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Zaurbek Aisanov1,*, Chunxue Bai2,*, Otto Bauerle3,*, Federico D Colodenco4,*, Charles Feldman5,6,*, Shu Hashimoto7,*, Jose Jardim8,*, Christopher KW Lai9,*, Rafael Laniado-Laborin10,*, Gilbert Nadeau11,*, Abdullah Sayiner12,*, Jae Jeong Shim13,*, Ying Huang Tsai14,*, Richard D Walters11,*, Grant Waterer15,* 1Pulmonology Research Institute, Moscow, Russia; 2Department of Pulmonary Medicine, Fudan University, Shanghai, People's Republic of China; 3Centro Médico de las Américas, Mérida, Yucatán, Mexico; 4Hospital de Rehabilitación Respiratoria "María Ferrer," Buenos Aires, Argentina; 5Department of Internal Medicine, Charlotte Maxeke Johannesburg Hospital, Johannesburg, South Africa; 6Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; 7Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan; 8Federal University of São Paulo, São Paulo, Brazil; 9Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, People's Republic of China; 10Faculty of Medicine, Universidad Autónoma de Baja California, Tijuana, Baja California, Mexico; 11Medical Affairs, GlaxoSmithKline, Brentford, UK; 12Department of Chest Diseases, Ege University Medical School, Izmir, Turkey; 13Department of Pulmonology, Guro Hospital, Korea University Medical Center, Seoul, South Korea; 14Department of Respiratory Care Medicine, Chang Gung Memorial Hospital, Chia-Yi, Taiwan; 15School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia*ICON group (International COPD Network), listed in alphabetical orderAbstract: Chronic obstructive pulmonary disease (COPD) is a multicomponent disorder that leads to substantial disability, impaired quality of life, and increased mortality. Although the majority of COPD patients are first diagnosed and treated in primary care practices, there is comparatively little information on the management of COPD patients in primary care. A web-based pilot survey was conducted to evaluate the primary care physician's, or general practitioner's (GP's), knowledge, understanding, and management of COPD in twelve territories across the Asia-Pacific region, Africa, eastern Europe, and Latin America, using a 10-minute questionnaire comprising 20 questions and translated into the native language of each participating territory. The questionnaire was administered to a total of 600 GPs (50 from each territory) involved in the management of COPD patients and all data were collated and analyzed by an independent health care research consultant. This survey demonstrated that the GPs' understanding of COPD was variable across the territories, with large numbers of GPs having very limited knowledge of COPD and its management. A consistent finding across all territories was the underutilization of spirometry (median 26%; range 10%–48%) and reliance on X-rays (median 14%; range 5%–22%) for COPD diagnosis, whereas overuse of blood tests (unspecified) was particularly high in Russia and South Africa. Similarly, there was considerable underrecognition of the importance of exacerbation history as an important factor of COPD and its initial management in most territories (median 4%; range 0%–22%). Management of COPD was well below guideline-recommended levels in most of the regions investigated. The findings of this survey suggest there is a need for more ongoing education and information, specifically directed towards GPs outside of Europe and North America, and that global COPD guidelines appear to have limited reach and application in most of the areas studied.Keywords: COPD, questionnaire, survey, guidelines

Targeted therapy combined with companion diagnostics has led to the advancement of next-generation sequencing (NGS) for detection of molecular alterations. However, using a diagnostic test to identify patient populations with low prevalence molecular alterations, such as gene rearrangements, poses efficiency, and cost challenges. To address this, we have developed a 2-step diagnostic test to identify NTRK1, NTRK2, NTRK3, ROS1, and ALK rearrangements in formalin-fixed paraffin-embedded clinical specimens. This test is comprised of immunohistochemistry screening using a pan-receptor tyrosine kinase cocktail of antibodies to identify samples expressing TrkA (encoded by NTRK1), TrkB (encoded by NTRK2), TrkC (encoded by NTRK3), ROS1, and ALK followed by an RNA-based anchored multiplex polymerase chain reaction NGS assay. We demonstrate that the NGS assay is accurate and reproducible in identification of gene rearrangements. Furthermore, implementation of an RNA quality control metric to assess the presence of amplifiable nucleic acid input material enables a measure of confidence when an NGS result is negative for gene rearrangements. Finally, we demonstrate that performing a pan-receptor tyrosine kinase immunohistochemistry staining enriches detection of the patient population for gene rearrangements from 4% to 9% and has a 100% negative predictive value. Together, this 2-step assay is an efficient method for detection of gene rearrangements in both clinical testing and studies of archival formalin-fixed paraffin-embedded specimens.

