Advances in craniosynostosis research and management.

The purpose of the present paper is to analyze the most recent advances in the field of craniosynostosis basic and clinical research and management, and to give an overview of the more frequently adopted surgical strategies. After reviewing some basic concepts regarding normal craniofacial embryology and growth, aetiopathogenesis of craniosynostosis and craniofacial dysostosis, classification and diagnosis and historical evolution of surgical treatment, the authors elaborate on a selection of topics that have modified our current understanding of and therapeutical approach to these disease processes. Areas covered include advances in molecular biology and genetics, imaging techniques and surgical planning, resorbable fixation technology, bone substitutes and tissue engineering, distraction osteogenesis and the spring-mediated cranioplasties, resorbable distractor devices, minimally invasive surgery and in utero surgery. A review of the main subtypes of craniosynostosis and craniofacial dysostosis is presented, including their specific clinical features and a commentary on the presently available surgical options.

Craniofacial surgery over 30 years in Göteborg.

Craniofacial surgery is a new sub-specialty in the field of plastic reconstructive surgery and is dedicated to the treatment of severe cranial and facial malformations. Craniofacial surgery gradually started in Göteborg in the late 1970's and has been acting as the Scandinavian center since 1983. Over these 30 years an almost complete change in surgical techniques has evolved. Also profound changes in timing of surgery have followed. Results have been dramatically improved based on critical evaluation of standardized registration of long-term results. One of the most dramatic developments has been the introduction of implantable stainless steel springs. This has changed the treatment of Craniosynostosis completely and has made midfacial advancement procedures possible without relapse.

Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases.

Dipeptidyl peptidase I (DPPI) or cathepsin C is the physiological activator of groups of serine proteases from immune and inflammatory cells vital for defense of an organism. The structure presented shows how an additional domain transforms the framework of a papain-like endopeptidase into a robust oligomeric protease-processing enzyme. The tetrahedral arrangement of the active sites exposed to solvent allows approach of proteins in their native state; the massive body of the exclusion domain fastened within the tetrahedral framework excludes approach of a polypeptide chain apart from its termini; and the carboxylic group of Asp1 positions the N-terminal amino group of the substrate. Based on a structural comparison and interactions within the active site cleft, it is suggested that the exclusion domain originates from a metallo-protease inhibitor. The location of missense mutations, characterized in people suffering from Haim-Munk and Papillon-Lefevre syndromes, suggests how they disrupt the fold and function of the enzyme.

Tetrameric dipeptidyl peptidase I directs substrate specificity by use of the residual pro-part domain.

The crystal structure of mature dipeptidyl peptidase I reveals insight into the unique tetrameric structure, substrate binding and activation of this atypical papain family peptidase. Each subunit is composed of three peptides. The heavy and light chains form the catalytic domain, which adopts the papain fold. The residual pro-part forms a beta-barrel with the carboxylate group of Asp1 pointing towards the substrate amino-terminus. The tetrameric structure appears to stabilize the association of the two domains and encloses a 12700 A3 spherical cavity. The tetramer contains six chloride ions, one buried in each S2 pocket and two at subunit interfaces.

Expander elements in craniofacial surgery: an experimental study in rabbits.

With the inception of craniofacial surgery elaborate surgical procedures were introduced for the treatment of craniosynostosis. Recently the use of implantable springs to aid simple strip craniectomies for these conditions has been described. Having shown the feasibility of using springs for dynamic skull reshaping, several questions remain to be answered, all of them about how to control the spring action clinically. One of the most important questions concerns force. The purpose of this study was to evaluate experimentally the effect of two springs of different strengths on the growth of rabbit calvaria after strip craniectomy. Thirty-two 6-week-old rabbits were randomised into one of four groups: sham-operation where only amalgam markers were inserted after subperiostal dissection; strip craniectomy of the sagittal suture, no expansion; strip craniectomy of the sagittal suture and insertion of an expander element made of titanium molybdenum alloy (TMA); and strip craniectomy sagittal suture and insertion of an expander element made of stainless steel (SS). SS springs delivered a range of forces from 2.42-2.18 N, whereas the TMA expander elements delivered a range from 1.39-1.09 N. The parietal bone marker separation after 12 weeks was 4.9 mm in the TMA group and 7.4 mm in the SS group. This resulted in a significant increase of the calvarian height compared with control groups. Histological examination showed intramembranous bone formation in the bone gap in all groups.

