Periodontitis and alveolar resorption in human skeletal remains: The relationship between quantitative alveolar bone loss, occlusal wear, antemortem tooth loss, dental calculus and age at death in a low socioeconomic status, modern forensic human collection from Yucatan.

OBJECTIVE: This paper assesses the relationship between the distance between the cemento-enamel junction and alveolar crest and risk factors commonly associated with periodontitis. MATERIALS: Eighty individuals between 28 and 92 years old with known biological sex and age were analyzed from a 20th century forensic human collection from Merida, Yucatan (Mexico). METHODS: Macroscopic assessment, along with metric analysis, was employed using a probe. RESULTS: Ante-mortem tooth loss was positively correlated with the distance between the cemento-enamel junction and alveolar crest, as was the presence of root calculus in females. CONCLUSIONS: Cemento-enamel junction to alveolar crest distance is not a reliable indicator of periodontitis since it is not directly related to periodontitis-causing infectious pathogens, and since ante-mortem tooth loss can affect root exposure. SIGNIFICANCE: This study demonstrates that a purely quantitative approach to diagnosing periodontitis in archaeological and forensic human remains can be misleading. LIMITATIONS: The skeletal collection is only representative of the low socioeconomic class of Merida, and its female cohort is underrepresented. In addition, because the Xoclan collection is modern, limitations (particularly with respect to tooth wear) of the applicability of these interpretations to older archaeological remains exist. SUGGESTION FOR FURTHER RESEARCH: A combination of quantitative and qualitative characteristics of alveolar bone is needed to reliably diagnose periodontitis in skeletal populations.

Reduced induction of human ß-defensins is involved in the pathological mechanism of cutaneous adverse effects caused by epidermal growth factor receptor monoclonal antibodies.

Epidermal growth factor receptor inhibitors (EGFRIs) frequently cause cutaneous adverse effects such as papulopustular eruptions. However, the mechanism of the reactions remains unclear. To assess the pathological mechanism of cutaneous adverse reactions caused by EGFRIs, we investigated whether EGFRIs have an influence on the innate immune response of the skin. Levels of human ß-defensins (hBDs), which serve as the first line of defence against infection by pathogenic microorganisms, in the stratum corneum samples of patients treated with EGFR. monoclonal antibodies were measured before and after starting therapy. There were no obvious trends in hBD production in patients without eruptions, whereas a significant decrease in hBD1 and hBD3 production and a nonsignficant decrease in hBD2 production were observed in patients who developed papulopustular eruptions. Our results suggest that a reduction in hBD contributes to the increased incidence of papulopustular eruptions.

Anatomy of the smooth muscle structure in the female anorectal anterior wall: convergence and anterior extension of the internal anal sphincter and longitudinal muscle.

AIM: The anatomy of the region between the vagina and anal canal plays an essential role when performing a proctectomy for low-lying tumours. However, the anatomical characteristics of this area remain unclear. The purpose of the present study was to clarify the configuration, and both lateral and inferior extensions, of the muscle bundles in the anorectal anterior wall in females. METHODS: Using cadaveric specimens, macroscopic anatomical and histological evaluations were conducted at the anatomy department of our institute. Macroscopic anatomical specimens were obtained from six female cadavers. Histological specimens were obtained from eight female cadavers. RESULTS: The smooth muscle fibres of the internal anal sphincter and longitudinal muscle extended anteriorly in the anorectal anterior wall of females and the muscle bundles showed a convergent structure. The anterior extending smooth muscle fibres merged into the vaginal smooth muscle layer, distributed subcutaneously in the vaginal vestibule and perineum and spread to cover the anterior surface of the external anal sphincter and the levator ani muscle. Relatively sparse space was observed in the region anterolateral to the rectum on histological analysis. CONCLUSION: Smooth muscle fibres of the rectum and vagina are intermingled in the median plane, and there is relatively sparse space in the region anterolateral to the rectum. Therefore, when detaching the anorectal canal from the vagina during proctectomy, an approach from both the lateral sides should be used.

Effects of Leukoreduction and Storage on Erythrocyte Phosphatidylserine Expression and Eicosanoid Concentrations in Units of Canine Packed Red Blood Cells.