The AP-1 family of transcriptional activators plays pivotal roles in regulating a wide range of biological processes from the immune response to tumorigenesis. Determining the roles of specific AP-1 dimers in cells, however, has remained challenging because common molecular biology techniques are unable to distinguish between the role of, for example, cJun/cJun homodimers versus cJun/cFos heterodimers. Here we used SELEX (systematic evolution of ligands by exponential enrichment) to identify and characterize DNA aptamers that are >100-fold more specific for binding cJun/cJun compared to cJun/cFos, setting the foundation to investigate the biological functions of different AP-1 dimer compositions.

Transcription of interleukin-2 (IL-2), a pivotal cytokine in the mammalian immune response, is induced by NFAT and AP-1 transcriptional activators in stimulated T cells. NFATc2 and cJun drive high levels of synergistic human IL-2 transcription, which requires a unique interaction between the C-terminal activation domain of NFATc2 and cJun homodimers. Here we studied the mechanism by which this interaction contributes to synergistic activation of IL-2 transcription. We found that NFATc2 can recruit cJun homodimers to the -45 NFAT element, which lacks a neighboring AP-1 site. The bZip domain of cJun is sufficient to interact with the C-terminal activation domain of NFATc2 in the absence of DNA and this interaction is inhibited by AP-1 DNA. When the -45 NFAT site was replaced by either an NFAT/AP-1 composite site or a single AP-1 site the specificity for cJun homodimers in synergistically activating IL-2 transcription was lost, and cJun/cFos heterodimers strongly activated transcription. These studies support a model in which IL-2 transcriptional synergy is mediated by the unique recruitment of a cJun homodimer to the -45 NFAT site by NFATc2, where it acts as a co-activator for IL-2 transcription., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Intranasal corticosteroids are widely prescribed for the treatment of perennial allergic rhinitis (PAR). The aim of this analysis was to determine whether the beneficial effects of once-daily (q.d.) fluticasone furoate nasal spray (FFNS) effectively improved individual nasal symptoms of PAR. An integrated analysis was performed on data from three randomized, double-blind, placebo-controlled, parallel-group trials designed to evaluate the efficacy and safety of FFNS at 110 micrograms, q.d. in subjects with PAR. The analysis included 460 subjects who received FFNS and 459 who received placebo for 4 weeks. All subjects evaluated the severity of individual nasal symptoms of nasal congestion, nasal itching, rhinorrhea, and sneezing on a four-point categorical scale. The main efficacy measures included change from baseline in daily reflective total nasal symptom score (rTNSS), reflective daily scores for each individual symptom, and predose instantaneous TNSS (iTNSS). Over 4 weeks of treatment, FFNS significantly improved rTNSS, iTNSS, and the reflective scores for each individual symptom compared with placebo. The least squares (LS) mean treatment difference over weeks 1-4 between FFNS and placebo for rTNSS was -0.93, ranging from -0.20 to -0.28 for the individual nasal symptoms (p < 0.001 for all versus placebo). For the iTNSS, the LS mean treatment difference between FFNS and placebo over weeks 1-4 was -0.95 (95% CI,-1.24, -0.66; p < 0.001). FFNS at 110 micrograms q.d. effectively relieved all nasal symptoms of PAR including nasal congestion over a 24-hour period.

