Inflammatory pathways of importance for management of inflammatory bowel disease

Inflammatory bowel disease(IBD)is a group of chronic disorders of the gastrointestinal tract comprising Crohn’s disease(CD)and ulcerative colitis(UC).Their etiologies are unknown,but they are characterised by an imbalanced production of pro-inflammatory mediators,e.g.,tumor necrosis factor(TNF)-α,as well as increased recruitment of leukocytes to the site of inflammation.Advantages in understanding the role of the inflammatory pathways in IBD and an inadequate response to conventional therapy in a large portion of patients,has over the last two decades lead to new therapies which includes the TNF inhibitors(TNFi),designed to target and neutralise the effect of TNF-α.TNFi have shown to be efficient in treating moderate to severe CD and UC.However,convenient alternative therapeutics targeting other immune pathways are needed for patients with IBD refractory to conventional therapy including TNFi.Indeed,several therapeutics are currently under development,and have shown success in clinical trials.These include antibodies targeting and neutralising interleukin-12/23,small pharmacologic Janus kinase inhibitors designed to block intracellular signaling of several pro-inflammatory cytokines,antibodies targeting integrins,and small anti-adhesion molecules that block adhesion between leukocytes and the intestinal vascular endothelium,reducing their infiltration into the inflamed mucosa.In this review we have elucidated the major signaling pathways of clinical importance for IBD therapy and highlighted the new promising therapies available.As stated in this paper several new treatment options are under development for the treatment of CD and UC,however,no drug fits all patients.Hence,optimisations of treatment regimens are warranted for the benefit of the patients either through biomarker establishment or other rationales to maximise the effect of the broad range of mode-of-actions of the present and future drugs in IBD.     

Effects of bone marrow or mesenchymal stem cell transplantation on oral mucositis (mouse) induced by fractionated irradiation

Background and purpose

Oral mucositis is a severe and dose limiting early side effect of radiotherapy for head-and-neck tumors. This study was initiated to determine the effect of bone marrow- and mesenchymal stem cell transplantation on oral mucositis (mouse tongue model) induced by fractionated irradiation.

Material and methods

Daily fractionated irradiation (5?×?3 Gy/week) was given over 1 (days 0–4) or 3 weeks (days 0–4, 7–11, 14–18). Each protocol was terminated (day 7 or 21) by graded test doses (5 dose groups, 10 animals each) in order to generate complete dose–effect curves. The incidence of mucosal ulceration, corresponding to confluent mucositis grade 3 (RTOG/EORTC), was analyzed as the primary, clinically relevant endpoint. Bone marrow or mesenchymal stem cells were transplanted intravenously at various time points within these fractionation protocols.

Results

Transplantation of 6?×?10⁶, but not of 3?×?10⁶ bone marrow stem cells on day ??1, +?4, +?8, +?11 or +?15 significantly increased the ED₅₀ values (dose, at which an ulcer is expected in 50?% of the mice); transplantation on day +?2, in contrast, was ineffective. Mesenchymal stem cell transplantation on day ??1, 2 or +?8 significantly, and on day +?4 marginally increased the ED₅₀ values.

Conclusion

Transplantation of bone marrow or mesenchymal stem cells has the potential to modulate radiation-induced oral mucositis during fractionated radiotherapy. The effect is dependent on the timing of the transplantation. The mechanisms require further investigation.     

Familial risk analysis of the association between attention-deficit/hyperactivity disorder and psychoactive substance use disorder in female adolescents: a controlled study

Background:  A robust and bi-directional comorbidity between attention-deficit/hyperactivity disorder (ADHD) and psychoactive substance use disorder (PSUD, alcohol or drug abuse, or dependence) has been consistently reported in the literature. However, this literature has been based almost exclusively on male only samples and, therefore, the findings may not generalize to females.
Methods:  First-degree relatives from a large sample of pediatrically and psychiatrically referred girls with (123 probands, 403 relatives) and without ADHD (112 probands, 359 relatives) were comprehensively assessed by blind raters with structured diagnostic interviews. Familial risk analysis examined the risks in first-degree relatives for ADHD and PSUD (alcohol or drug abuse or dependence) after stratifying probands by the presence and absence of these disorders.
Results:  ADHD in the proband significantly increased the risk for ADHD in relatives independently of the comorbidity with PSUD. PSUD in the proband was associated with a significantly increased risk for PSUD in relatives regardless of ADHD status. There was no evidence of co-segregation or non-random mating in the families of probands with ADHD and PSUD.
Conclusions:  Patterns of familial risk analysis suggest that the association between ADHD and PSUD in adolescent females is most consistent with the hypothesis that these disorders are independently transmitted, although the hypothesis of variable expressivity could not be ruled out. These findings are consistent with previously reported patterns of familial associations between ADHD and PSUD found in adolescent males. Longer follow-up periods are needed to more fully clarify the relationship between ADHD and PSUD, as well as provide adequate power for separate analyses of alcohol and drug use.     

