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CpG motifs in bacterial DNA cause inflammation in the lower respiratory tract.

Since unmethylated CpG motifs are more frequent in DNA from bacteria than vertebrates, and the unmethylated CpG motif has recently been reported to have stimulatory effects on lymphocytes, we speculated that bacterial DNA may induce inflammation in the lower respiratory tract through its content of unmethylated CpG motifs. To determine the role of bacterial DNA in lower airway inflammation, we intratracheally instilled prokaryotic and eukaryotic DNA in C3H/HeBFEJ mice and performed whole lung lavage 4 h after the exposure. Heat denatured, single stranded Escherichia coli genomic DNA (0.06 ng endotoxin/microg DNA) was compared to heat denatured, single stranded calf thymus DNA (0.007 endotoxin/microg DNA). 10 microg of bacterial DNA, in comparison to 10 microg of calf thymus DNA, resulted in a fourfold increase in the concentration of cells (P = 0.0002), a fivefold increase in the concentration of neutrophils (P = 0.0002), a 50-fold increase in the concentration of TNF-alpha (P = 0.001), and a fourfold increase in the concentration of both IL-6 (P = 0.0003) and macrophage inflammatory protein-2 (P = 0.0001) in the lavage fluid. Importantly, instillation of 0.60 ng of E. coli LPS resulted in a negligible inflammatory response. To test whether the stimulatory effects of bacterial DNA are due to its unmethylated CpG dinucleotides, we methylated the bacterial DNA and also prepared 20 base pair oligonucleotides with and without CpG motifs. In comparison to instillation of untreated bacterial DNA, methylation of the bacterial DNA resulted in a significant reduction in the concentration of cells and cytokines in the lower respiratory tract. Moreover, oligonucleotides containing embedded unmethylated CpG motifs resulted in inflammation in the lower respiratory tract that was indistinguishable from that observed with untreated bacterial DNA. In contrast, oligonucleotides without the embedded CpG motifs or with embedded but methylated CpG motifs resulted in significantly less inflammation in the lower respiratory tract. The possible relevance of these data to human disease was shown by extracting and analyzing DNA in sputum from patients with cystic fibrosis (CF). Approximately 0.1 to 1% of this sputum DNA was bacterial. Intratracheal instillation of highly purified CF sputum DNA caused acute inflammation similar to that induced by bacterial DNA. These findings suggest that bacterial DNA, and unmethylated CpG motifs in particular, may play an important pathogenic role in inflammatory lung disease.

Animals↗

Effect of roxithromycin on peripheral neutrophil adhesion molecules in patients with chronic lower respiratory tract disease.

To evaluate the effects of roxithromycin in patients with chronic lower respiratory tract disease including diffuse panbronchiolitis, we studied lymphocyte function-associated antigen-1 (LFA-1) and Mac-1, neutrophil adhesion molecules, using peripheral neutrophils from healthy volunteers and from patients with chronic lower respiratory tract disease. The number of Mac-1 expressed on neutrophils of the patients was significantly greater (0.68 +/- 0.16) than in the healthy subjects (0.45 +/- 0.14), while the number of LFA-1 expressed on neutrophils of the patients was nearly similar to that in the healthy volunteers (0.95 +/- 0.10 vs 0.89 +/- 0.11). The neutrophil numbers in bronchoalveolar lavage fluid and the number of Mac-1 expressed on peripheral neutrophils significantly decreased in all patients who responded clinically to a low dose of roxithromycin for a long period of time (56.0 +/- 25.2 vs. 22.7 +/- 19.7%, p < 0.05 and 0.70 +/- 0.16 vs. 0.59 +/- 0.08, p < 0.05, respectively), whereas roxithromycin had no effect on the quantitative expression of LFA-1 (0.96 +/- 0.14 to 1.00 +/- 0.09, not significant) in all responders.

Adult↗

Criteria used by clinicians to differentiate sinusitis from viral upper respiratory tract infection.

