Gene therapy in plastic and reconstructive surgery.

Gene therapy has been investigated in many aspects of plastic and reconstructive surgery. These areas ultimately involve various forms of tissue healing and the manipulation of bony and soft tissues to reconstruct defects secondary to neoplastic and congenital disorders and trauma. Most research has been limited to animal studies with the exception of clinical trials on the use of gene therapy in lower leg ulcer healing and as an adjunct to advanced recurrent squamous cell carcinoma of the head and neck. Overall, these preliminary studies have produced optimistic results. With the development of more efficient and safer delivery systems, the application of gene therapy in plastic surgery could become more widespread, especially in combination with tissue engineering technology.

Assessing diagnostic accuracy and tympanocentesis skills in the management of otitis media.

BACKGROUND: The distinction between acute suppurative otitis media (AOM) and otitis media with effusion (OME) is important for antibiotic treatment decisions. Tympanocentesis may be useful in the diagnosis of AOM in selected patients. OBJECTIVES: To assess physician accuracy in diagnosing AOM and OME from physical examination findings and technical competence in performing tympanocentesis. DESIGN AND SUBJECTS: Five hundred fourteen pediatricians and 188 otolaryngologists viewed 9 different videotaped pneumatic otoscopic examinations of tympanic membranes during a continuing medical education course. Diagnostic differentiation of AOM, OME, and a normal tympanic membrane was ascertained. An infant mannequin model was used to assess the technical proficiency of performing tympanocentesis on artificial tympanic membranes. RESULTS: Overall, the average correct diagnosis by pediatricians was 50% (range, 25%-73%) and by otolaryngologists was 73% (range, 48%-88%). Pediatricians and otolaryngologists correctly recognized the absence of normality 89% to 100% and 93% to 100% of the time, respectively, but overdiagnosed AOM in 7% to 53% (mean, 27%) and in 3% to 23% (mean, 10%) of examinations. Performance of tympanocentesis was optimally performed by 89% of otolaryngologists and by 83% of pediatricians. CONCLUSIONS: The use of video-presented examinations to assess diagnostic ability suggests that AOM and OME may be misdiagnosed often. Interactive continuing medical education courses with simulation technology may enhance skills and improve diagnostic accuracy and treatment paradigms.

Appropriate antibiotic use in treating respiratory tract infections.

The emergence of drug-resistant pathogens, especially Streptococcus pneumoniae and Haemophilus influenzae, has complicated empiric treatment of both upper and lower respiratory tract infections. Clinicians are now forced to reevaluate their choices of first-line antibiotics. Although some bacterial respiratory infections may resolve spontaneously, the use of antibiotics has demonstrated a faster resolution of symptoms and prevention of sequelae and recurrences, thereby improving the patient's quality of life and ability to function. Therefore, it is recommended that all diagnosed bacterial respiratory infections be treated with an antibiotic. Factors that clinicians need to consider in prescribing an antibiotic are the predominant causative pathogens, rates of pathogen resistance, patient history, the bacteriologic and clinical efficacy, safety profile, dosing regimen, and cost effectiveness of available antibiotic choices.

Does the sheep mandible relapse following lengthening by distraction osteogenesis?

AIM: Distraction osteogenesis is a technique used to lengthen the shortened mandible. However, the long term stability of the distracted mandibular bone is not known. The aim of this study was to assess if the sheep mandible relapses following lengthening, and to assess the quality of distracted bone up to 1 year post lengthening. METHODS: Twenty-four sheep had bilateral external mandibular distractors applied, with three sheep as controls. Titanium marker screws were positioned both proximal and distal to the distraction zone in all sheep. Following a 5 day latency period, the interdental gap was distracted 1 mm/day for 20 days, with a subsequent 20 day consolidation period. Ante-mortem serial X-rays were used to assess for relapse by measuring the distance between the screws. The animals were sacrificed at either 3, 6, 9 or 12 months post-distraction. At post mortem, the distance between the screws was re-measured. The distracted bone was assessed mechanically and histologically. RESULTS: The mean mandibular lengthening obtained was 13.2 mm. There was no relapse of the mandible over 12 months. The distracted bone had attained the strength and stiffness of undistracted bone by 6 months post-distraction (p < 0.05). Histological evaluation revealed significant amounts of lamellar bone by 6 months post-distraction. CONCLUSIONS: No relapse occurred for 12 months post distraction lengthening. The bone formed following distraction was stable and of good quality. These findings lend support to the use of distraction osteogenesis in clinical practice.

