Malin Hakelius

Regulation of fibroblast gene expression by keratinocytes in organotypic skin culture provides possible mechanisms for the antifibrotic effect of reepithelialization

To investigate the mechanisms behind the antifibrotic effect associated with epidermal regeneration, the expression of 12 fibroblast genes important for the modulation of the extracellular matrix (ECM), as well as α‐smooth muscle actin, was studied in a keratinocyte‐fibroblast organotypic skin culture model. The study was performed over time during epidermal generation and in the presence or absence of the profibrotic factor transforming growth factor‐β. the Presence of epidermal differentiation markers in the model was essentially coherent with that of native skin. Fibroblast gene expression was analyzed with real‐time polymerase chain reaction after removal of the epidermal layer. After 2 days of air‐exposed culture, 11 out of the 13 genes studied were significantly regulated by keratinocytes in the absence or presence of transforming growth factor‐β. The regulation of connective tissue growth factor, collagen I and III, fibronectin, plasmin system regulators, matrix metalloproteinases and their inhibitors as well as α‐smooth muscle actin was consistent with a suppression of ECM formation or contraction. Overall, the results support a view that keratinocytes regulate fibroblasts to act catabolically on the ECM in epithelialization processes. This provides possible mechanisms for the clinical observations that reepithelialization and epidermal wound coverage counteract excessive scar formation.

Intravelar veloplasty reinforced with palatopharyngeal muscle: a review of a 10-year consecutive series.

We describe a technique by which the intravelar veloplasty was reinforced by including the superior part of posterior pillars and their palatopharyngeal muscle sheet in patients with cleft lip and palate. Our aim was to increase the functional length and strength of the velum and to reduce nasal emission and the need for pharyngeal flaps. Since 1990 more than 200 patients have been operated on in this way at Uppsala University Hospital. This is a retrospective follow-up of 162 consecutive patients operated on by two senior surgeons between 1990 and 2000. We describe the technique, timing, and operative observations as well as the outcome and the need for revision of the palatoplasty in some cases because of complications. To facilitate speech, 21 patients born between 1990 and 1997 (16%) were provided with a pharyngeal flap.

Skoog Primary Periosteoplasty versus Secondary Alveolar Bone Grafting in Unilateral Cleft Lip and Alveolus: Long-term Effects on Alveolar Bone Formation and Maxillary Growth

Background: Clefts involving the alveolus are treated using one of two strategies: primary periosteoplasty at the time of lip repair or secondary alveolar bone grafting at mixed dentition. Most teams favor secondary alveolar bone grafting because of its high success rate, and concerns have been raised that primary periosteoplasty may interfere with maxillary growth. However, primary periosteoplasty may obviate the need for future bone grafting and is still practiced in some centers. Few studies compare the long-term outcomes of these two strategies. Methods: Fifty-seven consecutive patients born with unilateral cleft lip and alveolus were studied retrospectively. All patients underwent primary lip repair using Skoog’s method; 28 patients underwent primary periosteoplasty at the time of lip repair and the remaining 29 underwent secondary alveolar bone grafting at mixed dentition. Occlusal radiographs obtained at ages 10 and 16 years were analyzed for alveolar bone height. Cephalometric analysis assessed growth at ages 5, 10, and 18 years. Results: Seventeen of 28 patients treated using primary periosteoplasty required later secondary bone grafting, and the bone height at age 16 years was lower in the primary periosteoplasty group (p < 0.0001). There was a more pronounced decrease in maxillary protrusion from ages 5 to 10 years in the primary periosteoplasty group (p < 0.03). However, at age 18 there was no significant difference in maxillary growth between the two groups. Conclusion: Primary periosteoplasty did not seem to inhibit long-term maxillary growth but was ineffective as a method of reconstructing the alveolar cleft. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Correlations between initial cleft size and dental anomalies in unilateral cleft lip and palate patients after alveolar bone grafting

Abstract Objective To determine in individuals with unilateral cleft lip and palate the correlation between initial cleft size and dental anomalies, and the outcome of alveolar bone grafting. Methods A total of 67 consecutive patients with non-syndromic unilateral complete cleft lip and palate (UCLP) were included from the cleft lip and palate-craniofacial center, Uppsala University Hospital, Sweden. All patients were operated by the same surgeon and treated according to the Uppsala protocol entailing: lip plasty at 3 months, soft palate closure at 6 months, closure of the residual cleft in the hard palate at 2 years of age, and secondary alveolar bone grafting (SABG) prior to the eruption of the permanent canine. Cleft size was measured on dental casts obtained at the time of primary lip plasty. Dental anomalies were registered on radiographs and dental casts obtained before bone grafting. Alveolar bone height was evaluated with the Modified Bergland Index (mBI) at 1 and 10-year follow-up. Results Anterior cleft width correlated positively with enamel hypoplasia and rotation of the central incisor adjacent to the cleft. There was, however, no correlation between initial cleft width and alveolar bone height at either 1 or 10 years follow-up. Conclusions Wider clefts did not seem to have an impact on the success of secondary alveolar bone grafting but appeared to be associated with a higher degree of some dental anomalies. This finding may have implications for patient counseling and treatment planning.

Early Release of Interalveolar Synechiae Under General Anesthesia Through Fiberscopic Nasal Intubation

Abstract This article presents a treatment strategy for early release of interalveolar synechiae, aiming to facilitate early oral feeding and prevent temporomandibular joint ankylosis. The treatment results of 2 patients with van der Woude syndrome were retrospectively studied. Both patients underwent early surgical release of interalveolar synechiae under general anesthesia through fiberscopic nasal intubation. The 2 patients were treated at the ages of 6 and 14 days, respectively. The interincisival distances increased from 5 and 6 mm preoperatively to 11 and 10 mm immediately after surgery. This was increased further to 25 and 20 mm at long-term follow-up (6 and 24 months). In conclusion, synechiae between the upper and lower jaws can be safely treated at a very early age under general anesthesia with fiberscopic nasotracheal intubation. The purpose of early intervention in these cases is to facilitate oral feeding and prevent temporomandibular joint ankylosis.

Interleukin-1-mediated effects of normal oral keratinocytes and head and neck squamous carcinoma cells on extracellular matrix related gene expression in fibroblasts

OBJECTIVES The composition of tumor stroma and the activity of tumor associated fibroblasts are important for tumor growth. Interactions between carcinoma cells and fibroblasts regulate the turnover of extracellular matrix (ECM). Here, the in vitro effects of oral squamous cell carcinoma (SCC) cells (UT-SCC-30 and UT-SCC-87) on fibroblast expression of genes for ECM components and connective tissue growth factor (CTGF/CCN2), were compared to those of normal oral keratinocytes (NOK). MATERIALS AND METHODS Cocultures with fibroblasts in collagen gels and keratinocytes with the two cell types separated by a semi permeable membrane were used, and relative gene expression was measured with real-time PCR. RESULTS All investigated genes were regulated by NOK and the SCCs. The downregulation of pro-collagens α1(I) and α1(III) was more pronounced in cocultures with NOK, while the expression of CCN2 and fibronectin was downregulated by both NOK and the SCCs to a similar extent. UT-SCC-87, but not UT-SCC-30, secreted significantly more IL-1α than NOK. A recombinant interleukin-1 receptor antagonist reversed many of the observed effects on fibroblast gene expression suggesting involvement of IL-1 in cocultures with NOK as well as with SCCs. CONCLUSION The observed differential effects on fibroblast gene expression suggest that NOK are more antifibrotic compared to UT-SCC-30 and UT-SCC-87. These findings may contribute to a better understanding of the mechanisms behind ECM turnover in tumors.