Recommendations for the prevention and diagnosis of asthma in children: Evidence from international guidelines adapted for Mexico.

BACKGROUND: With the availability of high-quality asthma guidelines worldwide, one possible approach of developing a valid guideline, without re-working the evidence, already analysed by major guidelines, is the ADAPTE approach, as was used for the development of National Guidelines on asthma. METHODS: The guidelines development group (GDG) covered a broad range of experts from medical specialities, primary care physicians and methodologists. The core group of the GDG searched the literature for asthma guidelines 2005 onward, and analysed the 11 best guidelines with AGREE-II to select three mother guidelines. Key clinical questions were formulated covering each step of the asthma management. RESULTS: The selected mother guidelines are British Thoracic Society (BTS), GINA and GEMA 2015. Responses to the questions were formulated according to the evidence in the mother guidelines. Recommendations or suggestions were made for asthma treatment in Mexico by the core group, and adjusted during several rounds of a Delphi process, taking into account: 1. Evidence; 2. Safety; 3. Cost; 4. Patient preference - all these set against the background of the local reality. Here the detailed analysis of the evidence present in BTS/GINA/GEMA sections on prevention and diagnosis in paediatric asthma are presented for three age-groups: children with asthma ≤5 years, 6-11 years and ≥12 years. CONCLUSIONS: For the prevention and diagnosis sections, applying the AGREE-II method is useful to develop a scientifically-sustained document, adjusted to the local reality per country, as is the Mexican Guideline on Asthma.

Periodontal cytokines profile under orthodontic force and extracorporeal shock wave stimuli in a rat model.

BACKGROUND AND OBJECTIVE: Extracorporeal shock wave therapy has been used in various clinical conditions as a result of its ability to stimulate healing processes in acute and chronic inflammatory states. Orthodontic force application triggers an inflammatory reaction in the periodontal tissue surrounding the involved teeth, resulting in tooth movement. Preliminary work revealed that extracorporeal shock wave therapy increased the expression of the inflammatory cytokines involved. Our aim was to investigate the expression of inflammatory cytokines in the periodontal tissues following orthodontic force induction, with and without shock wave therapy, in experimental rats. MATERIAL AND METHODS: An orthodontic appliance was fabricated and applied between the molars and the incisors of adult Wistar rats. In conjunction with orthodontic force commencement, the rats were treated with a single episode of 1000 shock waves. Every day, during the 3 d of the study, rats were killed and the immunolocalization of RANKL, interleukin (IL)-1ß, IL-6 and tumor necrosis factor-alpha was evaluated. RESULTS: The percentage of the area staining positively for all inflammatory cytokines during the first 2 d decreased statistically significantly more in the shock wave-treated group compared with the nontreated control group. On the first day, the percentage of the area staining positively for IL-1ß and RANKL on the compression side peaked in both groups, with a sequential rise in the number of TRAP-positive cells. CONCLUSION: The induction of shock wave therapy during orthodontic tooth movement influences the expression of different inflammatory cytokines in the tissue and might alter the expected periodontal remodeling rate.

Treatment considerations in hutchinson-gilford progeria syndrome: a case report.

Hutchinson-Guilford progeria syndrome is an extremely rare condition classified as one of the premature ageing syndromes. This case presents a 16-year-old Israeli female patient, suffering from a variant of Hutchinson-Guilford progeria with a history of treatment with oral biphosphnates. The patient presented with typical cranial and facial features of the syndrome including delayed teeth eruption and root development probably due to insufficient jaw growth and severs retrognatic position of the maxilla and mandible. Orthodontic treatment considerations are described along with those required in light of the previous treatment by oral biphosphonates.All primary teeth were extracted in three appointments while creating as minimal trauma as possible to the surrounding tissue and alveolar bone. For now, the patient refuses to begin the orthodontic treatment course. There are no limitations to conduct any dental procedures in progeria patients, however, extreme caution must be exercised during oral surgery due to the inelasticity of tissues and dermal atrophy. Orthodontic procedure commencement should be early enough to manage the delayed development and eruption of teeth. Patients taking oral biphosphonates should be advised of this potential complication. If orthodontic treatment is considered appropriate, plans should be assessed and modified to include compromises.

Complement facilitates early prion pathogenesis.

