Ocular Hypertelorism: Principles and Management.

Background: Ocular hypertelorism (OH) was initially considered as un-differentiated congenital cranio-facial deformity, however, I.T Jackson mentioned it as teleorbitism, considering it as increase in the inter-canthal width, inter-pupillary as well as inter-orbital distance as a result of lateralization of the orbital complex in total. Furthermore, Sailer further refined it and included the distance from the lateral orbital wall, i.e. he denoted increased inter-orbital distance along with the distance between lateral orbital walls as true hypertelorism. This condition is rare and is seen in association with midline congenital defects affecting the cranio-facial region. Classification and review of cases: The ideal time for the OH correction is usually between 5 and 8 years of age. However, the management of OH is complex, and several techniques have been described in literature for the same. Here, we describe our classification of OH, along with the evolution of the surgical aspects, the key treatment principles we follow, together with the types of the osteotomies and their indications. Furthermore, we delineate the four main principles that we have set for OH management. Results: Though the improvement in appearance is seen immediately post-surgery, however, this challenging surgery faces a multitude and common postoperative complications which have been represented in this article. The surgeon needs both the technical expertise and an inclination towards aesthetics for the execution of such procedures. Conclusion: It is preferred that the management of OH should be individualized as per the stage of the craniofacial growth and the psychosocial needs of the patient and the parents.

Determining structures of individual RNA conformers using atomic force microscopy images and deep neural networks.

The vast percentage of the human genome is transcribed into RNA, many of which contain various structural elements and are important for functions. RNA molecules are conformationally heterogeneous and functionally dyanmics1, even when they are structured and well-folded2, which limit the applicability of methods such as NMR, crystallography, or cryo-EM. Moreover, because of the lack of a large structure RNA database, and no clear correlation between sequence and structure, approaches like AlphaFold3 for protein structure prediction, do not apply to RNA. Therefore determining the structures of heterogeneous RNA is an unmet challenge. Here we report a novel method of determining RNA three-dimensional topological structures using deep neural networks and atomic force microscopy (AFM) images of individual RNA molecules in solution. Owing to the high signal-to-noise ratio of AFM, our method is ideal for capturing structures of individual conformationally heterogeneous RNA. We show that our method can determine 3D topological structures of any large folded RNA conformers, from ~ 200 to ~ 420 residues, the size range that most functional RNA structures or structural elements fall into. Thus our method addresses one of the major challenges in frontier RNA structural biology and may impact our fundamental understanding of RNA structure.

Land-use induced soil carbon stabilization at the expense of rock derived nutrients: insights from pristine Andean soils.

Soils contain significantly more carbon than the atmosphere, hence we should understand how best to stabilize it. Unfortunately, the role of human interventions on soil organic carbon (SOC) persistence in the Anthropocene remains vague, lacking adequate sites that allow unbiased direct comparisons of pristine and human influenced soils. Here we present data from a unique study system in the High Andes that guarantees pristineness of the reference sites by physical inaccessibility through vertical cliffs. By comparing the isotopic signatures of SOC, mineral related carbon stabilization, and soil nutrient status across grazed versus pristine soils, we provide counterintuitive evidence that thousands of years of pastoralism increased soil C persistence. Mineral associated organic carbon (MAOC) was significantly higher in pastures. Land use increased poorly crystalline minerals (PCM's), of which aluminum correlated best with MAOC. On the other hand, human's acceleration of weathering led to acidification and higher losses of cations. This highlights a dilemma of lower soil quality but higher persistence of SOC due to millennia of pastoralism. The dynamics of soil genesis in the Anthropocene needs better understanding, but if human-induced weathering proves generally to promote soil carbon persistence it will need to be included in climate-soil feedback projections.

Women's perspectives on the acceptability and feasibility of an HPV screen-and-treat approach to cervical cancer prevention in Iquitos, Peru: a qualitative study.

BACKGROUND: The objective of this study was to explore women's experiences of a screen-and-treat approach with ablative therapy (referred to by the Spanish acronym TVT-TA) as a method of treatment following a positive HPV test in Iquitos, Peru. METHODS: A total of 111 in-depth interviews were conducted with 47 HPV positive women who attended the TVT-TA procedure at a primary-level healthcare facility. Interviews were conducted immediately before, immediately after, and six-weeks after TVT-TA. RESULTS: Most interviewed women reported experiencing moderate pain during ablative therapy and minimal pain immediately after and six weeks after ablative therapy. Women also stated that the pain was less intense than they had expected. The most common physical after-effects of treatment were bleeding and vaginal odor. Women experienced oscillating emotions with fear upon receiving a positive HPV result, calming after hearing about ablative therapy treatment, worry about pain from the treatment itself, relaxation with counseling about the procedure, and relief following treatment. CONCLUSIONS: Nearly all participants emphasized that they were pleased with the TVT-TA process even if they had experienced pain during TVT-TA, recommended that TVT-TA be expanded and available to more women, and stated that TVT-TA was faster and easier than expected. This study found that TVT-TA is a feasible and acceptable means of treating HPV according to the women receiving the treatment.

