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Biomedical subjects

Frank Heller

Publications and source records attributed to Frank Heller.

11 recordsLinked to original sources
PubMed2006

Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody.

BACKGROUND: Interleukin (IL)-12p70 and IL-23 are key T helper-1 (TH1) cytokines that drive the inflammation seen in numerous models of intestinal inflammation. These molecules contain an identical p40 chain that is bound to a p35 chain in IL-12 and a p19 chain in IL-23, making both potentially susceptible to modulation by an anti-IL-12p40 monoclonal antibody (mAb). METHODS: In the present study, we sought to determine whether active inflammation in Crohn's disease (CD) is associated with the increased synthesis of both of these cytokines and whether patients treated with an anti-IL-12p40 mAb down-regulate IL-23 as well as IL-12p70 as previous reported. RESULTS: To this end we initially determined that IL-12p70 secretion by control and CD antigen-presenting cells (macrophages) in lamina propria mononuclear populations is optimized by stimulation with CD40L and interferon-gamma. In subsequent studies using these stimulation conditions we found that patients with CD manifested both increased IL-12p70 and IL-23 secretion before anti-IL-12p40 mAb treatment and normal levels of secretion of these cytokines following cessation of treatment. Antigen-presenting cells in lamina propria mononuclear cells from ulcerative colitis patients, in contrast, produced only baseline levels of IL-23. Finally, we found that IL-23-induced T cell production of IL-17 and IL-6 are also greatly reduced after antibody treatment. The latter data are parallel to those from previous studies showing that anti-IL-12p40 down-regulates IFN-gamma and tumor necrosis factor-alpha secretion. CONCLUSIONS: We conclude that CD but not ulcerative colitis is associated with high levels of both IL-12p70 and IL-23 secretion as well as the secretion of downstream effector cytokines, and that this cytokine production is down-regulated following administration of IL-12p40 mAb.

Adolescent↗
PubMed2006

Distraction osteogenesis in adolescents with maxillary arch deficiency and dental crowding: a 3-year follow-up.

BACKGROUND: In this study, the authors evaluated the long-term results after using anterior segmental osteotomy and distraction osteogenesis for the correction of sagittal maxillary deficiency associated with dental crowding. METHODS: Six young adolescents (four boys and two girls) underwent surgery and distraction at a mean age of 11.2 years (range, 10 to 12 years) and were followed up for 3 years. A tooth-borne distraction device was used for interdental distraction. The evaluation consisted of hard- and soft-tissue profile analysis and dental arch measurements before, immediately after, and 3 years after distraction. RESULTS: The results showed that the facial profile, the occlusion, and the dental crowding could be successfully corrected and that the results were stable after 3 years' follow-up. The mean facial convexity angle was changed from 1 to 8 degrees. The average advancement at point A was 4 mm and the SNA increased by an average of 4 degrees. Lengthening of the dental arch by an average of 4 mm created approximately 8 mm of new space, sufficient to resolve the dental crowding in all patients, thus avoiding an extraction of healthy teeth. CONCLUSION: The results of this study demonstrated that anterior segmental maxillary osteotomy combined with distraction osteogenesis offers an alternative for the treatment of adolescents suffering from sagittal maxillary deficiency with dental crowding.

Child↗
PubMed2006

Disrupted barrier function through epithelial cell apoptosis.

Epithelial barrier function is determined by trans- and paracellular permeabilities, the latter of which is mainly influenced by tight junctions (TJs) and apoptotic leaks within the epithelium. The present article aims to present experimental evidence for a functional role of epithelial apoptoses by means of cell culture models as well as in tissues from patients with inflammatory bowel disease. It is shown that epithelial apoptoses are sites of elevated conductance within the intestinal epithelium and that proinflammatory cytokines like TNF-alpha upregulate both the apoptotic rate and single apoptotic conductivity, making cytokine-induced apoptosis functionally far more relevant than is spontaneous apoptosis. In ulcerative colitis and Crohn's disease (CD), but not in collagenous colitis, apoptotic rates are increased to about 5%, in mild-to-moderately inflamed colon specimens, where as the control apoptotic rate is about 2%. Thus, epithelial apoptoses lead to a loss of ions and water into the intestinal lumen, causing leak flux diarrhea and enabling small antigens of <4,000 Da in the intestinal lumen to enter the intestinal mucosa, thereby perpetuating inflammatory responses. In addition to TNF-alpha, interleukin (IL)-13 is an important inductor of epithelial apoptosis in Th2 immune responses. Therapeutically,TNF-alpha-antibodies (infliximab) can restore barrier function in Crohn's disease by downregulating epithelial apoptoses, while epithelial TJs are unaffected.

Apoptosis↗
PubMed2005

Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution.

BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by a Th2 immune response with inflammation and epithelial barrier dysfunction. So far, Th2 cytokines have not been shown to directly influence epithelial barrier function. METHODS: Lamina propria mononuclear cells (LPMCs) were stimulated and interleukin (IL)-13 was measured by enzyme-linked immunosorbent assay. Functional IL-13 and IL-4 effects were studied on HT-29/B6 colonic epithelial cells in Ussing chambers and by conductance scanning. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays. IL-13/IL-4 receptors were analyzed by reverse-transcription polymerase chain reaction and immunofluorescence. Western blotting combined with immunofluorescence was used to detect tight junction proteins. Furthermore, restitution velocity was measured. Finally, mucosal biopsy specimens from patients with UC were compared with cultured cells for these features. RESULTS: LPMCs from patients with UC produced large amounts of IL-13 (985 +/- 73 pg/mL), much more than from controls or patients with Crohn's disease. IL-13Ralpha1 and IL-4Ralpha receptors were present in HT-29/B6 cells and colonic epithelial cells of control patients and patients with UC. IL-13 had a dose-dependent effect on transepithelial resistance of HT-29/B6 monolayers (reduction to 60% +/- 4%), whereas IL-4 had no effect. This was due to an increased number of apoptotic cells (5.6-fold +/- 0.9-fold) and an increased expression of the pore-forming tight junction protein claudin-2 to 295% +/- 37%, both of which contributed equally. Finally, epithelial restitution velocity decreased from 15.1 +/- 0.6 to 10.6 +/- 0.5 microm/h after treatment with IL-13. Parallel changes were observed in human samples, with an increase in claudin-2 expression to 956% +/- 252%. CONCLUSIONS: IL-13 was identified as an important effector cytokine in UC that impairs epithelial barrier function by affecting epithelial apoptosis, tight junctions, and restitution velocity.