New-variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to the causative agent, and exhibit early prion replication in lymphoid organs. In mouse scrapie, depletion of B-lymphocytes prevents neuropathogenesis after intraperitoneal inoculation, probably due to impaired lymphotoxin-dependent maturation of follicular dendritic cells (FDCs), which are a major extracerebral prion reservoir. FDCs trap immune complexes with Fc-gamma receptors and C3d/C4b-opsonized antigens with CD21/CD35 complement receptors. We examined whether these mechanisms participate in peripheral prion pathogenesis. Depletion of circulating immunoglobulins or of individual Fc-gamma receptors had no effect on scrapie pathogenesis if B-cell maturation was unaffected. However, mice deficient in C3, C1q, Bf/C2, combinations thereof or complement receptors were partially or fully protected against spongiform encephalopathy upon intraperitoneal exposure to limiting amounts of prions. Splenic accumulation of prion infectivity and PrPSc was delayed, indicating that activation of specific complement components is involved in the initial trapping of prions in lymphoreticular organs early after infection.

Isolated soft tissue cleft lip: epidemiology and associated dental anomalies.

OBJECTIVES: The aim of this investigation was to study the epidemiology of the isolated soft tissue cleft lip (ICL) population and to evaluate the dental anomalies associated with permanent dentition. METHODS: The study included 19 children aged 9-13 years presenting ICL selected from 657 cleft lip-affected patients treated during the last 10 years in two craniofacial centers. Only 17 patients could be included for dental anomaly evaluation: Hyperdontia, Hypodontia, Gemination, Talon tooth, Microdontia, and Macrodontia. These were compared with cleft lip and palate (CLP) and cleft lip and alveolus (CLA)-affected populations and with normal populations. RESULTS: The prevalence of ICL was 2.8%. All types of tooth abnormalities were found to be higher and mainly significant for the cleft side of ICL compared with the normal population. On the side opposite the cleft, the prevalence of dental anomalies reduced toward the normal individuals and was not significantly different. The significant differences found between CLP, CLA, and ICL-affected populations were mostly depicted by lateral incisors and second pre-molar hypodontia. CONCLUSIONS: Isolated cleft lip is a rare phenomenon among the spectrum of the cleft-affected population. The prevalence of the dental anomalies in ICL maintains the proportional trend according to clefting severity.

Reliability of panoramic radiographs for the assessment of mandibular elongation after distraction osteogenesis procedures.

UNLABELLED: To determine whether panoramic radiographs could be used for evaluation of changes in the vertical and horizontal dimensions following internal curvilinear mandibular distraction osteogenesis. STUDY DESIGN: A retrospective cohort study included 25 patients who underwent bilateral mandibular distraction surgery. Three panoramic radiographs and lateral cephalograms from each patient were available: before distraction, immediately upon termination of the distraction process, and at the end of the follow-up period. The radiographs were traced by plotting Condylion, Gonion, and Menton. The linear distances between Condylion and Gonion and between Gonion and Menton were measured on each side, and the correlation was calculated. RESULTS: No significant differences were found between the values of the linear measurements determined by lateral cephalograms and panoramic radiographs (p ≥ 0.079), excluding one measurement. The correlation test for these radiographs showed very high, positive and statistically significant correlations, for both sides of the internal mandibular distraction (r > 0.77, p ≤ 0.0001), apart from three measurements. CONCLUSION: Panoramic radiographs, with mandibular length (Co-Go and Go-Me) measurements, can be used as an alternative to lateral cephalograms, i.e. as a reliable tool for assessing vertical and horizontal dimensional changes resulting from internal mandibular distraction achieved by a curvilinear distractor.

[Orthodontic tooth movement under extracorporeal shock wave therapy: the characteristics of the inflammatory reaction--a preliminary study].

Extracorporeal generated shock waves were introduced in medical therapy approximately 20 years ago in order to disintegrate kidney stones. Over the last 10 years, extracorporeal generated shock waves have been used to stimulate healing processes. No report to date has examined its influence on different inflammation mediators and growth factors in the periodontium. Orthodontic tooth movement is a model including the induction of an aseptic inflammation and its resolution. We conducted a preliminary study to investigate the periodontium cytokine concentration fluctuations after induction of orthodontic force with and without extracorporeal shock wave therapy (ESWT) in a rat model. An orthodontic appliance was fabricated and applied between the molars and the incisors of rats. The rats were treated by a single episode of 1000 shock waves and gingival crevicular fluid was collected for 3 days. The concentration of typical acute phase cytokines was evaluated by ELISA assay. Of the three tested cytokines, IL-1beta was the only detected cytokine along the study timeframe. IL-1beta concentration rose in both the treated and non treated shockwave groups on the first day, however it was statistically significantly higher in the treated group on day 2. On day 3, IL-1beta concentrations in both groups decreased and reached a lower level in the treated group, revealing a statistically significant difference than its level on the previous day. The application of ESWT during orthodontic force induction enhances IL-1beta production as part of mechanical forces transduction triggering a biologic response, which may contribute to accelerated periodontal remodeling and therefore foreshortening the orthodontic tooth movement period.

Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior.

Epitranscriptomic mechanisms linking tRNA function and the brain proteome to cognition and complex behaviors are not well described. Here, we report bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of Nsun2 in the mouse prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a decrease in tRNA m5C levels, resulting in deficits in expression of 70% of tRNAGly isodecoders. Altogether, 1488/5820 proteins changed upon neuronal Nsun2-deficiency, in conjunction with glycine codon-specific defects in translational efficiencies. Loss of Gly-rich proteins critical for glutamatergic neurotransmission was associated with impaired synaptic signaling at PFC pyramidal neurons and defective contextual fear memory. Changes in the neuronal translatome were also associated with a 146% increase in glycine biosynthesis. These findings highlight the methylation sensitivity of glycinergic tRNAs in the adult PFC. Furthermore, they link synaptic plasticity and complex behaviors to epitranscriptomic modifications of cognate tRNAs and the proteomic homeostasis associated with specific amino acids.

Lymphotoxin-alpha (LTalpha) supports development of splenic follicular structure that is required for IgG responses.

LTalpha-deficient (LTalpha-/-) mice show altered splenic microarchitecture. This includes loss of normal B cell-T cell compartmentalization, of follicular dendritic cell (FDC) clusters, and of ability to form germinal centers (GC). LTalpha-/- mice immunized with sheep red blood cells (SRBC) produced high levels of antigen-specific IgM but no IgG in either primary or secondary responses, demonstrating failure of Ig class switching. This inability to switch to IgG could have been due to the altered splenic microarchitecture in these mice. Alternatively, it could have been due directly to a requirement for LTalpha expression by lymphocytes cooperating in the antibody response. To investigate this, we performed reciprocal spleen cell transfers. When irradiated LTalpha-/- mice were reconstituted with wild-type splenocytes and immunized immediately with SRBC, splenic microarchitecture remained disturbed and there was no IgG response. In contrast, when irradiated wild-type animals received splenocytes from LTalpha-/- mice, follicle structure and a strong IgG response were retained. These data indicate that LTalpha-deficient B cells and T cells have no intrinsic defect in ability to generate an IgG response. Rather, the altered microenvironment characteristic of LTalpha-/- mice appears to result in impaired ability to switch to a productive IgG response. To investigate whether prolonged expression of LTalpha could alter the structure and function of spleen follicles, reciprocal bone marrow (BM) transplantation was performed. Six weeks after reconstitution of LTalpha-/- mice with wild-type BM, spleen follicle structure was partially restored, with return of FDC clusters and GC. B cell/T cell compartmentalization remained abnormal and white pulp zones were small. This was accompanied by restoration of IgG response to SRBC. Reconstitution of wild-type mice with LTalpha-/- BM resulted in loss of FDC clusters and GC, and loss of the IgG response, although compartmentalized B cell and T cell zones were largely retained. Thus, defective IgG production is not absolutely associated with abnormal B cell and T cell compartmentalization. Rather, expression of LTalpha supports the maturation of spleen follicle structure, including the development and maintenance of FDC clusters, which supports Ig class switching and an effective IgG response.

Distinct receptor and regulatory properties of recombinant mouse complement receptor 1 (CR1) and Crry, the two genetic homologues of human CR1.