Long-term follow-up of dynamic cranioplasty for brachycephaly--non-syndromal bicoronal synostosis.

We followed up 10 patients whose non-syndromal bicoronal synostosis had been operated on with a dynamic cranioplasty technique developed by this craniofacial unit in 1992. With this technique, the growth of the brain is redirected in an anteroposterior direction as wire-mediated compression and restraint are exerted on the transverse and vertical dimensions of the skull. The mean operating time was 160 minutes (range 120-275) and mean stay in the intensive care unit was 36 hours (range 23-58). There was no operative mortality and few complications. The surgical results were assessed objectively by analysis of cephalometric tracings. The mean (SD) cephalic index was 87.6 (4.9) preoperatively and 77.7 (1.8) postoperatively (p = 0.001). The modified Whitaker scale was used as a subjective outcome measurement, and nine patients were classified as Whitaker grade 1 (no additional surgery). One patient required additional intracranial surgery. A questionnaire was sent to all families to obtain an additional subjective measurement of outcome. Parents' satisfaction was high. We conclude that dynamic cranioplasty is a safe and efficient operation for treatment of brachycephaly.

Human recombinant pro-dipeptidyl peptidase I (cathepsin C) can be activated by cathepsins L and S but not by autocatalytic processing.

Human dipeptidyl peptidase I was expressed in the insect cell/baculovirus system and purified in its active (rhDPPI) and precursor (pro-rhDPPI) forms. RhDPPI was very similar to the purified enzyme (hDPPI) with respect to glycosylation, enzymatic processing, oligomeric structure, CD spectra, and catalytic activity. The precursor, which was a dimer, could be activated approximately 2000-fold with papain. Cathepsin L efficiently activated pro-rhDPPI in vitro at pH 4.5 (k(app) approximately 2 x 10(3) min(-)(1) M(-)(1)), and two cleavage pathways were characterized. The initial cleavage was within the pro region between the residual pro part and the activation peptide. Subsequently, the activation peptide was cleaved from the catalytic region, and the latter was cleaved into the heavy and light chains. Alternatively, the pro region was first separated from the catalytic region. Cathepsin S was a less efficient activating enzyme. Cathepsin B and rhDPPI did not activate pro-rhDPPI, and the proenzyme was incapable of autoactivation. Incubation of both pro-rhDPPI and rhDPPI with cathepsin D resulted in degradation. Cystatin C and stefins A and B inhibited rhDPPI with K(i) values in the nanomolar range (K(i) = 0.5-1.1 nM). The results suggest that cathepsin L could be an important activator of DPPI in vivo and that cathepsin D and possibly the cystatins may contribute to DPPI downregulation.

Clinical outcome of the modified pi-plasty procedure for sagittal synostosis.

The aim of the study was to evaluate the modified pi-plasty procedure for the treatment of sagittal synostosis, assessing the issues of safety, complications, morphological outcome, and degree of parental satisfaction. A retrospective evaluation of 110 patients with nonsyndromal single suture sagittal synostosis operated on with the modified pi-plasty procedure was undertaken. Cephalometric radiographs were obtained preoperatively and postoperatively at ages 3 and 5 years in three standardized projections. The Cephalic Index and the Axial Width Ratio were determined and used as objective outcome measures. An evaluation of the radiographic digital markings was carried out using a Beaten Copper Score. A parental questionnaire was used to obtain a subjective esthetical outcome assessment. The patient population consisted of 76% boys and 24% girls with a 20% incidence of a positive familial history of craniosynostosis. The mean age at surgery was 7.73 months. Morbidity from the procedure was minimal and there were no mortalities. The Cephalic Index changed from a mean preoperative value of 65% to a postoperative mean value of 72% (P = 0.00004). The mean Axial Width Ratio changed from a preoperative 80% to 72% at the 3-year evaluation (P = 0.00029). The Beaten Copper score changed from a mean preoperative value of 2.35 to 5.42 postoperatively at 3 years (P = 0.00001). The response rate to the questionnaire was 86%, and there were significant postoperative improvements in all studied aspects of the skull shape. The modified pi-plasty is a safe technique, and it induces significant objective changes in skull morphology toward normality. It also yields a high degree of parental satisfaction with regard to aesthetic outcome, as evaluated by a written questionnaire.

