Modeling future cliff-front waves during sea level rise and implications for coastal cliff retreat rates.

It is often assumed that future coastal cliff retreat rates will accelerate as global sea level rises, but few studies have investigated how SLR (sea level rise) might change cliff-front wave dynamics. Using a new simple numerical model, this study simulates the number and type (breaking, broken, or unbroken) of cliff-front waves under future SLR scenarios. Previous research shows breaking waves deliver more energy to cliffs than broken waves, and unbroken waves generate minimal impact. Here, we investigated six cliff-platform profiles from three regions (USA, New Zealand, and UK) with varied tidal ranges and wave climates. Model inputs included 2013-2100 hindcast/forecast incident wave height and tidal water level, and three future SLR scenarios. Results show the number of both cliff-front breaking and broken waves generally increase for a high-elevation (relative to tide) cliff-platform junction. In contrast, breaking/broken wave occurrence decrease by 38-92% for a near-horizontal shore platform with a low-elevation cliff-platform junction under a high SRL scenario, leading to high (96-97%) unbroken wave occurrence. Overall, results suggest the response of cliff-front waves to future SLR is complex and depends on shore platform geometries and SLR scenarios, indicating that future cliff retreat rates may not homogeneously accelerate under SLR.

Relationships between dietary diversity and gut microbial diversity in the elderly.

Diet is considered as a major driver of gut microbiota composition. However, little is known about the relationship between overall dietary balance and gut microbiota, especially in the elderly. Here, using the Quantitative Index for Dietary Diversity (QUANTIDD), we analysed the relationships between dietary diversity and gut microbiota diversity in 445 Japanese subjects aged 65-90 years. We also examined the effect of age by comparing the young-old group aged 65 to 74 years (<75 years group; n=246) and the old-old group aged 75 years and older (≥75 years group; n=199). QUANTIDD showed significant positive relationships with Pielou's evenness and Shannon indices, two α-diversity indices related to the uniformity of species distribution. This suggests that a more diverse diet is associated with a more uniform abundance of various bacterial groups, rather than a greater variety of gut bacteria. QUANTIDD also showed significant positive associations with the abundance of Anaerostipes, Eubacterium eligens group, and Eubacterium ventriosum group, which produce short-chain fatty acids (SCFAs) and are beneficial to health. Negative association was found with the abundance of Ruminococcus gnavus group, which produces inflammatory polysaccharides. Positive associations between QUANTIDD and α-diversity indices or the abundance of specific bacterial groups were identified among all subjects and in the <75 years group, but not in the ≥75 years group. Our results suggest that dietary diversity contributes to the diversity of the gut microbiota and increases the abundance of SCFAs-producing bacteria, but only up to a certain age. These findings help to understand the complex relationship between diet and gut microbiota, and provide hints for specific dietary interventions to promote beneficial gut microbiota in the elderly.

FRAX score and recent fall history predict the incidence for sarcopenia in community-dwelling older adults: a prospective cohort study.

We hypothesized that the baseline FRAX score and previous falls would predict the incidence of sarcopenia in community-dwelling older adults who received medical check-ups. The FRAX score (hazard ratio [HR] = 1.087, 95% CI 1.014-1.167) and previous falls (HR = 5.181, 95% CI 1.002-26.777) were determined to be independent risk factors for the incidence of sarcopenia. PURPOSE: This prospective study was performed to elucidate the prevalence and incidence of sarcopenia in community-dwelling older adults who received medical check-ups, and to determine whether FRAX score and fall history predict the incidence of sarcopenia. METHODS: Participants were recruited from a group of individuals who had registered for an annual town-sponsored medical check-up. Study inclusion criteria were aged older than 60 years, living independently, and ability to walk without assistance. Individuals who received nursing care were excluded from the study. A total of 426 residential participants were analyzed. Demographic information, fall history of the previous year, and FRAX score without bone mineral density were assessed. The assessment for sarcopenia was based on the recommendations of the Asian Working Group for Sarcopenia. RESULTS: The final sample for the assessment of sarcopenia incidence comprised 258 participants. The mean follow-up time was 2.92 years. The rate of sarcopenia was 1.06 cases per 100 person-years at risk. The Cox multivariate logistic regression model in our analysis was adjusted for age, gender, muscle mass, and covariates and showed that the FRAX score (HR = 1.087, 95% CI 1.014-1.167) and recent history of falls (HR = 5.181, 95% CI 1.002-26.777) were independent risk factors for the incidence of sarcopenia. CONCLUSION: FRAX and history of falling can be a simple screening tool to raise awareness of the prevention of osteoporosis and sarcopenia in clinical settings.

Low damage lamella preparation of metallic materials by FIB processing with low acceleration voltage and a low incident angle Ar ion milling finish.