The relationship between the characterized mouse regulators of complement activation (RCA) genes and the 190-kD mouse complement receptor 1 (MCR1), 155-kD mouse complement receptor 2 (MCR2), and mouse p65 is unclear. One mouse RCA gene, designated MCR2 (or Cr2), encodes alternatively spliced 21 and 15 short consensus repeat (SCR)-containing transcripts that crosshybridize with cDNAs of both human CR2 and CR1, or CR2 alone, respectively. A five SCR-containing transcript derived from a second unique gene, designated Crry, also crosshybridizes with human CR1. We have previously shown that the 155-kD MCR2 is encoded by the 15 SCR-containing transcript. To analyze the protein products of the other transcripts, which are considered the genetic homologues of human CR1, we have expressed the 21 and the 5 SCR-containing cDNAs in the human K562 erythroleukemia cell line. We demonstrate that cells expressing the 21 SCR transcript express the 190-kD MCR1 protein. These cells react with five unique rat anti-MCR1 monoclonal antibodies, including the 8C12 antibody considered to be monospecific for MCR1. In addition, these cells efficiently form rosettes with mouse C3b-bearing sheep erythrocytes. In contrast, cells expressing the five SCR-containing Crry transcript are strongly recognized by an anti-human CR1 antibody that also defines the mouse p65 protein. Using a functional assay that measures the surface deposition of C3 activated via the classical complement pathway, we show that Crry/p65-expressing cells have a markedly decreased amount of C3 deposited on them as compared with control cells expressing the antisense construct or cells expressing MCR1 or MCR2. This suggests that Crry has intrinsic complement regulatory activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Distinct roles of lymphotoxin alpha and the type I tumor necrosis factor (TNF) receptor in the establishment of follicular dendritic cells from non-bone marrow-derived cells.

In mice deficient in either lymphotoxin alpha (LT-alpha) or type I tumor necrosis factor receptor (TNFR-I), organized clusters of follicular dendritic cells (FDC) and germinal centers (GC) are absent from the spleen. We investigated the role of LT-alpha and TNFR-I in the establishment of spleen FDC and GC structure by using reciprocal bone marrow (BM) transfer. When LT-alpha-deficient mice were reconstituted with wild-type BM, FDC organization and the ability to form GC were restored, indicating that the LT-alpha-expressing cells required to establish organized FDC are derived from BM. The role of LT-alpha in establishing organized FDC structure was further investigated by the transfer of complement receptor 1 and 2 (CR1/2)-deficient BM cells into LT-alpha-deficient mice. Organized FDC were identified with both the FDC-M1 and anti-CR1 monoclonal antibodies in these BM-chimeric mice, indicating that these cells were derived from the LT-alpha-deficient recipient. Thus, expression of LT-alpha in the BM-derived cells, but not in the non-BM-derived cells, is required for the maturation of FDC from non-BM precursor cells. In contrast, when TNFR-I-deficient mice were reconstituted with wild-type BM, they showed no detectable FDC clusters or GC formation. This indicates that TNFR-I expression on non-BM-derived cellular components is necessary for the establishment of these lymphoid structures. TNFR-I-deficient BM was able to restore FDC organization and GC formation in LT-alpha-deficient mice, indicating that formation of these structures does not require TNFR-I expression on BM-derived cells. The data in this study demonstrate that FDC organization and GC formation are controlled by both LT-alpha-expressing BM-derived cells and by TNFR-I-expressing non-BM-derived cells.

Mouse complement regulatory protein Crry/p65 uses the specific mechanisms of both human decay-accelerating factor and membrane cofactor protein.

Normal host cells are protected from the destructive action of complement by cell surface complement regulatory proteins. In humans, decay-accelerating factor (DAF) and membrane cofactor protein (MCP) play such a biologic role by inhibiting C3 and C5 convertases. DAF and MCP accomplish this task by specific mechanisms designated decay-accelerating activity and factor I cofactor activity, respectively. In other species, including mice, structural and/or functional homologues of these proteins are not yet well characterized. Previous studies have shown that the mouse protein Crry/p65 has certain characteristics of self-protecting complement regulatory proteins. For example, Crry/p65 is expressed on a wide variety of murine cells, and when expressed on human K562 erythroleukemic cells, it prevents deposition of mouse C3 fragments on the cell surface during activation of either the classical or alternative complement pathway. We have now studied factor I cofactor and decay-accelerating activities of Crry/p65. Recombinant Crry/p65 demonstrates cofactor activity for factor I-mediated cleavage of both mouse C3b and C4b. Surprisingly, Crry/p65 also exhibits decay-accelerating activity for the classical pathway C3 convertase strongly and for the alternative pathway C3 convertase weakly. Therefore, mouse Crry/p65 uses the specific mechanisms of both human MCP and DAF. Although Crry/p65, like MCP and DAF, contains tandem short consensus repeats (SCR) characteristic of C3/C4 binding proteins, Crry/p65 is not considered to be a genetic homologue of either MCP or DAF. Thus, Crry/p65 is an example of evolutionary conservation of two specific activities in a single unique protein in one species that are dispersed to individual proteins in another. We propose that the repeating SCR motif in this family has allowed this unusual process of evolution to occur, perhaps driven by the use of MCP and DAF as receptors by human pathogens such as the measles virus.