There is comparatively little information on health-related quality of life (HRQoL) in subjects with allergic rhinitis (AR) or allergic rhinoconjunctivitis (AR/C) in countries beyond western Europe and North America. The primary aim of this investigation was therefore to review and assess the information in the public domain on HRQoL in AR/C patients from diverse regions of the world, represented by different countries, including Argentina, Australia, Brazil, Russia, Singapore, South Africa and Turkey. Second, in view of the absence of a standardized definition for 'AR control', the review aimed to determine whether a working definition of AR/C can be inferred from validated tests or other instruments documented to date. Despite the comparatively low number of studies, this review demonstrated that overall the symptoms of AR/C impair the HRQoL of patients in these regions by adversely impacting sleep, daily activities, physical and mental status and social functioning, similar to that demonstrated in much larger numbers of studies of AR/C patients in Europe and the United States. Furthermore, the findings of the review suggest that 'overall' control of the disease should encompass reduction of nasal and ocular symptoms, as well as improvements in HRQoL, comorbid conditions and cognition. Although some instruments are currently available for measuring control of AR, none are capable of assessing all these aspects, emphasizing the need to develop appropriate new instruments., (© 2012 Blackwell Publishing Ltd.)

An undergraduate biochemistry laboratory experiment is described that will teach students the practical and theoretical considerations for measuring the equilibrium dissociation constant (K(D) ) for a protein/DNA interaction using electrophoretic mobility shift assays (EMSAs). An EMSA monitors the migration of DNA through a native gel; the DNA migrates more slowly when bound to a protein. To determine a K(D) the amount of unbound and protein-bound DNA in the gel is measured as the protein concentration increases. By performing this experiment, students will be introduced to making affinity measurements and gain experience in performing quantitative EMSAs. The experiment describes measuring the K(D) for the interaction between the chimeric protein GAL4-p53 and its DNA recognition site; however, the techniques are adaptable to other DNA binding proteins. In addition, the basic experiment described can be easily expanded to include additional inquiry-driven experimentation. © 2012 by The International Union of Biochemistry and Molecular Biology., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: There is comparatively little information in the public domain on the diversity in prevalence and triggers/factors associated with allergic rhinitis (AR) or allergic rhinoconjunctivitis (AR/C) in countries beyond western-Europe and North America., Objective: To review the prevalence and the sensitizing agents/triggers and factors associated with AR/C in several countries in Africa, the Asia-Pacific region, Australia, Eastern Europe, Latin America, Middle East and Turkey., Methods: Articles published in English in peer-reviewed journals were assessed and selected for further review, following an extensive literature search using the Medline database., Results: This review demonstrated that prevalence of AR and AR/C in these regions has predominantly been investigated in children; with studies indicating wide inter- and intra-regional variations ranging from 2.9% AR and 3.8% AR/C in 10-18-years-old children from one region in Turkey to 54.1% AR and 39.2% AR/C in 13-14-years-old children in one region in Nigeria. Moreover, the prevalence of AR and AR/C has increased markedly over the last decade particularly in some of the more affluent African countries, China-Taiwan and several Middle East countries, likely as a consequence of improved living standards leading to increased exposure to multiple traditional and non-traditional sensitizing agents and risk factors similar to those noted in western-Europe and North America., Conclusions and Clinical Relevance: Our findings suggest that the greater diversity in prevalence of AR or AR/C in populations in these regions is in contrast to the lower diversity of AR or AR/C in the 'western populations (USA and Europe), which tend to be more uniform. This review provides a comprehensive database of the important allergens and triggers which are likely to influence the prevalence of allergic rhinitis in these diverse regions, where the prevalence of allergic rhinitis is increasing and its adverse impact on the quality of life of affected individuals is increasingly recognised., (© 2011 Blackwell Publishing Ltd.)