The role of newer macrolides in the treatment of community-acquired respiratory tract infection. A review of experimental and clinical data.

The macrolide class of antibiotics is well established and often recommended for use in the treatment of community-acquired respiratory tract infection (RTI). The newer agents clarithromycin and azithromycin are frequently prescribed as first- or second-line therapy, and have been considered as superior to erythromycin in microbiological activity and clinical efficacy. In-vitro data show that clarithromycin and azithromycin have good activity (MIC < or = 0.5 microg/ml) against certain RTI pathogens. However the activity of both compounds is intrinsically low against Haemophilus influenzae whilst several other important RTI pathogens - notably Streptococcus pneumoniae and Streptococcus pyogenes - exhibit a high prevalence of resistance to them. In many countries, the prevalence of resistance to clarithromycin and azithromycin is still rising with cross resistance with erythromycin. Maximum serum concentrations of clarithromycin and azithromycin are lower than the MIC90s for these agents against H. influenzae and S. pneumoniae. Concentrations in tissues have been reported to be much higher than those in serum. However, the high concentrations observed in tissues are largely a reflection of high concentrations inside cells. Concentrations of clarithromycin and azithromycin in extracellular tissue fluids, where Haemophilus and streptococci are located, are in equilibrium with concentrations in the serum, and remain low. It has been suggested that phagocytes deliver azithromycin to infection sites in a targeted fashion, but the evidence in support of this hypothesis is weak. Recent clinical experience with clarithromycin and azithromycin is consistent with preclinical results, and suggests that these agents have limited efficacy against certain respiratory infections. Clarithromycin and azithromycin are the first choice treatment of atypical infections caused by intracellular pathogens. For community-acquired RTIs, where H. influenzae and S. pneumoniae are present, they may no longer be an appropriate choice for first-line therapy. Indeed, in areas where levels of drug resistant S. pneumoniae are high, their use may be questionable as second-line therapy.

A focus on acute sinusitis in adults: changes in disease management.

Sinusitis is a prevalent and costly disease that affects >14% of the population and accounts for >$2 billion in yearly healthcare costs. It is one of the most common conditions treated by primary care physicians. The multiple host and environmental factors that contribute to the pathogenesis of the disease and the lack of clear guidelines for diagnosis and treatment pose a challenge to effective management of the problem. The diagnosis of uncomplicated cases rests mainly on the history and clinical examination; attempts have been made to identify the most useful clinical predictors of acute bacterial sinusitis. Microbiologic and imaging studies are rarely performed during the initial assessment and are usually reserved for recurrent or refractory disease. Treatment involves drainage of the congested sinuses and elimination of pathogenic organisms. Although antimicrobial therapy hastens the resolution of symptoms of acute sinusitis, the need for antimicrobial therapy remains questionable, and its judicious use is challenged by the increase in antibiotic-resistant Haemophilus influenzae and Streptococcus pneumoniae, the organisms most commonly implicated in acute sinusitis. A lack of resolution or frequent recurrence of sinusitis warrants evaluation by a specialist.

A quantitative analysis of the effect of insulin-like growth factor-1 infusion during mandibular distraction osteogenesis in rabbits.

AIM: To quantify, by histomorphometry, the effects of local insulin-like growth factor-1 (IGF-1) during mandibular distraction at various rates. METHODOLOGY: Mature rabbits underwent bilateral mandibular corticotomy and distraction lengthening. Recombinant IGF-1 was administered to two groups of rabbits via osmotic infusion pumps. Distraction regimes were as follows: Group A, 1 mm/day for 15 days; Group B, as for A plus IGF-1; Group C, 3 mm/day for 5 days; Group D, as for C plus IGF-1; and Group E, sham-operated controls. After a 28-day consolidation period, rabbits were sacrificed and bone deposition quantified using DEXA scanning, three-point bending, histological examination and sampled for histomorphometric analysis. RESULTS: DEXA scanning and three-point bending failed to detect any effect of distraction rate or of IGF-1 infusion. Histological and histomorphometric analysis suggested 1 mm/day to be the ideal distraction rate, as this was associated with greater osteoblastic activity and consistent bony union. However, IGF-1 infusion significantly enhanced osteoblastic activity at both distraction rates and resulted in bony union when distraction was performed at 3 mm/day. CONCLUSIONS: Distraction osteogenesis at a rate of 1 mm/day provides greater osteogenic stimulus than 3 mm/day. Exogenous IGF-1 has a positive influence on osteoblastic activity during distraction. Its effect is probably minimised by high levels of endogenous IGF-1.