BACKGROUND: Acute sinusitis and upper respiratory tract infections (URIs) share many common symptoms and signs. Objective criteria have been identified that are valid for distinguishing between these two clinical problems. The objective of this study was to determine how often clinicians use these validated criteria and how often they rely on clinical cues that are less valuable for differentiating sinusitis from URI. METHODS: We performed a retrospective review of 734 patients with a diagnosis of acute sinusitis (n = 367) or URI (n = 367) at a family practice residency training site over a 3-year period. Charts were reviewed to ascertain patient demographics, past history, current symptoms, physical findings, and treatment prescribed. RESULTS: Patients with sinusitis were likely to be older, female, smokers, have a history of allergic rhinitis, and have longer symptom durations. Complaints of sinus pressure or discolored nasal discharge and the finding of sinus tenderness were strongly associated with the diagnosis of sinusitis. In multivariate analysis, eight factors were independently associated with the diagnosis of sinusitis. Four clinical cues alone (sinus tenderness, sinus pressure, postnasal drainage, and discolored nasal discharge) were highly associated with the diagnosis of sinusitis and explained 60% of the variation in the diagnosis between sinusitis and URI. CONCLUSIONS: Physicians tend to rely on four factors to differentiate sinusitis from URIs. Only one of these has been shown to be a reliable predictor of acute sinusitis. This use of unreliable criteria may lead to misdiagnoses and inappropriate prescriptions for antibiotics.

Acute Disease↗

Diagnosis methods for pneumococcal etiology determination in lower respiratory tract infections.

A comparative study of etiological diagnosis in lower respiratory tract infections (LRTI), by conventional bacteriological methods and by pneumococcal antigen direct detection in sputum was performed. This work followed the establishing of rapid methods place, respectively of coagglutination (CoA), counterimmunoelectrophoresis (CIE), within the methodology of bacteriological diagnosis in lower respiratory tract infections presenting pneumococcal etiology. The results of investigations performed on 84 sputa from LRTI patients proved the utility of CoA method in determining a rapid etiological diagnosis, important for applying an emergence targetted antibiotherapy. CoA method, with the reagents in use, covering only 10 out of 83 serological types of S. pneumoniae in not capable of replacing conventional methods of bacteriological diagnosis; they complete each other, increasing the efficiency of etiological diagnosis in LRTI. CIE method is less sensitive and more difficult to perform, being less useful in rapid etiological diagnosis of LRTI.

Adult↗

Seroconversion rates to combined measles-mumps-rubella-varicella vaccine of children with upper respiratory tract infection.

OBJECTIVE: To determine if upper respiratory tract infection (URI) affects the seroconversion rate or quantitative response to each component of a combined measles-mumps-rubella-varicella vaccine. SUBJECTS AND METHODS: One hundred forty-nine children between 15 and 18 months of age were prospectively divided into two groups according to the presence of URI or recent history of URI symptoms within the 4 weeks before vaccination. Once stratified, 74 children in the healthy group and 75 children in the URI group were randomly assigned to receive one of three lots of measles-mumps-rubella varicella vaccine by subcutaneous injection into the deltoid area. Serum was obtained from each child just before vaccination and 4 to 6 weeks later for measuring antibody levels against each virus. RESULTS: Prevaccination antibody levels against each virus in the URI and healthy groups did not differ. Nine children had pre-existing antibodies to varicella and six to mumps; no child had positive serologies for measles or rubella before vaccination. Children with pre-existing antibody were excluded from analysis of seroconversion for that virus. Seroconversion to measles, mumps, and rubella occurred in 100% of children in both groups. Mean antibody levels did not differ between the healthy and URI groups for measles (111 vs 122), mumps (97 vs 108), or rubella (96 vs 102). Three (4%) of 70 children with URIs in whom varicella serologies were available failed to seroconvert to varicella vaccine although none of the 69 healthy children had vaccine failure (P = .24). The mean varicella antibody level was 11.3 +/- 1.4 in the healthy children, which did not differ significantly from the level of 9.5 +/- 0.9 in the URI group. CONCLUSIONS: Seroconversion to measles, mumps, rubella, and varicella was not significantly affected by the presence of a concurrent or recent URI in 15- to 18-month-old children.

Antibodies, Viral↗

Anaesthesia in children with viral respiratory tract infections.