Management of Tessier 30-Median Mandibular Cleft: 12-Year Follow-Up-A Case Report.

Midline clefts of mandible and lower lip are rare congenital facial deformities. Non-union of bone in the symphysis of the mandible, median cleft of the lower lip and tongue adherence in the midline to the floor of the mouth are the principle features of the anomaly. Early surgical correction of both hard and soft tissue defects resulted in excellent function such as mastication and speech. 12-yr follow-up shows total bony fusion of the symphysis and normal growth of mandible as per the chronologic age of patient.

Does the Timing of 1-Stage Palatoplasty With Radical Muscle Dissection Effect Long-Term Midface Growth? A Single-Center Retrospective Analysis.

OBJECTIVE: To evaluate the long-term effect of timing of 1-stage palatoplasty on midfacial growth in patients with cleft lip and palate (CLP). DESIGN: Retrospective observational cohort study. STUDY SETTING: Institutional hospital. PATIENTS: One hundred twelve patients with CLP who underwent palatoplasty and were divided into 3 groups: group I: operated between 9 and 11 months; group II: operated between 18 and 20 months; and group III: operated between 21 and 24 months. INTERVENTIONS: All patients underwent von Langenbeck palatoplasty technique, which was converted to a Bardach 2-flap technique in case of any technical difficulties. The patients were followed up between 8 and 9 years when they reported for secondary alveolar bone grafting. Postsurgical cephalometric and dental casts measurements were taken for midfacial growth analysis. MAIN OUTCOME MEASURES: The cephalometric measures were analyzed for midfacial growth and compared within the groups. RESULTS: Statistically significant difference (P < .01) was found on comparing the cephalometric parameters such as sella-nasion-A point angle (SNA), A point-nasion-B point angle (ANB), n toperpendicular to point A (N-perpA), condylon to point A (Co-A), anterior nasal spine to posterior nasal spine (ANS-PNS), nasion to Anterior nasal spine (N-ANS), nasion to menton (N Me), and witts appraisal (Witt (AO-BO)) in group I when compared to both group II and group III patients, implying deficient midfacial growth in group I. No statistical difference was found in the cephalometric values between group II and group III. Group II had better cephalometric measurements than group III, showing better growth in group II than group III. Overall, there was less incidence of midfacial hypoplasia in patients treated between 18 and 20 months (group II). CONCLUSION: We conclude that palatal closure carried out at 18 to 20 months and 21 to 24 months is associated with better midfacial growth when compared to closure at 9 to 11 months. The best time to operate would be between 18 and 20 months to avoid speech disturbances. Midfacial growth can be greatly influenced by the timing of 1-stage palatoplasty.

Correlation between surgical protocols for palatoplasty and midfacial growth in cleft lip and palate patients: A long-term, single centre study.

To evaluate and compare the outcomes of two different surgical protocols for palatoplasty for midfacial growth in patients with cleft lip and palate. A retrospective observational cohort study was conducted in 80 patients with cleft lip and palate, who were divided into two groups. Group 1 comprised patients who underwent operation between 9 and 11 months of age using the Bardach two-flap technique without a palatal pushback. Group 2 comprised patients who had undergone operation between 18 and 20 months of age using either a Bardach two-flap technique with a palatal pushback or a von Langenbeck technique. Patient follow-up was done between 8 and 9 years of age when they reported to the centre for secondary alveolar bone grafting. Post-surgical cephalometric measurements were taken for midfacial growth analysis. Group 1 underwent palatoplasty at significantly younger ages than Group 2 (p < 0.01). A statistically significant difference(p < 0.01) was found between the two groups of patients on comparison of cephalometric parameters such as SNA, ANB, CoA, NperpA ANS-PNS, N-ANS, N-Me, Witt's (AO-BO). Group 2 had more positive cephalometric values as compared to Group 1, thereby implying that there was less incidence of midfacial hypoplasia in patients treated at the age of 18-20 months. Between the types of palatoplasty techniques within Group 2, i.e., Bardach two-flap and von Langenbeck, there was no statistical difference found in the post-opertative cephalometric values, i.e., SNA, ANB, CoA, ANS-PNS, N-ANS, N-Me, Witt's (AO-BO) except for Nperp-A, which showed a statistical difference (p = 0.03). Within the limitations of the study which is only a single center experience it seems that palatal closure should be carried out at 18-20 months of age for better midfacial growth, leading to decreased incidence of maxillary hypoplasia at a later stage in life. Repair at less than 18 months of age is also associated with mid-facial hypoplasia.