A critical role for murine complement regulator crry in fetomaternal tolerance.

Complement is a component of natural immunity. Its regulation is needed to protect tissues from inflammation, but mice with a disrupted gene for the complement regulator decay accelerating factor were normal. Mice that were deficient in another murine complement regulator, Crry, were generated to investigate its role in vivo. Survival of Crry-/- embryos was compromised because of complement deposition and concomitant placenta inflammation. Complement activation at the fetomaternal interface caused the fetal loss because breeding to C3-/- mice rescued Crry-/- mice from lethality. Thus, the regulation of complement is critical in fetal control of maternal processes that mediate tissue damage.

Disability impact on quality of life in Mexican adults with juvenile idiopathic arthritis and juvenile ankylosing spondylitis.

OBJECTIVE: Our aim was to determine the disability impact on quality of life (QOL) in Mexican adults with juvenile idiopathic arthritis polyarticular course (JIAPA) and juvenile ankylosing spondylitis (JAS). METHODS: A cross-sectional study was performed on 32 adult patients with juvenile idiopathic arthritis. Functional outcome was evaluated using Global Functional Status (GFS) according to American College of Rheumatology (ACR) and Spanish Health Assessment Questionnaire-Disability Index (HAQ-DI) arthritis-specific measurements for functional disability in patients with polyarticular course and Bath Ankylosing Spondylitis Functional Index (BASFI) for those who developed JAS. Quality of life (QOL) was assessed using SF-36 and EuroQol 5D (EQ-5D). Descriptive statistics and associations among clinical, functional, and QOL measurements were examined using Spearman's correlation test. Multiple regression analysis was used to estimate predictor factors for impaired QOL. Differences between groups were evaluated by Fisher exact and Mann-Whitney U tests, and p values of <0.05 were considered statistically significant. RESULTS: JIAPA and JAS had GFS III/IV in 65 and 50%, respectively. A HAQ-DI score of > 1.5 was found in 35% of JIAPA, and a BASFI score of > 5 in 92% of JAS. Patients with JIAPA and JAS reported lower scores for all physical domains and for mental domains (physical role, social functioning, and emotional role) compared with Mexican population scores (p < 0.005). Health status between both groups studied does not show significant differences (p > 0.05). EQ-5D showed impairment in all five dimensions for both groups studied. Multiple regression analysis showed that GFS was the only variable that affects QOL assessed by SF36. CONCLUSIONS: In our study population, JIAPA and JAS exhibited a great disability impact on QOL and poor functional outcome during the patients' adult life. GFS has a significant impact on quality of life.

The combination of atorvastatin and ethanol is not more hepatotoxic to rats than the administration of each drug alone.

Animal studies and premarketing clinical trials have revealed hepatotoxicity of statins, primarily minor elevations in serum alanine aminotransferase levels. The combined chronic use of medicines and eventual ethanol abuse are common and may present a synergistic action regarding liver injury. Our objective was to study the effect of the chronic use of atorvastatin associated with acute ethanol administration on the liver in a rat model. One group of rats was treated daily for 5 days a week for 2 months with 0.8 mg/kg atorvastatin by gavage. At the end of the treatment the livers were perfused with 72 mM ethanol for 60 min. Control groups (at least 4 animals in each group) consisted of a group of 2-month-old male Wistar EPM-1 rats exposed to 10% ethanol (v/v) ad libitum replacing water for 2 months, followed by perfusion of the liver with 61 nM atorvastatin for 60 min, and a group of animals without chronic ethanol treatment whose livers were perfused with atorvastatin and/or ethanol. The combination of atorvastatin with ethanol did not increase the release of injury marker enzymes (alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase) from the liver and no change in liver function markers (bromosulfophthalein clearance, and oxygen consumption) was observed. Our results suggest that the combination of atorvastatin with ethanol is not more hepatotoxic than the separate use of each substance.