The effects and consequences of anaesthesia in a child with a respiratory tract infection (RTI) are controversial. There is a high incidence of viral RTI in children presenting for surgery and anaesthesia. The social and economic impact of postponing the procedure is significant; for the child, family and institution. The clinical effects of the common cold are well known, affecting the respiratory tract from the nose down to the small airways and lung parenchyma. The systemic effects of the toxic viraemic phase are also well recognized but not so the potential risk of a viral myocarditis. There is an increased incidence of intra- and postoperative respiratory related complications up to six weeks after a RTI. These include airway obstruction, laryngeal spasm, vagally mediated reflex bronchoconstriction, increased bronchial secretions, desaturation, atelectasis and postoperative respiratory complications. Children with symptoms of a moderate to severe RTI presenting for elective surgery should be postponed for six weeks. Emergency surgery should proceed with a mask anaesthetic for minor surgery or by adopting a modified rapid sequence induction (atropine but no cricoid pressure) to gain rapid control of the airway to avoid laryngeal spasm and vagally mediated reflex bronchoconstriction; IPPV, awake extubation, postoperative monitoring of respiratory function and appropriate analgesia.

Anesthesia↗

Evidence to support the rationale that bacterial eradication in respiratory tract infection is an important aim of antimicrobial therapy.

Clinical outcome is dependent upon antibiotic-mediated bacterial eradication in a number of infections. However, in respiratory tract infections, the need for bacterial eradication has been controversial. Clinical data are now available that support the need for active bacterial eradication in otitis media. This may also be the case for other respiratory tract infections. An increase in antimicrobial resistance reduces the probability of achieving eradication. Conversely, failure to eradicate bacteria may promote the emergence and dissemination of antimicrobial-resistant clones. Pharmacokinetic/pharmacodynamic parameters can be used to predict the bacteriological efficacy of antimicrobial therapy. In conclusion, the aim of antimicrobial therapy in respiratory tract infections should be the eradication of the infecting organism.

Anti-Bacterial Agents↗

Management of acute and chronic respiratory tract infections.

Pharyngitis, bronchitis, and pneumonia represent the most common respiratory tract infections. With a view to establishing effective management strategies, the origins of these illnesses and the diagnostic techniques that have been developed to discover them are reviewed. Therapeutic regimens with documented efficacy are outlined with emphasis on specific rather than empiric treatment. Although many respiratory tract pathogens remain exquisitely sensitive to penicillin, the emergence of resistant strains underscores the need for safe and effective alternative therapies.

Acute Disease↗

Susceptibility of respiratory tract pathogens in Finland to cefixime and nine other antimicrobial agents.

The in vitro activity of cefixime and 9 other orally used antimicrobial agents against 545 selected clinical respiratory tract pathogens was tested using the plate-dilution method. Of the strains tested, 144 were Haemophilus influenzae strains, 151 group A streptococci, 105 pneumococci and 145 Moraxella catarrhalis isolates. Ciprofloxacin was the most active drug, with a minimal inhibitory concentration (MIC) of < 0.06 mg/l for more than 87% of the isolates. With cefixime, a MIC of 0.06 mg/l inhibited 55% of the strains tested and a MIC of 1.0 mg/l inhibited all except one of the 545 strains. One pneumococcal strain was resistant to cefixime. Beta-lactamase producing H. influenzae and M. catarrhalis strains were clearly more susceptible to cefixime than to other oral cephalosporins (cephalexin, cefaclor, cefuroxime). However, penicillin, ampicillin and cefuroxime were more effective against beta-hemolytic streptococci and pneumococci than was cefixime. The new third generation cephalosporin, cefixime, showed markedly better in vitro activity against certain major respiratory tract pathogens than the other peroral antimicrobials commonly used against respiratory tract infections.

Anti-Bacterial Agents↗

Lesions of the respiratory tract associated with the finding of anti-neutrophil cytoplasmic autoantibodies with a perinuclear staining pattern.