Distribution, behavior, and erosion of uranium in vineyard soils.

Phosphate fertilization contributes to an input of uranium (U) in agricultural soils. Although its accumulation and fate in agricultural soils have been previously studied, its colloidal transport and accumulation along slopes through erosion have been studied to a lesser extent in viticulture soils. To bridge this gap, the contents and potential mobility of U were investigated in vineyard model soils in the Rhineland-Palatinate region, Germany. In addition to elevated U contents, U was expected to associate with colloids and subject to erosion, thus accumulating on slope foots and in soils with fine structure, and reflecting a greater variability. Moreover, another expectation was the favorable erosion/mobility of U in areas with greater carbonate content. This was tested in three regional locations, at different slope positions and through soil horizon depths, with a total of 57 soil samples. The results show that U concentrations (0.48-1.26 ppm) were slightly higher than proximal non-agricultural soils (0.50 ppm), quite homogenous along slope positions, and slightly higher in topsoils. Assuming a homogeneous fertilization, the vertical translocation of U in soil was most probably higher than along the slope by erosion. In addition, carbonate content and soil texture correlated with U concentrations, whereas other parameters such as organic carbon and iron contents did not. The central role of carbonate and soil texture for the prediction of U content was confirmed using decision trees and elastic net, although their limited prediction power suggests that a larger sample size with a larger range of U content is required to improve the accuracy. Overall, we did not observe neither U nor colloids accumulating on slope foots, thus suggesting that soils are aggregate-stable. Lastly, we suggested considering further soil parameters (e.g., Ca2+, phosphorus, alkali metals) in future works to improve our modelling approach. Overall, our results suggest U is fortunately immobile in the studied locations.

Association between ABO, Rh blood groups, lip and dermatoglyphic patterns, and nonsyndromic oral clefts: A case-control study.

OBJECTIVE: The objective of the study is to determine the association between nonsyndromic oral clefts (OC) in children and ABO, Rh blood groups, lip, and dermatoglyphic patterns of their unaffected parents. METHODS: This case-control study was conducted at a tertiary cleft center in Chennai, India, among 240 individuals comprising 80 units (40 cases and controls, respectively). Each unit (triad) was constituted by a child (0-12 years of age) either born with nonsyndromic OC (cases) or with no diagnosed congenital anomaly (control) and their unaffected parents (mother and father). ABO and Rh blood groups, specific lip print, fingerprint pattern, and palmar asymmetry were recorded for each individual. Strength of association of related factors was assessed by multivariable logistic regression reported as adjusted odds ratios and 95% confidence interval. RESULTS: A1-positive blood group was found to be considerably higher among case mothers (14.39 [1.57-32.27]). A higher odds of OCs were observed among case mothers with whorl lip pattern (1.51 [1.16-3.17]) and radial loop pattern in fingers (1.44 [1.09-2.31]) relative to controls. In addition, palmar asymmetry was distinctively higher among case parents compared to controls (P < 0.01). CONCLUSION: Findings indicate that A1-positive blood group, higher frequency of whorl lip, and radial loop finger patterns in mothers and higher ulnar loop pattern in fathers and palmar asymmetry in both parents increases odds of occurrence of OC among their offspring. These identifiable traits offer potential scope for better service planning among resource-constrained disadvantaged communities in India.

Distraction Osteogenesis Versus Orthognathic Surgery: Demystifying Differences in Concepts, Techniques and Outcomes.

INTRODUCTION: The popularity and interest evoked by orthognathic surgery and distraction osteogenesis are undisputed in the field of oral and maxillofacial surgery. However, questions regarding the individual identities of either of them with clarity in their concepts, techniques and outcomes have remained unanswered. The aim of this review is to shed light on these questions. METHODS: This review is structured as a narrative review of thirty years of literature available in the specialities of orthognathic surgery and distraction osteogenesis. CONCLUSION: The authors present a review of existing literature combined with contrasting experience gained over the years in providing an overview of the merits and demerits of the two surgical techniques which will aid the clinician in justifying the use of one technique over the other.