International surveys have demonstrated that asthma is still underdiagnosed and undertreated in many parts of the world. Despite improvements in the standard of asthma care delivered in many areas, as evidenced by improved global asthma mortality data, much information on projects and programmes undertaken in resource-limited regions of the world is not in the public domain. The aim of this report is to review projects and programmes in diverse regions around the world so that health care providers, planners and consumers may draw on the successes, failures and lessons learnt. Such real world experiences may contribute to achieving Global Initiative for Asthma goals of asthma control. Asthma projects and programmes in Argentina, Australia, Brazil, China, Japan, Mexico, Philippines, Russia, South Africa and Turkey were discussed by a group of experts in asthma care, the Advancing Asthma Care Network, from their respective countries, over a course of three satellite meetings in 2010. Collective analyses consistently identified low rates of dissemination and implementation of national and international treatment guidelines, low levels of continuing medical education and training of primary health care professionals and access and distribution of inhaled corticosteroids to be major barriers that are critical to the overall success of a national asthma management programme. In the less developed asthma programmes, under-recognition and undertreatment further limited the success of the programmes. Evidence from well-established national asthma management programmes suggests that establishment of a successful programme entails a logical progression through specific developmental stages, starting with political/stakeholder endorsement and commitment, followed by epidemiological evaluation, evaluation of disease burden, evaluation of access to care and best therapy, and finally optimisation and maintenance therapy for individual patients.

Intranasal steroids have been shown to affect ocular symptoms of allergic rhinitis (AR). The results of the published literature, however, are not uniform across all products. This study was designed to evaluate whether the effects of fluticasone furoate nasal spray (FFNS) are consistent across different allergy seasons and different geographic regions for individual nasal and ocular symptoms of seasonal allergic rhinitis (SAR). An integrated analysis was performed on data from four randomized, double-blind, placebo-controlled, parallel-group, multicenter trials, designed to evaluate the efficacy and safety of FFNS, 110 micrograms, once daily for 14 days in 1141 adult and adolescent SAR patients exposed to mountain cedar, ragweed, or grass pollen allergen. All patients evaluated severity of seven individual nasal and ocular symptoms on a 4-point categorical scale. The main efficacy measures included change from baseline in daily reflective, morning (A.M.) predose instantaneous, and daily A.M. and evening (P.M.) reflective score for each nasal/ocular symptom. FFNS significantly improved daily mean reflective, A.M. predose instantaneous, and daily A.M. and P.M. reflective scores for nasal itching, sneezing, congestion, rhinorrhea, and ocular itching/burning, tearing/watering, and redness, compared with placebo (p < 0.001 for all versus placebo). The least square (LS) mean treatment differences ranged from -0.44 to -0.33 (p < 0.0001) for the individual nasal symptoms and from -0.22 to -0.19 (p < 0.0001) for the individual ocular symptoms. FFNS also significantly improved daily reflective total nasal symptom scores (TNSS)/reflective total ocular symptom scores (TOSS), and A.M. predose instantaneous TNSS and instantaneous TOSS, compared with placebo (LS mean treatment differences = -1.47, -0.65, -1.49, and -0.63, respectively; p < 0.001 for all). FFNS, 110 micrograms, once daily consistently relieved all nasal and ocular symptoms of SAR across different allergy seasons and geographical locations.

At eukaryotic promoters, multi-faceted protein-protein and protein-DNA interactions can result in synergistic transcriptional activation. NFAT and AP-1 proteins induce interleukin-2 (IL-2) transcription in stimulated T cells, but the contributions of individual members of these activator families to synergistically activating IL-2 transcription is not known. To investigate the combinatorial regulation of IL-2 transcription we tested the ability of different combinations of NFATc2, NFATc1, cJun, and cFos to synergistically activate transcription from the IL-2 promoter. We found that NFATc2 and cJun are exclusive in their ability to synergistically activate human IL-2 transcription. Protein-protein interaction assays revealed that in the absence of DNA, NFATc2, but not NFATc1, bound directly to cJun/cJun dimers, but not to cFos/cJun heterodimers. A region of NFATc2 C-terminal of the DNA binding domain was necessary and sufficient for interaction with cJun in the absence of DNA, and this same region of NFATc2 was required for the synergistic activation of IL-2 transcription in T cells. Moreover, expression of this C-terminal region of NFATc2 specifically repressed the synergistic activation of IL-2 transcription. These studies show that a previously unidentified interaction between human NFATc2 and cJun is necessary for synergistic activation of IL-2 transcription in T cells., ((c) 2010 Elsevier Ltd. All rights reserved.)