OBJECTIVE: To characterize the clinicopathologic spectrum of respiratory tract involvement in patients with positive results of immunofluorescence microscopy for anti-neutrophil cytoplasmic autoantibodies with a perinuclear staining pattern (p-ANCA) and to assess the clinical value of p-ANCA testing. DESIGN: We retrospectively reviewed the medical records of all patients at Mayo Clinic Rochester in whom p-ANCA were detected by indirect immunofluorescence microscopy during 1992. MATERIAL AND METHODS: Additional target antigen identification was performed with use of enzyme-linked immunosorbent assays for antibodies against myeloperoxidase (MPO) and proteinase 3. We summarized the clinical findings in MPO-positive and MPO-negative patients. RESULTS: Sera were positive for p-ANCA in 42 of 2,381 patients (1.8%). In 13 of these 42 patients (31%), the respiratory tract was involved. Twelve patients had chest roentgenographic abnormalities, including a diffuse alveolar filling pattern (N = 8), a diffuse interstitial pattern (N = 2), and a combined interstitial and alveolar pattern (N = 2); three others had nasal inflammation. Ten of 16 sera tested were positive for MPO, and proteinase 3 antibodies were detected in 1 specimen. All patients with alveolar hemorrhage were positive for MPO antibodies. CONCLUSION: Testing for p-ANCA by immunofluorescence microscopy discloses a wide range of clinical disorders distinct from the main cytoplasmic-staining ANCA-associated disease--namely, Wegener's granulomatosis. In particular, the respiratory tract is affected much less frequently. Further evaluation of positive p-ANCA immunofluorescence test results by enzyme-linked immunosorbent assay to determine whether MPO is the target antigen is necessary to obtain clinically useful information from this test.

Adolescent↗

[Virological surveillance of acute respiratory tract illnesses of children in Morioka, Japan. II. Rhinovirus infection].

Rhinoviruses (HRVs) were isolated from 307 children (7.1%) in the virological surveillance of 4334 children with acute respiratory tract illnesses in Morioka, Japan (September 1973-December 1983). Although HRVs were isolated throughout the year, frequency of HRV infection was significantly higher (p less than 0.001) during the April-November (233/2853; 8.2%) than during the December-March (47/1481; 5.0%). There were two peaks of incidence in May (9.5%) and September (9.1%). During the May-September, the rate of HRV infection was higher in patients under the age of 11 months than the next higher group of 1-2 years old (p less than 0.001). The incidence decreased with increasing age. The illnesses of HRV infection were analysed in 294 patients, except one patient who had symptoms of measles, from whom HRV was isolated singly. Although HRV-associated illnesses were generally mild (57.5%). Upper respiratory tract illnesses (URTIs) with fever were found in 22.1% and lower respiratory tract illnesses (LRTIs) in 20.4% of these. The rate of LRTI was higher during the epidemic period (April-September) than other periods (p less than 0.02). Major symptoms of HRV-associated illnesses observed were sore throat (87.4%), cough (84.0%), and nasal obstruction and/or discharge (72.8%). Wheezing was observed in 21.8% of these. From 19 (21.8%) of 47 patients clinically diagnosed as asthmatic bronchitis in this survey, viruses were isolated. HRV was detected most frequently in 12.8% of these patients, followed by respiratory syncytial virus (RSV, 6.4%) and adenovirus (2.1%). HRV- and RSV-associated asthmatic bronchitis were observed during April-September and November-February, respectively. Viral dual infections were detected in total 20 cases included 12 HRV-associated cases. In no case was the illness of greater severity than might have been caused by either agent acting singly.

Acute Disease↗

Efficacy and tolerance of roxithromycin in comparison with erythromycin stearate in patients with lower respiratory tract infections.

The efficacy and tolerance of roxithromycin 150 mg b.i.d. were compared with those of erythromycin stearate 500 mg b.i.d. in patients with lower respiratory tract infections. Out of 86 patients recruited for the study, 79 were evaluable for tolerance and 76 for efficacy. These patients were evenly distributed among the 3 investigational clinics, with 26, 25 and 28 patients, respectively. The diagnosis of lower respiratory tract infections was based on clinical, laboratory, radiological and/or physical findings and, when available, bacteriological and serological findings. The duration of treatment was 10 days, with follow-up at post-treatment visits directly after treatment and 6 weeks thereafter. The clinical outcome was satisfactory with no significant difference between the drugs. More patients reporting adverse events were on erythromycin than on roxithromycin (51.3% vs 17.5%; p = 0.003). The results suggest that roxithromycin is as effective as erythromycin stearate in the treatment of lower respiratory tract infections and causes fewer adverse effects.

Adult↗

[Clinical results of rokitamycin dry syrup on respiratory tract infections in pediatric field].