N2O emissions from plants are reduced under photosynthetic activity.

New plant functions in the exchange of greenhouse gases between ecosystems and atmosphere have recently been discovered. We tested whether photosynthetic activity has an effect on N2O emission rates from incubated plant-soil systems.Two laboratory experiments were performed. One to unravel possible effect of photosynthetic activity on the net N2O ecosystem exchange for two species (beech and ash saplings). The other to account for possible effects from rhizosphere and aboveground plant parts separately (ash sapling only).Total N2O emissions from both plant and plant-soil systems were significantly lower under light than in darkness (31%-65%). The photosynthetic effect only applied to the aboveground plant parts.Underlying processes have now to be unraveled to improve our understanding of ecosystem functioning. This will improve modeling and budgeting of greenhouse gas exchanges between ecosystems and the atmosphere.

Retrospective analysis of a TMJ ankylosis protocol with a 9 year follow up.

OBJECTIVE: Temporomandibular joint ankylosis (TMJa) is a debilitating condition that causes difficulty in mastication, speech and mouth opening. Its treatment poses surgical and rehabilitative challenges along with a high incidence of reankylosis. This study was designed to assess the long-term outcomes with a new two phase physiotherapy protocol following conservative resection of the ankylotic mass. MATERIALS AND METHODS: 143 patients who were treated for TMJa were initially recruited, among whom 98 were inducted into the study and retrospectively evaluated using clinical records and 3-dimensional computed tomography. All the patients underwent a minimal pre auricular incision and conservative interpositional gap arthroplasty with collagen membrane. This was followed by the new two phase physiotherapy protocol with the use of a bite block. The primary outcome measures were the maximum interincisal distance, vertical ramus height and complications. The patients were followed up at monthly intervals during the first year, quarterly intervals during the second year, and at intervals of 6 months during subsequent follow-up years. The mean follow up period was 6.38 ± 2.36 years after ankylotic release. Paired student t test was used for statistical analysis. RESULTS: The mean scores for mouth opening at T1, T2 and T3 were statistically significantly different at all intervals (p < 0.0005). The mean scores for ramal length were statistically significantly different at T1 and T2 interval (p < 0.0005) and insignificant at T2 and T3 interval. No reankylosis was observed in patients who followed the physiotherapy protocol. CONCLUSIONS: In the management of TMJa, the success of the conservative surgical technique with interpositional arthroplasty is less dependent on the longevity and rigidity of the interpositional material but more indebted to the patient compliance in following the proposed physiotherapy protocol.

Does Sphenopalatine Ganglion Block Improve Pain Control and Intraoperative Hemodynamics in Children Undergoing Palatoplasty? A Randomized Controlled Trial.

PURPOSE: Children undergoing cleft palate repair have pain, dysphagia, and wound irritation in the immediate postoperative phase that may compromise surgical outcomes. This trial evaluates the efficacy of the sphenopalatine ganglion block (SPGB) in optimizing intraoperative hemodynamics and postoperative analgesia in children undergoing primary palatoplasty. MATERIALS AND METHODS: The study was designed as a prospective, double-blind, randomized controlled trial comparing the use of SPGB with general anesthesia (GA) (study group) versus the use of only GA (control group). Routine preoperative documentation included type of cleft, patient weight, hemoglobin (Hb%), packed cell volume (PCV), blood pressure, and echocardiogram. Intraoperative monitoring included heart rate, blood pressure, and surgical field assessment. Postoperatively, the pain score, pain-free duration, and need for rescue analgesics were recorded. Postsurgical changes in Hb% and PCV values were assessed. Data analysis of collected variables was performed using SPSS software (version 16; IBM, Armonk, NY). Quantitative data were assessed for normality using the Shapiro-Wilk test and analyzed using the independent-sample t test, and the Fisher exact test was used for comparison of the binary variable (gender). The outcome variables were compared between the study and control groups after adjustment for confounding variables. P < .05 was considered statistically significant. RESULTS: We randomized 100 patients undergoing primary palatoplasty under GA into the control group (n = 49) and study group (SPGB) (n = 51). Three patients were excluded from the control group because of changes in intraoperative anesthetic protocol. The results showed statistically significant differences in the postsurgical pain-free duration (19.46 minutes vs 87.59 minutes) and mean blood loss (105.5 mL vs 62 mL) in favor of the study group. Surgical field and postoperative reduction of Hb% and PCV were also significantly favorable for the study group. CONCLUSIONS: SPGB is a potent pre-emptive technique offering excellent perioperative analgesia, hemodynamic stability, and a clear surgical field.