The 2006 European National Health and Wellness Survey (NHWS) showed that a large proportion of asthmatics had uncontrolled asthma. The current analysis estimated the prevalence of asthma and asthma control (Asthma Control Test™ (ACT); QualityMetric Inc., Lincoln, RI, USA) in five European countries using the 2008 NHWS. Health-related quality of life (HRQoL), using the Short Form-12 (SF-12) health survey, and work productivity/activity impairment were assessed. Of 3,619 respondents aged ≥18 yrs, the prevalence of self-reported physician diagnosis of asthma was 6.1% (15 million people); 56.6% of treated asthmatics were not well-controlled (NWC; ACT score ≤19). Individual components of the ACT showed that, compared with at least well-controlled patients (ALWC; ACT score ≥20), NWC patients had activity limitations at least some of the time (40.8% versus 1.5%, p<0.001), were breathless ≥3 times per week (72.5% versus 5.4%, p<0.001), suffered sleep difficulties due to asthma at least once per week (60.3% versus 4.6%, p<0.001) and required rescue medication ≥2-3 times per week (77.4% versus 15.9%, p<0.001). NWC patients had also received more healthcare contact in the past 6 ;months, including hospitalisation (17.4% versus 9.9%, p<0.001). The SF-12 physical and mental summary scores were 7.46 and 4.73 points higher, respectively, for ALWC patients compared with NWC patients (p<0.001). ALWC patients reported less absenteeism (5.5% versus 12.2%) and work impairment (15.4% versus 30.0%) than NWC patients (both p<0.001). The proportion of asthmatics with NWC asthma has not improved since 2006. ALWC asthma is associated with a significant positive impact on healthcare resource use, HRQoL and work productivity.

The short interspersed elements (SINEs) Alu and B2 are retrotransposons that litter the human and mouse genomes, respectively. Given their abundance, the manner in which these elements impact the host genome and what their biological functions might be is of significant interest. Finding that Alu and B2 SINEs are transcribed, both as distinct RNA polymerase III transcripts and as part of RNA polymerase II transcripts, and that these SINE encoded RNAs indeed have biological functions has refuted the historical notion that SINEs are merely "junk DNA." This article reviews currently known cellular functions of both RNA polymerase II and RNA polymerase III transcribed Alu and B2 RNAs. These RNAs, in different forms, control gene expression by participating in processes as diverse as mRNA transcriptional control, A-to-I editing, nuclear retention, and alternative splicing. Future studies will likely reveal additional contributions of Alu and B2 RNAs as regulators of gene expression.

Noncoding RNAs (ncRNAs) have recently been discovered to regulate mRNA transcription in trans, a role traditionally reserved for proteins. The breadth of ncRNAs as transacting transcriptional regulators and the diversity of signals to which they respond are only now becoming recognized. Here we show that human Alu RNA, transcribed from short interspersed elements (SINEs), is a transacting transcriptional repressor during the cellular heat shock response. Alu RNA blocks transcription by binding RNA polymerase II (Pol II) and entering complexes at promoters in vitro and in human cells. Transcriptional repression by Alu RNA involves two loosely structured domains that are modular, a property reminiscent of classical protein transcriptional regulators. Two other SINE RNAs, human scAlu RNA and mouse B1 RNA, also bind Pol II but do not repress transcription in vitro. These studies provide an explanation for why mouse cells harbor two major classes of SINEs, whereas human cells contain only one.