Metallic materials are known to be very sensitive to Gallium (Ga) focused ion beam (FIB) processing. Crystal defects formed by FIB irradiation degrade the transmission electron microscope image quality, and it is difficult to distinguish original defects from FIB process-induced damage. A solution to this problem is the low acceleration voltage and low incident angle (LVLA) Argon ion milling, which can be incorporated as an extensional countermeasure for FIB damage removal and eventually for preparation of high-quality lamellae. The transmission electron microscope image quality of iron single crystal could be improved by removing crystal defects using the low acceleration voltage and low incident angle Argon ion milling finish. Lamella quality of the processing result was almost similar with that of the conventional electrolytic polishing. As a practical application of the process, low damage lamella of stainless cast steel could be prepared. Effectiveness of the FIB system equipped with the low acceleration voltage and low incident angle Argon ion milling function as a tool to make high-quality metallic material lamellae is illustrated.

Psychosis is an extension of mood swings from the perspective of neuronal plasticity impairments.

We previously hypothesized that depressive and manic states may be consecutive presentations of the same underlying neuronal plasticity, and that moderate impairments in neuronal plasticity cause depressive states while further impairment to neuronal plasticity causes manic states. Psychopathological or biological relationships between bipolar disorder and schizophrenia have also been revealed. Therefore, in addition to depressive and manic states, psychosis may also be considered a manifestation resulting from additional impairments to neuronal plasticity. In the present manuscript, we hypothesize that moderate and more severe impairments to neuronal plasticity cause depressive and manic states, respectively, and that more serious impairments to neuronal plasticity cause psychosis. Many studies have suggested that impairments in neuronal plasticity contribute to schizophrenia and other mental disorders with psychotic features, and that the impairment of neuronal plasticity in schizophrenia is more severe than that in bipolar disorder. Therefore, we hypothesize more specifically that impairments in neuronal plasticity may be more severe in the order of the cases featuring psychosis, mania, and depression. This progression notably overlaps with the arrangement of schizophrenia, bipolar disorder, and depressive disorder in the DSM-5. Psychotic symptoms are thought to appear further towards the base of the psychopathological hierarchy than are manic or depressive symptoms. If impairments to neuronal plasticity contribute to this psychopathological hierarchy, as we contest that they do, our hypothesis may serve as a bridge between clinical psychopathology, diagnosis, and biological psychiatry.

Independent Factors Contributing to Daytime and Nighttime Asthmatic Cough Refractory to Inhaled Corticosteroids.

BACKGROUND: Cough is a common feature of asthma, which is often resistant to inhaled corticosteroids (ICSs). The pathophysiology of this refractoriness may differ between daytime and nighttime asthmatic cough. We sought to identify factors contributing to ICS-refractory daytime and nighttime asthmatic cough. METHODS: Sixty-seven patients with asthma presenting solely or predominantly with chronic cough were prospectively enrolled from April 2012 to December 2014. At baseline and 12 weeks after ICS treatment, the capsaicin cough threshold (C2, C5) and methacholine airway sensitivity and reactivity were examined. A visual analog scale (VAS) and numeric scores were used to evaluate daytime and nighttime cough symptoms separately. The Japanese version of the Leicester Cough Questionnaire was also completed. When either the VAS or numeric scores showed an improvement of ≥50% or ≥2 points, patients were considered responders to ICS treatment. RESULTS: Fifty-five patients were eligible for evaluation. Subjective cough indices improved significantly at 12 weeks after ICS treatment (P<.001). Multivariate analysis revealed that lower C2 significantly contributed to residual daytime cough (P=.04). Meanwhile, methacholine hyperreactivity and lower IgE levels were predictors of the nighttime residual cough (P=.002 and P=.03, respectively). CONCLUSIONS: Heightened cough reflex sensitivity is an independent factor of daytime asthmatic cough that is refractory to ICSs. In contrast, airway hyperreactivity and less atopic status contribute to ICS-refractory nighttime cough.

Independent factors contributing to daytime and nighttime asthmatic cough refractory to inhaled corticosteroids

Background: Cough is a common feature of asthma, which is often resistant to inhaled corticosteroids (ICSs). The pathophysiology of this refractoriness may differ between daytime and nighttime asthmatic cough. We sought to identify factors contributing to ICS-refractory daytime and nighttime asthmatic cough. Methods: Sixty-seven patients with asthma presenting solely or predominantly with chronic cough were prospectively enrolled from April 2012 to December 2014. At baseline and 12 weeks after ICS treatment, the capsaicin cough threshold (C2, C5) and methacholine airway sensitivity and reactivity were examined. A visual analog scale (VAS) and numeric scores were used to evaluate daytime and nighttime cough symptoms separately. The Japanese version of the Leicester Cough Questionnaire was also completed. When either the VAS or numeric scores showed an improvement of ≥50% or ≥2 points, patients were considered responders to ICS treatment.Results: Fifty-five patients were eligible for evaluation. Subjective cough indices improved significantly at 12 weeks after ICS treatment (P<.001). Multivariate analysis revealed that lower C2 significantly contributed to residual daytime cough (P=.04). Meanwhile, methacholine hyperreactivity and lower IgE levels were predictors of the nighttime residual cough (P=.002 and P=.03, respectively). Conclusions: Heightened cough reflex sensitivity is an independent factor of daytime asthmatic cough that is refractory to ICSs. In contrast, airway hyperreactivity and less atopic status contribute to ICS-refractory nighttime cough

