (RR 4.7, 95% CI 1.18-18.4). Investigation of the operating room revealed 3 problems: there was significant traffic through the door on the left of the patient; a nonstandard horizontal-flow air conditioner had been installed above that door; a tool-washing sink was in use on the other side of that door. Infection control guidelines were rehearsed: the sink was removed, the air conditioner was disconnected, and the door was locked. In a prospective survey performed 2 y later only 1/45 patients (2.2%) undergoing TKR developed a superficial SSI (p = 0.5). Correction of independent risk factors for infection following TKR led to a decrease in SSI rate.     

Comparing the Effectiveness of Shared versus Private Latrines in Preventing Trachoma in Rural Tanzania

Sharing latrines is common in sub-Saharan Africa with anecdotal accounts suggesting a link between water-, sanitation-, and hygiene-related disease and poorly maintained communal latrines. This study examines this link by assessing the association between shared latrines compared with private latrines and risk of trachoma. In 2007, as part of a larger case-control study, we conducted a sub-study on latrine sharing in 594 households (92 cases, 502 controls) in seven rural Tanzanian communities. Case households were defined by having a child with clinical signs of trachoma. Latrine use was associated with a decreased risk of trachoma and there was no difference in risk between households using shared compared with private latrines (adjusted odds ratio = 0.95 [95% confidence interval = 0.55–1.67]). This study emphasizes the need to promote latrine use, which can be facilitated through latrine sharing in resource scarce areas, for prevention of trachoma.Understanding the relationship between sanitation practices and related diseases is important for developing effective strategies that address both access to sanitation and health outcomes.¹ Trachoma, the world''s leading cause of preventable blindness,² is particularly suited to sanitation studies. The disease is transmitted both directly and through mechanical transport by eye-seeking flies that breed in feces, preferring those of human origin.^3,4 Latrines allow for the safe removal of human feces from the environment, thereby eliminating fly breeding material and potentially blocking mechanical transmission.⁵Latrine use is associated with a decreased risk of trachoma in various sub-Saharan African countries.^6,7 However, the practice of latrine sharing and the effect on disease remains largely undocumented. Assessing latrine sharing and trachoma in sub-Saharan Africa is important given that an estimated 18% of individuals in the region use a shared latrine.⁸ The widespread use of shared latrines combined with a high prevalence of trachoma in the region⁹ provided the motivation to conduct this study. The objective is to compare the effectiveness of shared latrines to private latrines in preventing risk of trachoma in rural Tanzania. We examined households that share latrines as a single entity and grouped them into categories based on the number of households sharing latrines. We hypothesize that latrine sharing, especially when it involves many households, could lead to inadequate maintenance and overuse, thereby diminishing the association of latrines with decreased risk of trachoma.     

Hue geometry and horizontal connections.

Primate visual systems support an elaborate specialization for processing color information. Concentrating on the hue component, we observe that, contrary to Mondrian-like assumptions, hue varies in a smooth manner for ecologically important natural imagery. To represent these smooth variations, and to support those information processing tasks that utilize hue, a piecewise smooth hue field is postulated. The geometry of hue-patch interactions is developed analogously to orientation-patch interactions in texture. The result is a model for long-range (horizontal) interactions in the color domain, the power of which is demonstrated on a number of examples. Implications for computer image processing, computer vision, visual neurophysiology and psychophysics are discussed.     

Herbal medicine and epilepsy: proconvulsive effects and interactions with antiepileptic drugs

The use of complementary and alternative medicine is on the rise, including among patients with epilepsy. Herbal medicine, one of the most popular forms of CAM, is considered to be both safe and effective by most consumers. Yet many herbs may increase the risk for seizures, through intrinsic proconvulsant properties or contamination by heavy metals, as well as via effects on the cytochrome P450 enzymes and P-glycoproteins, altering antiepileptic drug (AED) disposition. Herb-drug interactions may be difficult to predict, especially since the quality and quantity of active ingredients are often unknown. Since most patients do not inform their physicians that they are taking herbal medicines, health care professionals must initiate a dialogue in order to prevent complications with the combined regimen. At the same time, further research is required regarding the effect of herbs on seizure activity and interactions with AED treatment.     

The Mechanisms of the Anti-Inflammatory and Anti-Apoptotic Effects of Omega-3 Polyunsaturated Fatty Acids during Methotrexate-Induced Intestinal Damage in Cell Line and in a Rat Model

Background: The aim of this study was to examine the anti-inflammatory and anti-apoptotic patterns of omega-3 polyunsaturated fatty acids (n-3 PUFAs) during methotrexate (MTX) induced intestinal damage in cell culture and in a rat model. Methods: Non-treated and treated with MTX HT 29 and HCT116cells were exposed to increasing doses of n-3 PUFAs and cell viability was evaluated using PrestoBlue^® assay. Male Sprague-Dawley rats were divided into 4 experimental groups: Control rats, CONTR+n-3 PUFA rats that were treated with oral n-3 PUFA, MTX rats were treated with MTX given IP, and MTX+n-3 PUFA rats were treated with oral n-3 PUFA before and following injection of MTX. Intestinal mucosal parameters and mucosal inflammation, enterocyte proliferation and apoptosis, TNF-α in mucosal tissue and plasma (ELISA), NF-κB, COX-2, TNF-α, Fas, FasL, Fadd, Bid, Bax and Bcl-2gene and protein levels were determined 72 h following MTX injection. Results: Exposure of HT 29 and HCT116cells to n-3 PUFA attenuated inhibiting effects of MTX on cell viability. MTX-n-3 PUFA rats demonstrated a lower intestinal injury score and enhanced intestinal repair. A significant decrease in enterocyte apoptosis in MTX+n-3 PUFA rats was accompanied by decreased TNF-α, FAS, FasL, FADD and BID mRNA levels. Decreased NF-κB, COX-2 and TNF-α levels in mucosa was accompanied by a decreased number of IELs and macrophages. Conclusions: n-3 PUFAs inhibit NF-κB/COX-2 induced production of pro-inflammatory cytokines and inhibit cell apoptosis mainly by extrinsic pathway in rats with MTX-induced intestinal damage.     

Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation.

PURPOSE: the choices available for patients whose partial seizures are poorly controlled include seven new antiepileptic drugs (AEDs) or vagal nerve stimulation (VNS) as add-on therapy. Comparisons are needed to help physicians and patients select among the options for treatment. METHODS: we compared efficacy and adverse events of new treatments from controlled clinical trials of patients with uncontrolled partial seizures. Response rates (> or =50% decrease in partial seizures) at doses recommended in product labeling for adjunct therapy were tabulated for overall success (placebo response rate subtracted from AED response rate). Adverse events listed in product labeling were tabulated as complaint rates (placebo events subtracted from AED events). VNS trials used low dose stimulation as a pseudo-placebo. RESULTS: overall success rates fell into two general groups with ranges of 12-20% for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), zonisamide and 27-29% for levetiracetam, oxcarbazepine, and topiramate (TPM). Summary Complaint Scores also fell into two general groups with ranges of -27 to -82 for GBP, levetiracetam, TGB, zonisamide and -113 to -205 for LTG, oxcarbazepine and TPM. VNS scores were in the lower or higher success and summary complaint categories depending on whether scores from the pseudo-placebo group were subtracted from the high dose group. CONCLUSIONS: these data allow comparisons among AEDs and VNS using similar data from standard types of clinical trials.