The cytokine interleukin-2 (IL-2) is produced by T cells when they recognize a foreign antigen. Transcription of the IL-2 gene is tightly controlled by the combined actions of multiple transcriptional activators. However, the contribution of sequences in the IL-2 core promoter and the architecture of the IL-2 regulatory region to setting levels of IL-2 transcription are not understood. We have probed these properties of the human IL-2 promoter to understand how the regulatory and core promoter regions cooperate in response to T cell stimulation, thereby setting high levels of inducible transcription. We found that the IL-2 core promoter contains a TATA box that is critical for inducible expression. Moreover, the spacing and orientation between the IL-2 regulatory and core promoter regions is important for setting the level of transcription. The regulatory region of the IL-2 promoter is capable of mediating high levels of expression even when the helical phasing between transcription factor binding sites is perturbed. Although long considered an enhancer, our studies indicate that the regulatory region in the IL-2 promoter is better considered as a proximal regulatory element, since it lacks multiple properties associated with enhancer elements.

Objective: To assess the functional response of the urethral striated muscle to activation of its nerves, using a novel isolated organ-bath preparation., Materials and Methods: The urethra of the female guinea-pig was chosen as a suitable model for investigation, as it is functionally and structurally similar to the human urethra. Female Dunkin-Hartley guinea-pigs (400-500 g) were used; for the histochemical and immunohistochemical experiments, unfixed urethras were cryo-sectioned (14 microm thick) and were stained using established methods. For in vitro experiments, whole urethras were suspended vertically, with pudendal nerves intact, for isometric tension and intraluminal pressure recording in a 40-mL organ bath. Drugs were applied directly to the bathing solution., Results: In the striated muscle layer of the urethra there was positive beta-NADPH-diaphorase activity. In organ-bath studies the pudendal nerve-evoked contractions (0.2 ms pulses, 5 s trains, 70 V and 1-100 Hz) were abolished in the presence of tubocurarine (10(-6)m), and unaffected by guanethidine and atropine (both 10(-6)m). Pre-incubation with sodium nitroprusside and SIN-1 chloride significantly reduced the initial peak pressure responses (P < 0.05, anova for paired data) evoked by electrical field stimulation of the pudendal nerves at stimulus parameters of 0.2 ms pulses, 5 s trains, 70 V and 25 Hz., Conclusion: Electrically induced contractions were abolished by tubocurarine, confirming that the pudendal nerve innervates the striated muscle of the guinea-pig external urethral sphincter via nicotinic receptors. beta-NADPH-diaphorase histochemistry gave positive staining around guinea-pig striated muscle cells and possibly identified neuromuscular junction sites staining positively for the nitric oxide synthase marker. Together with the results of the organ-bath experiments, the results suggest that the striated muscle cells of the guinea-pig urethra have the machinery to respond to nitric oxide.

Aims: The main focus of this study was to profile and compare urethral function in the female guinea pig and rat, and to characterize urodynamically distinctive patterns in the micturition cycle of the two species. This exercise aimed to investigate potential species-related differences and determine a suitable animal model for the human urethra., Materials & Methods: Female Dunkin-Hartley guinea pigs (400-500 g) and Sprague-Dawley rats (200-300 g) were used throughout the study. For in vitro experiments urethral rings were suspended vertically for isometric tension recording in 5 ml organ baths and drugs (phenylephrine 10(-4) M and carbachol 10(-4) M) were applied directly to the bathing solution. In vivo urethral pull-through and urodynamic studies were performed under urethane anesthesia, and phenylephrine (200 microg/kg) was administered during urethral pull-through experiments via the intravenous (i.v.) route. Urethral, bladder and arterial pressures, and external urethral sphincter electromyographic (EMG) spike activity were recorded simultaneously throughout., Results: Organ bath studies coupled with in vivo pull-through experiments produced urethral profiles with distinct regional variations for both species. Urodynamic studies with the urethral probe fixed in the high pressure zones of the proximal urethra produced similar recordings in both species during bladder filling and marked differences during micturition. The guinea pig showed complete sphincteric inhibition immediately prior and during micturition as also seen in the human, whereas the rat exhibited high frequency bursts in EMG activity at this stage in the cycle., Conclusions: The EMG activity seen in the rat during micturition is presumably necessary for efficient voiding, thus the guinea pig is a more suitable comparative model for the human in relation to urethral properties during micturition., (Neurourol. Urodynam. (c) 2005 Wiley-Liss, Inc.)