Adult↗
PubMed2005

The medial surface of the mandible as an alternative source of bone grafts in orthognathic surgery.

A technique of harvesting bone grafts from the medial surface of the angle of the mandible during a bilateral sagittal split osteotomy procedure is described. In 20 patients who underwent mandibular setback for the correction of class III dentofacial deformities, bone grafts were harvested from the medial mandibular angle and used for simultaneous augmentation of the midface or for interpositioning and stabilization of the maxilla after LeFort I maxillary anterior or inferior repositioning. The mean postoperative follow-up was 6 months (range, 3-12 months). No complications occurred, and postoperative morbidity was similar to that encountered by patients who undergo sagittal split osteotomy without bone harvest. The technique described shows that the medial mandibular angle is a suitable donor site for membranous bone grafts in patients who undergo sagittal split osteotomy.

Adolescent↗
PubMed2005

A non-tooth-borne mouth-opening device for postoperative rehabilitation after surgical release of trismus.

BACKGROUND: The treatment of severe trismus requires a combination of surgical release and postoperative rehabilitation; the latter is essential for preventing a relapse due to postoperative inactivity and scarring. Mouth-opening devices for this purpose are placed between or fixed to the teeth to keep the dental arches apart; but patients suffering from severe trismus often present with partially or totally edentulous arches, decayed teeth, or periodontitis, which do not allow for the use of such devices. METHODS: In this article, a new mouth-opening device is described. It applies force to two intraoral screws placed in the vestibulum of the maxillary and mandibular bones. It can be used in patients with poor dental conditions and allows rehabilitation to start immediately after trismus release. RESULT: A case is presented. The interalveolar distance was improved from 5 mm to 45 mm and maintained at 6-month follow-up. CONCLUSION: Our non-tooth-borne mouth opening device is useful for postoperative rehabilitation after surgical release of trismus.

Bone Screws↗
PubMed2004

Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis.

While Crohn disease (CD) has been clearly identified as a Th1 inflammation, the immunopathogenesis of its counterpart inflammatory bowel disease, ulcerative colitis (UC), remains enigmatic. Here we show that lamina propria T (LPT) cells from UC patients produce significantly greater amounts of IL-13 (and IL-5) than control cells and little IFN-gamma, whereas comparable cells from CD patients produce large amounts of IFN-gamma and small amounts of IL-13. We then show that stimulation of UC LPT cells bearing an NK marker (CD161) with anti-CD2/anti-CD28 or with B cells expressing transfected CD1d induces substantial IL-13 production. While this provided firm evidence that the IL-13-producing cell is an NK T (NKT) cell, it became clear that this cell does not express invariant NKT cell receptors characteristic of most NKT cells since there was no increase in cells binding alpha-galactosylceramide-loaded tetramers, and alpha-galactosylceramide did not induce IL-13 secretion. Finally, we show that both human NKT cell lines as well as UC CD161(+) LPT cells are cytotoxic for HT-29 epithelial cells and that this cytotoxicity is augmented by IL-13. These studies show that UC is associated with an atypical Th2 response mediated by nonclassical NKT cells producing IL-13 and having cytotoxic potential for epithelial cells.

Antigens, CD1↗
PubMed2004

Anterolateral thigh fasciocutaneous flap for simultaneous reconstruction of refractory scalp and dural defects. Report of two cases.

Infected full-thickness defects of the calvaria including the scalp, cranial bone, and dura mater, are often refractory to treatment and pose a difficult and urgent therapeutic problem for reconstructive surgeons. The authors report two cases in which successful reconstruction was achieved in one stage by using an anterolateral thigh fasciocutaneous flap. The well-vascularized fascia components were used to repair the infected dural defects. The skin flaps were used for coverage reconstruction.

Adult↗
PubMed2003

Intestinal flora and mucosal immune responses.

The normal intestinal flora and the mucosal immune system exist in close spatial proximity. A normal structure and function of both very complex systems is required for health and develops in a constant and interactive process. An abnormal host response to the normal intestinal flora leads to chronic intestinal inflammation. Probiotic bacteria may modulate the intestinal flora and the mucosal immune response and are an effective therapy for remission maintenance of ulcerative colitis and pouchitis.

Animals↗
PubMed2002

Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells.

Oxazolone colitis (OC) is an experimental colitis that has a histologic resemblance to human ulcerative colitis. Here we show that IL-13 production is a significant pathologic factor in OC since its neutralization by IL-13Ralpha2-Fc administration prevents colitis. We further show that OC is mediated by NK-T cells since it can be induced neither in mice depleted of NK-T cells nor in mice that cannot present antigen to NK-T cells and mice lacking an NK-T cell-associated TCR. Finally, we show that NK-T cells are the source of the IL-13, since they produce IL-13 upon stimulation by alpha-galactosylceramide, an NK-T cell-specific antigen. These data thus describe a cellular mechanism underlying an experimental colitis that may explain the pathogenesis of ulcerative colitis.

Adjuvants, Immunologic↗