Dynamic cranioplasty for brachycephaly in apert syndrome: long-term follow-up study.

OBJECT: Brachycephaly is a characteristic feature of Apert syndrome. Traditional techniques of cranioplasty often fail to produce an acceptable morphological outcome in patients with this condition. In 1996 a new surgical procedure called "dynamic cranioplasty for brachycephaly" (DCB) was reported. The purpose of the present study was to analyze perioperative data and morphological long-term results in patients with the cranial vault deformity of Apert syndrome who were treated with DCB. METHODS: Twelve patients have undergone surgery performed using this technique since its introduction in 1991 (mean duration of follow-up review 60.2 months). Eleven patients had bicoronal synostosis and one had a combined bicoronal-bilambdoid synostosis. Perioperative data and long-term evolution of skull shape visualized on serial cephalometric radiographs were analyzed and compared with normative data. Changes in mean skull proportions were evaluated using a two-tailed paired-samples t-test, with differences being considered significant for probability values less than 0.01. The mean operative blood transfusion was 136% of estimated red cell mass (ERCM) and the mean postoperative transfusion was 48% of ERCM. The mean operative time was 218 minutes. The duration of stay in the intensive care unit averaged 1.7 days and the mean hospital stay was 11.8 days. There were no incidences of mortality and few complications. An improvement in skull shape was achieved in all cases, with a change in the mean cephalic index from a preoperative value of 90 to a postoperative value of 78 (p = 0.000254). CONCLUSIONS: Dynamic cranioplasty for brachycephaly is a safe procedure, yielding high-quality morphological results in the treatment of brachycephaly in patients with Apert syndrome.

Mental development after modified pi procedure: dynamic cranioplasty for sagittal synostosis.

A prospective developmental assessment was performed on 26 patients operated on with dynamic cranioplasty for sagittal synostosis. Because this technique entails the application of compressive force, it was of great concern to assess the effect of surgery on development and mental status. The surgical technique used was a modified pi procedure. Perioperative variables were recorded. Six patients underwent preoperative intracranial pressure (ICP) measurements. To evaluate objectively the developmental outcome, the Griffiths' Mental Development Scales was used for analysis before and after surgery. A parental questionnaire was used for subjective outcome measurement. Preoperative ICP recordings during sleep ranged from 12.8 to 22.8 mmHg (mean, 16.1 mmHg). The mean age at the time for surgery was 6.9 months (range, 4-16 months; standard deviation [SD], 2.32 months). The surgical technique included shortening of the anteroposterior diameter of the skull by a mean of 16.6 mm. The mean global development quotient (GDQ) preoperatively was 104.5 (range, 82-144; SD, 12.4) and the mean GDQ postoperatively was 101.4 (range, 62-129; SD, 13.6). Mean age at follow-up was 16.3 months (range, 9-40 months; SD, 4.04 months). There was no significant correlation between the amount of intraoperative shortening and mental development. In comparison of means, the GDQ preoperatively did not differ significantly from the GDQ postoperatively. The modified pi procedure is safe and efficient. When surgery was performed before 1 year of age, no significant (p = 0.33) effect on mental development-either detrimental or beneficial-was demonstrated.

[Gynecological problems of the aging woman]. / Gynäkologische Probleme der alternden Frau.