Impacts of land-use and land-cover change on stream hydrochemistry in the Cerrado and Amazon biomes.

Studies on the impacts of land-use and land-cover change on stream hydrochemistry in active deforestation zones of the Amazon agricultural frontier are limited and have often used low-temporal-resolution datasets. Moreover, these impacts are not concurrently assessed in well-established agricultural areas and new deforestations hotspots. We aimed to identify these impacts using an experimental setup to collect high-temporal-resolution hydrological and hydrochemical data in two pairs of low-order streams in catchments under contrasting land use and land cover (native vegetation vs. pasture) in the Amazon and Cerrado biomes. Our results indicate that the conversion of natural landscapes to pastures increases carbon and nutrient fluxes via streamflow in both biomes. These changes were the greatest in total inorganic carbon in the Amazon and in potassium in the Cerrado, representing a 5.0- and 5.5-fold increase in the fluxes of each biome, respectively. We found that stormflow, which is often neglected in studies on stream hydrochemistry in the tropics, plays a substantial role in the carbon and nutrient fluxes, especially in the Amazon biome, as its contributions to hydrochemical fluxes are mostly greater than the volumetric contribution to the total streamflow. These findings demonstrate that assessments of the impacts of deforestation in the Amazon and Cerrado biomes should also take into account rapid hydrological pathways; however, this can only be achieved through collection of high-temporal-resolution data.

Combined Layer/Particle Approaches in Surface Molecular Imprinting of Proteins: Signal Enhancement and Competition.

Herein we report novel approaches to the molecular imprinting of proteins utilizing templates sizing around 10 nm and some 100 nm. The first step comprised synthesizing nanoparticles of molecularly imprinted polymers (MIP) towards bovine serum albumin (BSA) and characterizing them according to size and binding capacity. In a second step, they were utilized as templates. Quartz crystal microbalances (QCM) coated with MIP thin films based on BSA MIP nanoparticles lead to a two-fold increase in sensor responses, compared with the case of directly using the protein as the template. This also established that individual BSA molecules exhibit different "epitopes" for molecular imprinting on their outer surfaces. In light of this knowledge, a possible MIP-based biomimetic assay format was tested by exposing QCM coated with BSA MIP thin films to mixtures of BSA and imprinted and non-imprinted polymer (NIP) nanoparticles. At high protein concentrations (1000 ppm) measurements revealed aggregation behavior, i.e., BSA binding MIP NP onto the MIP surface. This increased sensor responses by more than 30% during proof of concept measurements. At lower a BSA concentration (500 ppm), thin films and particles revealed competitive behavior.

Neocondyle distraction osteogenesis in the management of temporomandibular joint ankylosis: Report of five cases with review of literature.

INTRODUCTION AND OBJECTIVES: Management of temporomandibular joint (TMJ) ankylosis is a challenging and rather daunting task owing to complex abnormal anatomy and its sequel to craniofacial structures. Various autogenous grafts and alloplastic materials have been tried with variable success for creation of a near-normal joint. In recent years, neocondyle distraction has added a new dimension to the management of TMJ ankylosis. The aim of this paper is to describe the role of neocondyle distraction in TMJ ankylosis. MATERIALS AND METHODS: Neocondyle distraction was carried out in five patients with TMJ ankylosis following gap arthroplasty. Computed tomogram scans were taken before surgery and 1-year postdistraction for surgical planning and postoperative assessment, respectively. The intraoral distractors (KLS Martin, Jacksonville, FL, USA) were used in this study. RESULTS: All five patients reported with adequate mouth opening and functional jaw movements. The procedure was well tolerated by all the patients. None of the patients underwent reankylosis following neocondyle distraction. CONCLUSION: With proper surgical planning and distraction protocol, neocondyle distraction is an effective and safe technique for TMJ reconstruction and preventing reankylosis.

Relict high-Andean ecosystems challenge our concepts of naturalness and human impact.