1. A total of 15 patients with pediatric respiratory tract infections were mediated with rokitamycin (RKM) dry syrup, and its clinical effects were excellent in 2, good in 10, fair in 1 and poor in 1. 2. The efficacy rate in Streptococcus pneumoniae pneumonia and mycoplasmal pneumonia was 100%. 3. Clinical effects on 7 patients with Haemophilus influenzae were excellent in 1, good in 4, fair in 1 and poor in 1. 4. No adverse reaction was observed, and the taste and odor of RKM was well accepted by the children. 5. RKM is useful and one of the first choice antibiotics on respiratory tract infections in pediatric field.

Child↗

Disposition of polycyclic aromatic hydrocarbons in the respiratory tract of the beagle dog. III. Mechanisms of the dosimetry.

The disposition of polycyclic aromatic hydrocarbons (PAHs) in the respiratory tract of the Beagle dog was measured and presented in two previous papers. In this paper, the data were used to demonstrate that highly lipophilic toxicants, such as PAHs, were diffusion-limited during clearance from the respiratory tract. Organic toxicants are usually regarded as perfusion-limited during clearance from the lungs. Within minutes after inhalation, the perfusion-limited substance is though to be cleared from all regions of the respiratory tract to the circulating blood. However, the length of time required for appearance of highly lipophilic PAHs in blood exiting the lungs following transient exposures of the alveolar region suggested that alveolar clearance of highly lipophilic PAHs was diffusion-limited. But even though this transport was diffusion-limited, clearance of the highly lipophilic PAH benzo(a)pyrene (BaP) from the thin alveolar epithelium of the dog took only minutes, whereas clearance through the thicker epithelium of the conducting airways took hours. This phenomenon of slow airway clearance results from slower diffusion of highly lipophilic substances through the thicker air/blood barrier of the conducting airways compared to the thinner alveolar epithelium. A direct result of slowed clearance is a high concentration of BaP in the bronchial walls and an increased opportunity for metabolism to reactive forms. For this reason, the bronchial epithelium may become a preferential target of inhaled highly lipophilic toxicants. While the elevated dose during diffusion-limited clearance involves only a few cell layers, the importance of this microdosimetry in contributing to local toxicity should not be overlooked. The findings suggest that bronchial cancer following inhalation exposures is more likely to be induced by highly lipophilic carcinogens such as PAHs than by less lipophilic carcinogens.

Animals↗

Cefotiam therapy of lower respiratory tract infections.

Cefotiam, a new cephalosporin, was evaluated in the treatment of lower respiratory tract infections in 29 patients. The bacteria isolated from the sputum of these patients included Streptococcus pneumoniae (31%), Klebsiella pneumoniae (31%), and Haemophilus influenzae (28%). Satisfactory response was observed in 90% of the patients. There were three treatment failures, two superinfections, and four colonizations with gram-negative organisms resistant to the drug. Superficial phlebitis was noted in two patients. The results of this study suggest that cefotiam is an effective and well-tolerated antibiotic for the treatment of lower respiratory tract infections due to susceptible organisms.

Adult↗

Coincidence of different structures of mucosa-associated lymphoid tissue (MALT) in the respiratory tract of children: no indications for enhanced mucosal immunostimulation in sudden infant death syndrome (SIDS).

Mucosa-associated lymphoid tissue (MALT) is the principal inductive site for mucosal immune responses that are capable of T and B cell responses and antigen-specific responses. In previous independent studies different structures of MALT, e.g. bronchus-, larynx- and nose-associated lymphoid tissue (BALT, LALT, NALT) have been described separately in various frequencies in the human respiratory tract over life spans. Because upper respiratory tract infections are common in infants, dysregulations of mucosal immune responses might be seriously involved in the aetiology of sudden infant death syndrome (SIDS). In the present study the coincidental occurrence of the three different MALT structures in the respiratory tract within the same patients were studied, and cases of SIDS and children who had died from different traumatic and natural causes of death (non-SIDS) were compared. First, the frequency of BALT and LALT in 46 children (35 SIDS, 11 non-SIDS) with or without NALT were examined. A tendency was found of a coincidence of respiratory MALT structures. In 50 additional cases of infant death (30 SIDS, 20 non-SIDS) from the multi-centric German Study on Sudden Infant Death Syndrome (GeSID) where death had occurred in the first year of life, the coincidence was evaluated. A coincidental occurrence of BALT, LALT and NALT or BALT and LALT (each about 30%) was found in both groups, whereby the coincidence in SIDS and the control patients did not differ. Interestingly, the children with coincidental MALT were strikingly older, supporting the hypothesis of respiratory MALT formation via environmental stimulation over time.