The increasing number of old aged women requires the establishment of geriatric gynecology as a new subspecialty of our profession. The care of senior women in the gynecologists office should not be limited to the conventional gynecological diseases. These are of course dealt with in this paper; however should also be included, in a new understanding and broadening of our specialty, the women-specific diseases of old age. These extragenital diseases are therefore also touched upon. This extension of gynecology follows logically from the broad spectrum of effects of the female sexual hormones in the hands of the gynecologists and especially of long-term estrogen substitution into many neighbour medical specialties, like internal medicine, orthopedics, psychiatry and others. The gynecologist must have a working knowledge of these women-diseases including their physiopathology, differential diagnosis, treatment and, above all, prevention. The new understanding is moreover based upon the unique position of the gynecologist in the regular prevention and last, not least, upon the special confidence of the clients to their women-doctor and upon the special human intimacy in the relation between female patients and gynecologists. The care of senior women today includes life style counseling with the aim of prevention of preventable diseases. Also these points of view are touched upon. Medicine, which has given thirty additional years to the life of women, has also to take the responsibility to preserve physical and mental wellness through this segment of existence in good life quality saving the seniors from suffering of the preventable diseases of old age.

Carica papaya glutamine cyclotransferase belongs to a novel plant enzyme subfamily: cloning and characterization of the recombinant enzyme.

A full-length cDNA encoding Carica papaya glutamine cyclotransferase was cloned by RT-PCR on the basis of results from amino acid sequencing of tryptic fragments of the native enzyme. The cDNA of 1036 nucleotides encodes a typical 22-residue signal peptide and a mature protein of 266 residues with a calculated molecular mass of 30,923 Da. Five plant ESTs encoding putative QCs highly homologous to PQC were identified and the numbers and locations of cysteines and N-glycosylation sites are conserved. The plant QC amino acid sequences are very different from the known mammalian QC sequences and no clear homology was observed. The PQC cDNA was expressed in Escherichia coli as either His-tagged PQC, with three different signal peptides and in fusions with thioredoxin, glutathione S-transferase, and (pre-) maltose-binding protein. In all cases, the expressed protein was either undetectable or insoluble. Expression in Pichia pastoris of PQC fused to the alpha-factor leader resulted in low levels of PQC activity. Extracellular expression of PQC in the insect cell/baculovirus system was successful and 15-50 mg/liter of active PQCs with three different secretion signals was expressed and purified. Further, PQC N-terminally fused to a combined secretion signal/His-tag peptide was correctly processed by the host signal peptidase and the His-tag could subsequently be removed with dipeptidyl peptidase I. The expressed products were characterized by activity assays, SDS-PAGE, N-terminal amino acid sequencing, MALDI-TOF mass spectroscopy, and peptide mass fingerprint analysis.

Evaluation of a surgical technique for trigonocephaly.

Clinically diagnosed trigonocephaly have been treated by a standard surgical technique developed at Göteborg University Craniofacial Unit. To evaluate the technique we designed a study to include both subjective and objective assessments. Of 30 patients operated on between 1988-1997, 15 patients with at least three years postoperative follow-up have been included. An evaluation of the surgical outcome of the bitemporal width, the forehead contour, and the intercanthal distance was made both subjectively using a visual analogue scale (VAS) and objectively with analyses of cephalograms taken preoperatively and postoperatively at 3 and 5 years of age. For the subjective evaluation a control group of 10 randomly selected children from a Child Welfare Centre were selected. For the objective evaluation the control group consisted of cephalograms from children born with cleft lip and palate who were matched regarding sex and age. Both cephalometric analysis and subjective studies of the outcome indicated improvement. When the forehead contour was investigated the number of patients who had been improved or corrected completely was higher when evaluated subjectively. When interorbital distance on cephalograms and intercanthal distance scores on VAS were evaluated, again the subjective study indicated improvement in more subjects.

[Assymetric skull? Early correct diagnosis is a must! Positional skull deformities can be avoided]. / Sned barnskalle? Ställ rätt diagnos i tid! Lägesbetingade skalldeformationer går att undvika.

During the past few years the supine sleeping position has successfully been reintroduced for infants in order to prevent sudden infant death syndrome. However, the change in sleeping position has not been accompanied by a soft pillow under the infants head, which has probably caused a higher incidence of acquired skull deformities. These positional skull deformities need to be prevented or treated.