Expression of growth factors in the mandibular distraction zone: a sheep study.

Interest in craniofacial osteodistraction has increased in recent years parallel with the growing attention given to the role of growth factors in tissue healing and regeneration. This study was embarked upon to investigate the expression of bFGF, TGF-beta and IGF-1 in the distraction zone of the mandible. Fourteen growing sheep were allocated to three experimental groups. Six animals were allocated to Groups A and B (n = 12) and underwent bilateral mandibular corticotomies with fixation of an external lengthening device. The distraction protocol consisted of a rate of 1.0 mm/day (twice daily) for 20 days followed by a consolidation phase of 20 days after which the sheep were sacrificed. Group C comprised of age matched sham operated animals (n = 2). Bone histochemistry for growth factors were performed in the harvested mandibles. A strong staining of bFGF was seen in the osteoblasts, osteocytes and osteoid matrix following 20 days of distraction and 20 days of consolidation compared to the control group. TGF-beta and IGF-1 demonstrated mild but clear staining in osteocyte and osteoblast cells and TGF-beta stained positively in the osteoid seam in the experimental groups. These finding suggest that bFGF, IGF-1 and TGF-beta may play different roles in the remodelling phase of distraction osteogenesis.

The role of latency in mandibular osteodistraction.

Even though osteodistraction has been well established in the extremities, the parameters used in craniofacial distraction have been essentially borrowed from orthopaedic experience. Latency is widely practised but its relevance has not been fully investigated. The purpose of this study was to establish the role of latency in mandibular distraction osteogenesis. Twenty-two growing Wethers sheep were allocated to four experimental groups. Six animals were allocated to each of Groups A, B and C and underwent bilateral mandibular corticotomies and attachment of an external lengthening device. Latent periods of 0, 4 and 7 days respectively were observed prior to beginning distraction. The distraction protocol consisted of a rate of 0.5 mm twice daily for 20 days, followed by a consolidation phase of 20 days after which the sheep were killed. Histology, bone densitometry and 3-point mechanical testing were performed on the harvested mandibles. Group D formed the control group (n = 4). Histologically, the distracted bone exhibited bone formation primarily via intramembranous ossification with scattered islands of cartilage. The regenerated bone had mechanical properties significantly weaker than the undistracted control group (P < 0.05), but between the experimental groups no statistically significant differences were demonstrable either in mechanical strength or DEXA density. These data indicate that a change in latency does not alter the properties of the regenerated bone in mandibular distraction osteogenesis and indeed no latent interval may be necessary at all in craniofacial distraction. This has implications for the duration of device fixation in distraction procedures.

Mandibular distraction osteogenesis: a comparison of distraction rates in the rabbit model.

The rabbit model has been used to study the effects of different rates of distraction upon mandibular bone. Bilateral distraction was performed at two different rates anterior to the molar teeth. Both experimental groups were significantly inferior to sham operated controls in terms of bone density (DEXA) and mechanical testing. No difference in new bone formation between the two distraction rates was detected by these modalities. However, histological examination revealed non-union to be more common in the rapidly distracted group. This suggests that attempts to shorten the duration of external fixation in clinical mandibular distraction osteogenesis should be by methods other than more rapid distraction.

Distraction osteogenesis in craniofacial surgery: a review.