Bronchi↗

Cefpodoxime proxetil. An appraisal of its use in antibacterial cost-containment programmes, as stepdown and abbreviated therapy in respiratory tract infections.

Cefpodoxime proxetil is an orally administered prodrug which is converted in vivo to the third generation cephalosporin cefpodoxime. Cefpodoxime has a similar spectrum of antibacterial activity to the parenteral cephalosporins ceftriaxone and cefotaxime and a long elimination half-life, which allows once- or twice-daily administration. Cefpodoxime proxetil has proven efficacy in the treatment of community-acquired pneumonia and upper respiratory tract, skin and soft tissue and urinary tract infections. It has been evaluated for use in cost-containment programmes, as stepdown (parenteral-to-oral conversion) therapy in the treatment of community-acquired pneumonia and as abbreviated therapy in upper respiratory tract infections. Substituting oral for parenteral therapy can achieve considerable savings (in acquisition, delivery and labour costs). Moreover, oral administration has advantages for the patient in terms of comfort and mobility, avoids the hazards of parenteral delivery and may allow earlier discharge from hospital, or even allow home treatment from the outset in low-risk patients. As hospitalisation is usually the major cost component in treating serious infections, considerable savings can be made in this way. Pharmacy-driven stepdown programmes in 2 US hospitals have achieved cost savings by targeting patients with community-acquired pneumonia for early conversion from intravenous ceftriaxone therapy to oral cefpodoxime proxetil. Costs were compared with those from a control group of patients who continued to receive intravenous ceftriaxone until physicians deemed that oral therapy (with various agents) was appropriate. In one study, duration of parenteral therapy in the cefpodoxime proxetil group was reduced from 6.18 to 3.82 days and duration of hospitalisation was reduced from 10.06 to 6.23 days (p < 0.02), with corresponding hospitalisation cost reductions of $US7300 per patient. However, clinical trial data relating to the efficacy of cefpodoxime proxetil as stepdown therapy in patients initially requiring parenteral antibacterials are lacking. Abbreviated (4-to 7-day) cephalosporin regimens appear to be as effective as traditional 10-day penicillin regimens in the treatment of upper respiratory tract infections. Short regimens may improve patient compliance and tolerability, thereby reducing the costs of adverse effects and treatment failures. Data from preliminary clinical studies suggest that a 5-day course of cefpodoxime proxetil is as effective as an 8-day course of amoxicillin/clavulanic acid in treating either acute otitis media or sinusitis, and as effective as a 10-day course of amoxicillin/ clavulanic acid and more effective than a 10-day course of phenoxymethyl- penicillin in the treatment of pharyngotonsillitis. Cefpodoxime proxetil tended to be better tolerated and was associated with better compliance than penicillin-based regimens. Indeed, a pharmacoeconomic study showed that a 10-day regimen of cefpodoxime proxetil was associated with lower costs for treating adverse effects and treatment failures than a 10-day regimen of amoxicillin/clavulanic acid in the treatment of acute otitis media in children. A 5-day course of cefpodoxime proxetil had a lower cost per patient treated per month free of recurrence than a 10-day course of phenoxymethylpenicillin (non-generic) or amoxicillin/clavulanic acid in the treatment of recurrent pharyngotonsillitis. Thus, evidence to date suggests that cefpodoxime proxetil has potential for use as stepdown therapy in community-acquired pneumonia and in abbreviated therapy courses in upper respiratory tract infections. These preliminary observations require confirmation in well designed studies.

Ceftizoxime↗

[Distraction osteogenesis of the mandible in 2 children with obstruction of the upper respiratory tract due to micrognathia].

A girl approximately 2 years old with Pierre Robin sequence had periods of nocturnal respiratory insufficiency as a consequence of micrognathia and a boy nearly 4 years old with Nager syndrome and tracheostomy was retarded in his speech development, had problems swallowing and often had respiratory tract infections. The obstruction of the upper respiratory tract was resolved by performing a distraction osteogenesis of the lower jaw. A tracheostomy was avoided or else removed. The girl became more active and there was an improvement in the boy's speech development. Distraction osteogenesis is a good alternative to the current practice of mandibular reconstruction in micrognathic patients, which involves extensive bone grafts.

Child, Preschool↗