BACKGROUND: Storage of canine packed red blood cells (pRBCs) can increase erythrocyte phosphatidylserine (PS) expression and eicosanoid concentrations. HYPOTHESIS/OBJECTIVES: To determine the effects of leukoreduction on erythrocyte PS expression and eicosanoid concentrations in stored units of canine pRBCs. Our hypothesis was that leukoreduction would decrease PS expression and eicosanoid concentrations. ANIMALS: Eight healthy dogs. METHODS: In a cross-over study, units of whole blood were leukoreduced (LR) or non-LR and stored (10 and 21 days) as pRBCs. Samples were collected at donation, and before and after a simulated transfusion. PS expression was measured by flow cytometry, and concentrations of arachidonic acid (AA), prostaglandin F2α (PGF2α ), prostaglandin E2 (PGE2 ), prostaglandin D2 (PGD2 ), thromboxane B2 (TXB2 ), 6-keto-prostaglandin F1α (6-keto-PGF1α ), and leukotriene B4 (LTB4 ) were quantified by liquid chromatography-mass spectrometry. RESULTS: There was no change in PS expression during leukoreduction, storage, and simulated transfusion for non-LR and LR units. Immediately after leukoreduction, there was a significant increase in TXB2 and PGF2α concentrations, but during storage, these eicosanoids decreased to non-LR concentrations. In both LR and non-LR units, 6-keto-PGF1α concentrations increased during storage and simulated transfusion, but there was no difference between unit type. There was no difference in AA, LTB4 , PGE2 , and PGD2 concentrations between unit types. CONCLUSIONS AND CLINICAL IMPORTANCE: Leukoreduction, storage, and simulated transfusion do not alter erythrocyte PS expression. Leukoreduction causes an immediate increase in concentrations of TXB2 and PGF2α , but concentrations decrease to non-LR concentrations with storage. Leukoreduction does not decrease the accumulation of 6-keto-PGF1α during storage.

Mouth breathing, another risk factor for asthma: the Nagahama Study.

BACKGROUND: Allergic rhinitis, a known risk factor for asthma onset, often accompanies mouth breathing. Mouth breathing may bypass the protective function of the nose and is anecdotally considered to increase asthma morbidity. However, there is no epidemiological evidence that mouth breathing is independently associated with asthma morbidity and sensitization to allergens. In this study, we aimed to clarify the association between mouth breathing and asthma morbidity and allergic/eosinophilic inflammation, while considering the effect of allergic rhinitis. METHODS: This community-based cohort study, the Nagahama Study, contained a self-reporting questionnaire on mouth breathing and medical history, blood tests, and pulmonary function testing. We enrolled 9804 general citizens of Nagahama City in the Shiga Prefecture, Japan. RESULTS: Mouth breathing was reported by 17% of the population and was independently associated with asthma morbidity. The odds ratio for asthma morbidity was 1.85 (95% CI, 1.27-2.62) and 2.20 (95% CI, 1.72-2.80) in subjects with mouth breathing alone and allergic rhinitis alone, which additively increased to 4.09 (95% CI, 3.01-5.52) when mouth breathing and allergic rhinitis coexisted. Mouth breathing in nonasthmatics was a risk for house dust mite sensitization, higher blood eosinophil counts, and lower pulmonary function after adjusting for allergic rhinitis. CONCLUSION: Mouth breathing may increase asthma morbidity, potentially through increased sensitization to inhaled allergens, which highlights the risk of mouth-bypass breathing in the 'one airway, one disease' concept. The risk of mouth breathing should be well recognized in subjects with allergic rhinitis and in the general population.

Smoking attenuates the age-related decrease in IgE levels and maintains eosinophilic inflammation.