Distraction osteogenesis is a technique of new bone formation by the gradual separation of bony fragments. The method, although initially developed for limb lengthening, is now being applied in the treatment of craniofacial deformities. A number of principles have been established through careful scientific study to guide clinical practice, such as the ideal rate and rhythm of distraction, the need for periosteal preservation during bone division, a "latent period" of neutral fixation before, and a "consolidation period" after distraction. The technique is being applied in craniofacial surgery particularly for mandibular deformities and offers considerable advantages over previous methods such as osteotomy and inlay bone grafting. Donor site morbidity is avoided, the investing soft tissue envelope is concurrently expanded, and the magnitude of the procedure is less. However, the technique is still in its infancy and requires further modification and refinement before widespread acceptance as a treatment in mainstream craniofacial surgery. Problems with cutaneous scarring and socially undesirable external hardware, particularly in the pediatric population, have led to the emergence of intraoral miniature devices, with the ultimate goal of development of a multiplanar internal autodistractor. Furthermore, many principles well established in leg lengthening, such as the rate and rhythm of distraction, need to be reexamined and the parameters redefined with particular reference to the craniofacial skeleton. Distraction osteogenesis has an expanding role in craniofacial surgery.

Treatment of obstructive sleep apnea syndrome by rapid maxillary expansion.

The precise role of maxillary constriction in the pathophysiology of obstructive sleep apnea (OSA) is unclear. However, it is known that subjects with maxillary constriction have increased nasal resistance and resultant mouth-breathing, features typically seen in OSA patients. Maxillary constriction is also associated with alterations in tongue posture which could result in retroglossal airway narrowing, another feature of OSA. Rapid maxillary expansion (RME) is an orthodontic treatment for maxillary constriction which increases the width of the maxilla and reduces nasal resistance. The aim of this pilot study was to investigate the effect of rapid maxillary expansion in OSA. We studied 10 young adults (8 male, 2 female, mean age 27 +/- 2 [sem] years) with mild to moderate OSA (apnea/hypopnea index-AHI 19 +/- 4 and minimum SaO2 89 +/- 1%), and evidence of maxillary constriction on orthodontic evaluation. All patients underwent treatment with RME, six cases requiring elective surgical assistance. Polysomnography was repeated at the completion of treatment. Nine of the 10 patients reported improvements in snoring and hypersomnolence. There was a significant reduction in AHI (19 +/- 4 vs 7 +/- 4, p < 0.05) in the entire group. In seven patients, the AHI returned to normal (i.e., = < 5); only one patient showed no improvement. These preliminary data suggest that RME may be a useful treatment alternative for selected patients with OSA.

The impact of day care on ventilation tube insertion.

OBJECTIVE: To study the effect of day care and tube type, as well as other risk factors related to ventilation tube insertion and reinsertion. DESIGN: A case series of 456 consecutive cases with 162 controls from a well-baby examination group evaluated for age, sex, smoking history and day care attendance. SETTING: Private practice in a mid-sized, southeastern university town. PATIENTS AND CONTROLS: This was a referred sample of patients who were entered consecutively in a private-practice setting. All children were age five or less at entry into the study. INTERVENTIONS: Children underwent ventilation tube insertion with or without adenoidectomy, using standing indications. MAIN OUTCOME MEASURES: The primary outcome measures were whether or not a child had the need for a second set of tubes, and also determining the status of the child's ears for at least 1 year after tubes had extruded. RESULTS: Day care and younger age were both identified as risk factors associated with initial ventilation tube insertion. Only 11% (seven out of 63) of home care children, as compared with 31% (108 out of 346) day care children, had the insertion of ventilation tubes (P = 0.000). Day care children who had tubes inserted and adenoidectomy (with or without tonsillectomy) had a significantly lower rate of reintubation than children who had tube insertion alone (P = 0.00). Day care and young age are significant risk factors for any child, both with a first set of tubes and for ventilation tube reinsertion. Children in day care had a reintubation rate of 36% as compared to 11% for those in home care. Parents should be aware that day care can represent a two-fold hazard both in the observed connection between day care and tube insertion and the demonstrated increased probability of reinsertion. Any studies looking at ventilation tube outcomes need to make certain to monitor for day care attendance.

Antimicrobial therapy for sinusitis.

Rational antibiotic therapy for sinusitis is a difficult goal, made difficult by few satisfactory comparative trials with sufficient clinical power, the large numbers of therapeutic options, prescribing pressures from the pharmaceutical industry, and rapid changes in bacterial resistance patterns. Controversies exist about the relative need of antibiotics for uncomplicated disease, duration of therapy, and relative efficacy of various agents. Nonetheless, limited data support the notion of superior efficacy of more potent antimicrobials, and an analysis of in vitro activity versus tissue concentrations of the various antibiotics can predict efficacy of eradication of causative bacteria. Multidrug-resistant pneumococci render any algorithm for empiric antibiotic use problematic and prone to fail.