What would current ecosystems be like without the impact of mankind? This question, which is critical for ecosystem management, has long remained unanswered due to a lack of present-day data from truly undisturbed ecosystems. Using mountaineering techniques, we accessed pristine relict ecosystems in the Peruvian Andes to provide this baseline data and compared it with the surrounding accessible and disturbed landscape. We show that natural ecosystems and human impact in the high Andes are radically different from preconceived ideas. Vegetation of these 'lost worlds' was dominated by plant species previously unknown to science that have become extinct in nearby human-affected ecosystems. Furthermore, natural vegetation had greater plant biomass with potentially as much as ten times more forest, but lower plant diversity. Contrary to our expectations, soils showed relatively little degradation when compared within a vegetation type, but differed mainly between forest and grassland ecosystems. At the landscape level, a presumed large-scale forest reduction resulted in a nowadays more acidic soilscape with higher carbon storage, partly ameliorating carbon loss through deforestation. Human impact in the high Andes, thus, had mixed effects on biodiversity, while soils and carbon stocks would have been mainly indirectly affected through a suggested large-scale vegetation change.

Mid-Face Degloving: An Alternate Approach to Extended Osteotomies of the Midface.

Extended osteotomies for mid-face advancement require generous exposure of the anterior maxilla, nasal bones, infraorbital rims, orbital floor, zygoma, and the anterior third of the zygomatic arches. This cannot be obtained with an exclusive transoral approach. Hence, the surgeon is usually compelled to utilize supplemental cutaneous incisions that are a compromise on the purpose behind a cosmetic surgery. In order to alleviate the need for such compromise, the authors advocate the mid face degloving approach for extended osteotomies at Lefort II and Lefort III levels. Mid face degloving involves a combination of circumvestibular incision, with inter cartilaginous and transfixation components from a nasal incision. The authors have utilized this technique for 9 patients and documented favorable results. The purpose of this paper is to focus the utility of this approach in orthognathic surgery and promote this as a viable alternative to traditional approaches in surgery of the mid face because of the absence of external scars.

On the influence of provenance to soil quality enhanced stress reaction of young beech trees to summer drought.

Climate projections propose that drought stress will become challenging for establishing trees. The magnitude of stress is dependent on tree species, provenance, and most likely also highly influenced by soil quality. European Beech (Fagus sylvatica) is of major ecological and economical importance in Central European forests. The species has an especially wide physiological and ecological amplitude enabling growth under various soil conditions within its distribution area in Central Europe. We studied the effects of extreme drought on beech saplings (second year) of four climatically distinct provenances growing on different soils (sandy loam and loamy sand) in a full factorial pot experiment. Foliar δ13C, δ15N, C, and N as well as above- and belowground growth parameters served as measures for stress level and plant growth. Low-quality soil enhanced the effect of drought compared with qualitatively better soil for the above- and belowground growth parameters, but foliar δ13C values revealed that plant stress was still remarkable in loamy soil. For beeches of one provenance, negative sandy soil effects were clearly smaller than for the others, whereas for another provenance drought effects in sandy soil were sometimes fatal. Foliar δ15N was correlated with plant size during the experiment. Plasticity of beech provenances in their reaction to drought versus control conditions varied clearly. Although a general trend of declining growth under control or drought conditions in sandy soil was found compared to loamy soil, the magnitude of the effect of soil quality was highly provenance specific. Provenances seemed to show adaptations not only to drought but also to soil quality. Accordingly, scientists should integrate information about climatic pre-adaptation and soil quality within the home range of populations for species distribution modeling and foresters should evaluate soil quality and climatic parameters when choosing donor populations for reforestation projects.

Basophils Trigger Fibroblast Activation in Cardiac Allograft Fibrosis Development.

Fibrosis is a major component of chronic cardiac allograft rejection. Although several cell types are able to produce collagen, resident (donor-derived) fibroblasts are mainly responsible for excessive production of extracellular matrix proteins. It is currently unclear which cells regulate production of connective tissue elements in allograft fibrosis and how basophils, as potential producers of profibrotic cytokines, are involved this process. We studied this question in a fully MHC-mismatched model of heart transplantation with transient depletion of CD4(+) T cells to largely prevent acute rejection. The model is characterized by myocardial infiltration of leukocytes and development of interstitial fibrosis and allograft vasculopathy. Using depletion of basophils, IL-4-deficient recipients and IL-4 receptor-deficient grafts, we showed that basophils and IL-4 play crucial roles in activation of fibroblasts and development of fibrotic organ remodeling. In the absence of CD4(+) T cells, basophils are the predominant source of IL-4 in the graft and contribute to expansion of myofibroblasts, interstitial deposition of collagen and development of allograft vasculopathy. Our results indicated that basophils trigger the production of various connective tissue elements by myofibroblasts. Basophil-derived IL-4 may be an attractive target for treatment of chronic allograft rejection.