BACKGROUND: Epidemiological studies have shown that smoking increases the propensity for atopy and asthma. However, the effects of smoking on atopy and eosinophilic inflammation in asthmatics, including the elderly, remain unknown. OBJECTIVE: To determine the effects of smoking on serum immunoglobulin E (IgE) levels and eosinophilic inflammation in asthmatics of all ages. METHODS: The associations of serum IgE levels, blood eosinophil counts and fractional exhaled nitric oxide (FeNO) levels with smoking and age in steroid-naive asthmatics were cross-sectionally assessed (n = 307). Levels of sputum eosinophil and thymic stromal lymphopoietin (TSLP) that promotes Th2 inflammation were also analysed. Current smokers were excluded when analysing contributing factors of FeNO. RESULTS: Levels of serum IgE, blood eosinophil and FeNO decreased with increasing age in never-smokers, whereas decrease in serum IgE levels with increasing age was not observed in current smokers. In addition, current smoking was associated with higher blood eosinophil counts. In atopic asthmatics, age-related declines in serum IgE levels were less steep in ex-smokers than in never-smokers, and atopic ex-smokers with asthma showed higher blood eosinophil counts and higher FeNO irrespective of age. Lastly, sputum TSLP levels were associated with sputum eosinophil proportions and pack-years. Current and ex-smokers had higher TSLP levels than never-smokers. CONCLUSIONS AND CLINICAL RELEVANCE: In steroid-naive asthmatics, smoking may attenuate the age-related decrease in IgE levels and maintain eosinophilic inflammation, in which TSLP may be involved.

Predictors of 5-year mortality in pulmonary Mycobacterium avium-intracellulare complex disease.

SETTING: Kyoto, Japan. OBJECTIVE: To determine predictors of 5-year mortality in pulmonary Mycobacterium avium-intracellulare complex (MAC) disease. DESIGN: Retrospective study of 164 patients diagnosed with pulmonary MAC disease between 1999 and 2005 and followed for 5 years. RESULTS: Overall 5-year mortality was 28.0%. Among 117 patients with microbiological outcomes, 54 were treated (treated MAC patients) and 24 were not treated and did not experience sputum culture conversion during follow-up (untreated chronic MAC patients); 39 patients were not treated and experienced sputum culture conversion. Five-year all-cause overall mortality among the 78 patients with definite MAC disease (including treated and untreated chronic MAC patients) was 25.6%. The mortality rate was 33.3% for untreated chronic MAC patients only vs. 22.2% for treated MAC patients (P = 0.30). After adjustment for clinical, microbiological and radiological confounders, independent factors for 5-year mortality were a high Charlson comorbidity index in cases with definite MAC disease (hazard ratio [HR] 1.76) and untreated chronic MAC (HR 3.08), and presence of cavitary lesions in cases with definite MAC disease (HR 1.82) and treated MAC patients (HR 3.91). CONCLUSION: Patients with cavitary lesions require immediate treatment for sputum culture conversion and to improve their chances of survival.

Body mass index in male patients with COPD: correlation with low attenuation areas on CT.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by the presence of airflow limitation caused by loss of lung elasticity and/or airway narrowing. The pathological hallmark of loss of lung elasticity is emphysema, and airway wall remodelling contributes to the airway narrowing. Using CT, these lesions can be assessed by measuring low attenuation areas (LAA) and airway wall thickness/luminal area, respectively. As previously reported, COPD can be divided into airway dominant, emphysema dominant and mixed phenotypes using CT. In this study, it is postulated that a patient's physique may be associated with the relative contribution of these lesions to airflow obstruction. METHODS: CT was used to evaluate emphysema and airway dimensions in 201 patients with COPD. Emphysema was evaluated using percentage of LAA voxels (LAA%) and airway lesion was estimated by percentage wall area (WA%). Patients were divided into four phenotypes using LAA% and WA%. RESULTS: Body mass index (BMI) was significantly lower in the higher LAA% phenotype (ie, emphysema dominant and mixed phenotypes). BMI correlated with LAA% (rho = -0.557, p<0.0001) but not with WA%. BMI was significantly lower in the emphysema dominant phenotype than in the airway dominant phenotype, while there was no difference in forced expiratory volume in 1 s %predicted between the two. CONCLUSION: A low BMI is associated with the presence of emphysema, but not with airway wall thickening, in male smokers who have COPD. These results support the concept of different COPD phenotypes and suggest that there may be different systemic manifestations of these phenotypes.

Impact of gastro-oesophageal reflux disease symptoms on COPD exacerbation.