Craniofrontonasal dysplasia.

A series of 10 patients with craniofrontonasal dysplasia presenting to the Oxford Craniofacial Unit since 1983 is presented. In addition to the well-described combination of coronal synostosis and frontonasal dysplasia, 9 patients had very characteristic dry, curly or frizzy hair. All the patients were female. Recognition of the syndrome is important for genetic counselling, although the precise mode of genetic transmission is unclear with females predominating and males being less severely affected. Surgical correction was in two stages: early frontal advancement followed by correction of hypertelorism when the child became aware of the deformity. Four patients had their craniosynostosis treated in the Oxford Craniofacial Unit. Three patients had previously had frontal remodelling elsewhere. Nine patients had surgery for hypertelorism. The preferred technique for hypertelorism correction was facial bipartition. Following hypertelorism correction, the excess skin was allowed to redrape and subsequently dealt with by medial canthoplasties, thus avoiding a midline scar. Careful attention to the primary frontal advancement procedure is important to avoid complications following difficult dissection of the frontal bone flap at the time of hypertelorism correction.

Timing of hard palatal closure: a critical long-term analysis.

The controversy about timing of cleft palate surgical procedures is focused on early palatoplasty for improved speech versus delayed hard palate repair for undisturbed facial growth. Timing and technique of palate repair are the most important influences on speech and facial growth, yet there is no consensus on the age or technique for surgery. The Oxford Cleft Palate Study was initiated to evaluate critically the long-term follow-up of 44 patients with early versus late closure of the hard palate. A multidisciplinary approach was used to determine the incidence of speech deficiencies, palatal fistulas, maxillofacial growth disturbances, and hearing abnormalities and to assess objectively the long-term effects of two different treatment modalities on the cleft palate patient. The 44 patients were selected randomly, interviewed, and examined by the multidisciplinary Oxford Cleft Palate Study team. The average age at follow-up in the early closure group was 17.0 years versus 18.2 years in the late closure group. There was a similar number of unilateral and bilateral clefts in both the early and late closure groups. The hard palate was closed in the early group at an average age of 10.8 months versus 48.6 months in the late closure group. All operative procedures in each group were performed by the same senior plastic surgery consultant. Both consultants have since retired and did not participate in the study. Each patient was evaluated by the same plastic surgeon, speech pathologist, orthodontist, and otologist. All examiners were blinded in that they were unaware of the type or timing of the surgical technique and had no prior knowledge of or access to the patient's medical records. Furthermore, none of the examiners participated in the initial care and surgery of these patients. Statistically significant greater speech deficiencies were noted with delayed hard palate closure, especially in articulation, nasal resonance, intelligibility, and substitution pattern assessment (overall intelligibility, p < 0.01). Likewise, the persistent palatal fistula rate in the late closure group was 35 percent in comparison with 5 percent for the early closure group (p <0.02). No significant differences in hearing or maxillofacial growth impairment were delineated in either group. Our data suggest that delaying hard palate closure results in significant speech impairment without a beneficial maxillofacial growth response.

Vertical orbital dystopia.

Many pathologic processes may lead to vertical orbital dystopia. We reviewed 47 consecutive cases seen over a 13-year period. Twenty-nine patients underwent eye leveling procedures to improve cosmesis, 2 of these by camouflage procedures and 27 by orbital translocation. Ten patients had 16 secondary operations. There was one death, serious complications occurred in 3 patients, and nuisance complications occurred in 20 others. Seven patients developed diplopia postoperatively, and in 6 patients it was troublesome. In these, it resolved fully in 2 patients, improved to be of no consequence in 2, and in the remaining 2 troublesome symptoms persisted requiring inferior oblique muscle recession in 1. Binocular vision was never restored when not present preoperatively, and in 3 patients temporary loss occurred. There was an overall modest but significant improvement in appearance after surgery. It is concluded that vertical orbital translocation is rewarding and worthwhile.