The position of the lower incisor with respect to hard tissue references has been evaluated. Two samples were used for this purpose: one containing 78 patients with posttreatment records having a postretention period of at least 4 years, and the other composed of 82 normal occlusions. The results indicated: 1) There was no significant difference in relapse of lower incisor crowding between cases where the lower incisor had been moved lingually, labially, or held in the same relative position during treatment. 2) The position of the maxilla should be considered when placing the lower incisor. The APo plane adequately serves as a guide to this purpose, whereas other reference lines such as mandibular plane or facial plane do not. 3) The positions of the incisors with respect to popular cephalometric reference lines such as APo, NB, or mandibular plane were not correlated with the relapse of mandibular crowding. Therefore, other clinical guides might be more successful for determining stability.

The classical effects of lateral orthopedic stress on the midpalatal suture were confirmed in this study conducted on ten female Macaca mulatta monkeys in the mixed dentitional period. The suture was opened with consequent expansion of the maxillary arch, of the intranasal space, and of the palatal vault. There was marked buccal displacement of the upper posterior teeth together with a definite broadening of the entire midface. Modest relapse of maxillary expansion and of palatal depth occurred when retention was terminated after four months. Normal angulation of the upper first molars at the end of the experimental period is indicative of a predominantly translatory expansion of the arch or of a rapid restoration of normal tooth alignment and inclination. Subsidiary expansion of the mandibular arch and reclosure of the midpalatal suture also occurred. Of particular importance to this study was confirmation of changes in the bony configuration of the midface manifested by prominence of the canine eminence and the general pug-nosed appearance of treated animals althrough this could not be attributed to retrusion of the premaxilla.

Heavy, interupted orthopedic forces were employed for the cervical retraction of the maxillae in two Macaca mulatta monkeys. The nature, location and magnitude of resultant movements and remodelling were studied with the help of plaster casts, amalgam implants, lateral cephalometric tracings, and of gross and microscopic study of the skulls themselves. The principal effect of the retractive force was a marked downward and backward rotational movement of the maxillae which carried the maxillary teeth into posterior crossbite and a severe Class III molar relationship. Posterior movement of the tuberosity entirely closed the pterygomaxillary fissure so that the tuberosity impinged upon the pterygoid plates. Like the maxillae, the mandible, premaxilla, and nasal boned also moved downward and backward. These changes increased the vertical dimension of the face and diminished it horizontally leaving a flattened facial profile from the nasal opening to the maxillary incisors. Movement of facial elements posteriorly against an unhielding anterior cranial base imposed a number of other compensatory changes. These included generalized resorption at the craniofacial sutures and sliding of the sutures upon each other. They also involved mutual resorption of the maxillary tuberosity and of the pterygoid plates together with remodelling and lateral extension of the malar bones. Tolerance of the animals and of the localized tissues for these intensive forces suggests a significant role for this form of therapy. Clinical application, however, should be tempered by judicious concern for the vital structures of the pterygomaxillary fissure which could be impinged or strangulated by excessive retrusive force.

The mandibles of three baboons are expanded laterally by surgical osteotomy at the symphysis, followed by different regimes of stabilization and orthodontic movement.

It has been demonstrated that there are reliable methods of predicting the ultimate position of the lower incisor and the soft tissue. However, the concept of treating this tooth to any one number for every individual was not supported by the evidence. An optimum system would allow the clinician to select and combine factors from all methods and arrive at a balance of esthetics, function, and stability, obtaining a suitable compromise for his individual patient. This is undoubtedly attempted intuitively by many experienced clinicians.