BACKGROUND: The association between gastro-oesophageal reflux disease (GORD) and chronic obstructive pulmonary disease (COPD) exacerbation has so far remained unclear. OBJECTIVE: To prospectively establish the clinical significance of GORD symptoms on exacerbation. METHODS: 82 patients with COPD and 40 age matched controls were enrolled in this study. Symptoms were evaluated by a questionnaire using the Frequency Scale for the Symptoms of GORD (FSSG). Patients with COPD were prospectively surveyed for 6 months, and episodes of exacerbation were identified using a diary based on modified Anthonisen's criteria. Exhaled breath condensate (EBC) pH was measured in both groups, and induced sputum was evaluated in patients with COPD. RESULTS: Positive GORD symptoms were reported in 22 (26.8%) patients with COPD and in five (12.5%) controls (p = 0.10). The frequency of exacerbations was significantly associated with the FSSG score (p = 0.03, r = 0.24, 95% CI 0.02 to 0.43). Multiple regression analysis revealed that GORD symptoms were significantly associated with the occurrence of exacerbations (p<0.01; relative risk 6.55, 95% CI 1.86 to 23.11). EBC pH was inversely correlated with FSSG score in both groups (p = 0.01, r = -0.37, 95% CI -0.55 to -0.14 in patients with COPD, and p<0.01, r = -0.45, 95% CI -0.67 to -0.16 in control subjects). CONCLUSIONS: GORD symptoms were identified as an important factor associated with COPD exacerbation.

[Bilateral central serous chorioretinopathy with subretinal exudation]. / Coriorretinopatía serosa central con exudados subretinianos bilaterales.

CLINICAL CASE: A 37-year-old man was referred because of a bilateral loss of visual acuity and metamorphopsia. On examination there was yellowish exudation bilaterally associated with serous retinal detachments, corresponding to hyperfluorescence spots in the early stage of fluorescein angiography. Photocoagulation of the leakage spots was performed in both eyes. Six months later he had recovered his visual acuity and the lesions had remitted. DISCUSSION: The clinical findings, ancillary tests and subsequent clinical course allowed a diagnosis of Best's disease to be ruled out. The presence of sub-retinal yellowish exudation in the posterior pole does not necessarily rule out the diagnosis of central serous chorioretinopathy.

Coriorretinopatía serosa central con exudados subretinianos bilaterales / Bilateral central serous chorioretinopathy with subretinal exudation

Caso clínico: Varón de 37 años con disminución de agudeza visual bilateral y metamorfopsia. Presenta exudados subretinianos bilaterales amarillentos con levantamiento neurosensorial en el polo posterior, que en la angiografía se corresponden con puntos hiperfluorescentes en fases precoces. Tratado con fotocoagulación de los puntos de fuga, a los 6 meses recuperó su agudeza visual con una remisión prácticamente completa de las lesiones. Discusión: La exploración clínica, las pruebas complementarias y la evolución del cuadro nos permiten descartar el diagnóstico de enfermedad de Best. La presencia de exudados subretinianos amarillentos no nos debe hacer desechar de entrada el diagnóstico de coriorretinopatía serosa central (AU)

Clinical case: A 37-year-old man was referred because of a bilateral loss of visual acuity and metamorphopsia. On examination there was yellowish exudation bilaterally associated with serous retinal detachments, corresponding to hyperfluorescence spots in the early stage of fluorescein angiography. Photocoagulation of the leakage spots was performed in both eyes. Six months later he had recovered his visual acuity and the lesions had remitted. Discussion: The clinical findings, ancillary tests and subsequent clinical course allowed a diagnosis of Best's disease to be ruled out. The presence of sub-retinal yellowish exudation in the posterior pole does not necessarily rule out the diagnosis of central serous chorioretinopathy (AU)

High sensitivity C-reactive protein in asthma.

Asthma is characterised by chronic inflammation of the airways, but the relevance of high-sensitivity assays for C-reactive protein (hs-CRP), which are known to be a sensitive marker of low-grade systemic inflammation, has not been fully studied in asthma. The objective was to examine serum hs-CRP levels in patients with asthma and their relationship to clinical characteristics and degree of airway inflammation. Serum hs-CRP levels were cross-sectionally examined in steroid-naive (n = 22) and steroid-inhaling (n = 23) adult patients with asthma and healthy controls (n = 14). All were nonsmokers. Serum hs-CRP levels were significantly increased in steroid-naive patients (mean+/-sd 1.33+/-1.48 mg.L(-1)) compared with controls (0.21+/-0.30 mg.L(-1)), but not in patients on inhaled corticosteroid. Among steroid-naive patients, serum hs-CRP levels significantly negatively correlated with indices of pulmonary function (forced expiratory volume in one second/forced vital capacity and forced mid-expiratory flow) and positively with sputum eosinophil count. Among patients on inhaled corticosteroid, hs-CRP levels did not correlate with any indices. In conclusion, an increase in serum C-reactive protein levels measured by high-sensitivity assays may be associated with airflow obstruction and airway inflammation, and may serve as a surrogate marker of airway inflammation in asthma.