Serum interferon activity in inflammatory bowel disease

Serum interferon (IFN) of-class was studied in 64 consecutive patients, 26 with Crohn's disease, 38 with ulcerative colitis, and in 34 healthy volunteers. Detectable IFN- in 10 patients was associated with a moderate to severe activity of chronic inflammatory bowel disease (CIBD). However, 19 of 28 patients (68%) with activity in their disease did not have elevated IFN- levels. The three groups, ulcerative colitis, Crohn's disease, and healthy volunteers did not reveal any statistically significant difference in serum IFN-, as four of 34 healthy controls without intercurrent infections had elevated levels as well. Possible effects of, , and classes of IFN on endogenous arachidonic acid (AA) release and metabolism in human neutrophils was investigated in a substudy. IFN- caused a dose-dependent release of AA from phospholipids and metabolism of a modest fraction of leukotriene B₄ (LTB₄) and 5-hydroxyeicosatetraenoic acid (5-HETE) at doses reaching a maximum of 100 IU/ml. IFN of the and classes did not exert such effects. Addition of complement 5a to cells activated by IFN- caused induction of increased 5-li-poxygenase activity with unchanged release of AA. As only 16% of all CIBD patients had elevated IFN- levels as compared to 12% among the group of healthy volunteers, IFN- does not seem to be of importance for the perpetuation of the inflammatory reaction in ulcerative colitis or Crohn's disease, and other factors may therefore be responsible for activation of the inflammatory cells to production of LTB₄ and 5-HETE.     

Effects of age and breed on the phospholipid composition of canine surfactant

To investigate possible age- and breed-related changes in the composition of canine pulmonary surfactant, we determined the phospholipid patterns of surfactants isolated by bronchoalveolar lavage of 3 age categories of beagles (3-7 months; 3-7 years; 12 years and older) and of 1 group of greyhounds (4-14 years). There was a significant (p = 0.01) increase in the proportion of phosphatidylcholine in surfactant with age, whereas the proportions of phosphatidylserine and sphingomyelin were significantly lower in old beagles compared to young dogs. Although the differences were generally rather small, they may nevertheless be of biological importance, as was indicated by comparing the minimal surface tensions of lavage fluids obtained from young and old beagles. It is attractive to speculate that the shift in surfactant lipid composition could be 1 of the mechanisms that permit efficient lung function in old dogs, despite changes in morphology and mechanics in the aging lung. The phospholipid composition of surfactant isolated from greyhounds differed significantly from that in beagles. The surfactant of greyhounds was enriched in phosphatidylglycerol compared to all age groups of beagles. The degree of saturation of surfactant phosphatidylcholine was also higher in greyhounds, although this differences was significant only when compared to young and middle-aged beagles.     

Gastric emptying rate and small bowel transit time in patients with irritable bowel syndrome determined with99mTc-labeled pellets and scintigraphy

A new method employing^99mTc-labeled pellets for determination of the gastric emptying rate and small bowel transit time is described. The participants were six normal subjects and 16 patients with irritable bowel syndrome (eight with diarrhea and eight with obstipation as the primary complaint). The gastric emptying rate was the same in the three groups. The patients in the obstipation group had a significantly longer small bowel transit time than the normals (P<0.02) and the patients in the diarrhea group (P<0.01). There was no demonstrable difference between the small bowel transit time in the normals and in the patients in the diarrhea group.Supported by a grant from Direktør Jacob Madsen's og hustru Olga Madsen's foundation, and handelsgartner Ove Villiam Buhl Olesen's and aegtefaelle Edith Buhl Olesen's foundation.     

Serologie. Blutgruppen. Bakteriologie und Immunitätslehre

International Journal of Legal Medicine -