Retraso del crecimiento intrauterino y enfermedad celiaca: ¿relación y características clínicas? / Intrauterine growth retardation and celiac disease: a coincidence or a casual relationship?

La enfermedad celiaca constituye una enfermedad autoinmune de gran relevancia en la edad pediátrica y, aunque se desconoce como se pone en marcha su desarrollo en pacientes geneticamente predispuestos, se postula que, entre otros, los factores fetales podrían tener influencia sobre el desarrollo posterior de esta enfermedad. Presentamos el caso de una niña con retraso del crecimiento intrauterino cuya madre sufrió una infección vírica durante la gestación, y que más tarde desarrolló enfermed celiaca. Especulamos con la posibilidad de que la infección viral durante la gestación pudiera haber sido la causante del retraso del crecimiento intrauterino y del desarrollo de la enfermedad celiaca. La similitud existente entre los antígenos víricos y la gliadina explicarían que una exposición intraútero a dichos antígenos virales sensibilizara fentre a la gliadina. Y posteriormente la, exposición al gluten a, partir de su introducción en la dieta, pondría en marcha el resto de los mecanismos de la enfermedad

Celiac disease is an autoimmune disease that has important consequences during childhood. Although the factors that trigger its development in genetically predisposed patients are unknown, it is thought that fetal factors, among others, could play a role in the later development of the disease. We report the case of a girl who presented intrauterine growth retardation and was later diagnosed as having celiac disease. Her mother had had a viral infection during pregnancy and we speculate that this circumstance could have caused both the intrauterine growth retardation and the development of celiac disease. The similarity between viral antigens and gliadin could explain why intrauterine exposure to those antigens would produce sensitization to gliadin and, thus, a later exposure to gluten, when introduced in to the diet, would trigger the mechanisms of the disease

Targeting of antioxidant and anti-thrombotic drugs to endothelial cell adhesion molecules.

The endothelium represents an important therapeutic target for containment of oxidative stress, thrombosis and inflammation involved in a plethora of acute and chronic conditions including cardiovascular and pulmonary diseases and diabetes. However, rapid blood clearance and lack of affinity to the endothelium compromise delivery to target and restrict medical utility of antioxidant enzymes (e.g., catalase) and fibrinolytics. The use of "stealth" PEG-liposomes prolongs circulation, whereas conjugation with antibodies to endothelial determinants permits targeting. Constitutive endothelial cell adhesion molecules (CAM, such as ICAM-1 and PECAM-1, which are stably expressed and functionally involved in oxidative stress and thrombosis) are candidate determinants for targeting of antioxidants and fibrinolytics. CAM antibodies and compounds conjugated with anti-CAM bind to endothelial cells and accumulate in vascularized organs (preferentially, lungs). Pathological stimuli enhance ICAM-1 expression in endothelial cells and facilitate targeting, whereas PECAM-1 expression and targeting are stable. Endothelial cells internalize 100-300 nm diameter conjugates possessing multiple copies of anti-CAM, but not monomolecular antibodies or micron conjugates. This permits size-controlled sub-cellular targeting of antioxidants into the endothelial interior and fibrinolytics to the endothelial surface. Targeting catalase to PECAM-1 or ICAM-1 protects endothelial cells against injury by oxidants in culture and alleviates vascular oxidative stress in lungs in animals. Anti-CAM/catalase conjugates are active for a few hours prior to lysosomal degradation, which can be delayed by auxiliary drugs. Conjugation of fibrinolytics to monovalent anti-ICAM permits targeting and prolonged retention on the endothelial surface. Therefore, CAM targeting of antioxidants and fibrinolytics might help to contain oxidative and thrombotic stresses, with benefits of blocking CAM. Avenues for improvement and translation of this concept into the clinical domain are discussed.

Relationship of airway wall thickening to an imbalance between matrix metalloproteinase-9 and its inhibitor in asthma.

BACKGROUND: The balance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) may be critical in extracellular matrix remodelling, a characteristic of asthmatic airways. An excess of TIMP-1 over MMP-9 has been associated with chronic airflow obstruction but the mechanisms underlying this association remain unknown. Recent computed tomographic (CT) studies indicate that airway wall thickening is associated with chronic airflow obstruction. METHODS: Sputum levels of MMP-9, TIMP-1, and their molar ratio were examined in 26 patients with stable asthma and their relationship with pulmonary function and airway wall thickness, assessed by a validated CT technique which measured wall area corrected by body surface area (WA/BSA), the ratio of WA to outer wall area (WA%), and the absolute wall thickness corrected by radicalBSA of a segmental bronchus (T/ radicalBSA), was examined. RESULTS: Sputum MMP-9 levels were inversely correlated with WA% and TIMP-1 levels were positively correlated with WA/BSA and T/ radicalBSA. The MMP-9/TIMP-1 molar ratio was inversely correlated with WA% and T/ radicalBSA and positively correlated with post-bronchodilator values of mid-forced expiratory flow and maximum expiratory flow at the quartile of lung volume. CONCLUSION: Excess TIMP-1 may have a pathogenetic role in airway wall thickening in asthmatic patients which may result in chronic airflow obstruction.

Miocardiopatía dilatada neonatal: a propósito de un caso / Neonatal dilated cardiomyopathy: a case report

Se comunica un nuevo caso de miocardiopatía dilatada neonatal en una recién nacida que, a las pocas horas del parto, comenzó con un cuadro de insuficiencia cardiaca congestiva (ICC) con tendencia al colapso cardiovascular. Las ecocardiografías 2D y Doppler demostraron una función del ventrículo izquierdo muy deprimida, con una fracción de acortamiento del 12 por ciento y una fracción de eyección del 27 por ciento. No se pudo determinar la etiología de la alteración, aunque no se descartó una base génica o familiar. La paciente, que reunía criterios de mal pronóstico evolutivo, se mantuvo con digoxina, furosemida, ácido acetilsalicílico (AIS) y enalapril en una situación de ICC crónica, falleciendo a los tres meses de vida a la espera de un trasplante cardiaco. En el presente trabajo se revisan aspectos de interés de esta afección (AU)

Síndrome de megavejiga-microcolon-hipoperistaltismo intestinal. A propósito de un caso de supervivencia prolongada / Megacystis-microcolon-intestinal hypoperistalsis syndrome: a propos of a case of prolonged survival

El síndrome de megavejiga-microcolon-hipoperistaltismo intestinal (MMIHS) es un trastorno multisistémico con alteración de la motilidad intestinal que origina síntomas recurrentes de obstrucción intestinal en ausencia de oclusión mecánica, asociada a vejiga distendida sin obstrucción distal del tracto urinario. Es un trastorno poco frecuente con una alta morbilidad y mortalidad, y pueden precisar nutrición parenteral durante largos períodos de tiempo. Se presenta el caso de una paciente que en la actualidad cuenta 18 años de edad controlada por nuestro servicio desde el nacimiento y que tras seguir diversos tratamientos médicos, quirúrgicos y soporte nutricional adecuado presenta buena tolerancia oral y buena calidad de vida, habiendo precisado únicamente nutrición parenteral durante los períodos de descompensación (AU)

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Pubertad precoz en niñas adoptadas de países en vías de desarrollo / Early puberty in girls adopted from developing countries

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[Megacystis-microcolon-intestinal hypoperistalsis syndrome: a case of prolonged survival]. / Síndrome de megavejiga-microcolon-hipoperistaltismo intestinal. A propósito de un caso de supervivencia prolongada.

Megacystis-microcolon-intestinal hypoperistalsis syndrome is a multisystemic disorder in which impaired intestinal motor activity causes recurrent symptoms of intestinal obstruction in the absence of mechanical occlusion, associated with bladder distention without distal obstruction of the urinary tract. It is an uncommon disorder with high morbidity and mortality, and long-term total parenteral nutrition may be required. We describe an 18-year-old girl with long-term survival, followed-up by our service since birth. With medical, surgical and nutritional management she currently presents a good oral tolerance and good quality of life, only requiring parenteral nutrition during periods of decompensation.