Introducción: La tos es una característica común del asma, que a menudo es resistente a los corticosteroides inhalados (ICS). La fisiopatología involucrada en dicha refractariedad al tratamiento esteroideo puede ser diferente entre la tos asmática diurna y nocturna. El objetivo del estudio es intentar identificar los factores que contribuyen a esta insensibilidad al tratamiento en la tos asmática diurna y nocturna. Métodos: Sesenta y siete pacientes, con asma solo o con tos crónica, se inscribieron prospectivamente desde abril de 2012 a diciembre de 2014. Al inicio del estudio y 12 semanas después del tratamiento con ICS, se examinaron el umbral de tos frente a capsaicina (C2, C5) y la sensibilidad y reactividad de las vías respiratorias a la metacolina. Se usaron escalas analógicas visuales (VAS) y puntajes numéricos para evaluar los síntomas de tos diurna y nocturna de forma separada. La versión japonesa del Leicester Cough Questionnaire también se completó. Cuando las VAS o los puntajes numéricos mostraron una mejoría de ≥50% o ≥2 puntos, los pacientes se consideraron respondedores al tratamiento con ICS. Resultados: Cincuenta y cinco pacientes completaron adecuadamente toda la evaluación. Los índices subjetivos de tos mejoraron significativamente a las 12 semanas después del tratamiento con ICS (p <0,001). El análisis multivariante reveló que una C2 más baja contribuía significativamente a la tos diurna residual (p = 0,04). Por otra parte, la hiperreactividad a la metacolina y los niveles más bajos de IgE fueron predictores de la tos residual nocturna (p = 0,002 y p = 0,03, respectivamente).Conclusiones: La sensibilidad aumentada a la tos es un factor independiente de la tos asmática diurna refractaria a los corticoides. Por el contrario, la hiperreactividad de las vías respiratorias y la ausencia de atopia contribuyen a la tos nocturna refractaria a los ICS

Influence of backrest angle on swallowing musculature activity and physical strain during the head lift exercise in elderly women compared with young women.

The head lift exercise (HLE) is the most common exercise for strengthening the swallowing musculature in clinical situations. This study investigated whether a change in the backrest angle of a bed influences swallowing musculature activity and physical strain during the HLE and whether it can generate an appropriate exercise load for swallowing musculature activity for older women compared with younger women. Participants were 10 elderly women and 10 young women, each of whom performed the HLE with a backrest randomly angled at 0°, 15°, 30° and 45°. The activity of the suprahyoid, infrahyoid and sternocleidomastoid muscles was assessed with electromyography. The perception of fatigue was measured with the Borg Rating of Perceived Exertion Scale. The activity of the infrahyoid and sternocleidomastoid muscles in elderly women was significantly lower when the angle of the backrest was raised to 45° vs 0°. In both groups, the Borg rating decreased significantly at the 30° and 45° backrest positions vs the 0° and 15° positions. The activity required for the suprahyoid and infrahyoid muscles in elderly women at a 30° backrest position was almost equal to the activity required by these muscles in young women at a 0° backrest position. In elderly women, it is possible that the HLE with the backrest at a 30° angle may be easier and provide a more appropriate exercise load for strengthening the swallowing muscles.

Effect of Disturbances of Zinc and Copper on the Physical and Mental Health Status of Patients with Alcohol Dependence.

The concentrations of copper and zinc in the tissues of alcohol-addicted people can significantly correlate with the variables describing their mental state. Studies on the homeostasis of zinc in alcohol-dependent patients have often been characterized by low hypozincemia detection. This may be caused by a low content of zinc in blood serum (1%) compared to the average zinc level in the body. Unfortunately, most authors have identified extracellular zinc in their studies. In the available literature, data on the level of copper in patients suffering from alcohol dependence are inconsistent. Our study included 100 alcohol-addicted patients (the study group) and 50 healthy subjects (the control group). Mental state was measured using appropriate psychometric scales. We used inductively coupled plasma mass spectrometry (ICP-MS) to determine copper and zinc content. Our results confirm the purposefulness of the use of zinc concentration in erythrocytes as a diagnostic parameter for low zinc status in alcohol-dependent patients. Alcohol-dependent patients with reduced concentrations of zinc in erythrocytes/copper in blood plasma differed significantly from alcohol-dependent patients with normal concentrations in terms of clinical parameters. With regard to zinc in blood plasma and copper in erythrocytes, this situation has not been found. The clinical symptoms of hypozincemia and copper deficiency in patients addicted to alcohol usually relate to disorders in central nervous system functioning, and they result in a decreased quality of physical and mental life.

A pulsed-air model of blue whale B call vocalizations.

Blue whale sound production has been thought to occur by Helmholtz resonance via air flowing from the lungs into the upper respiratory spaces. This implies that the frequency of blue whale vocalizations might be directly proportional to the size of their sound-producing organs. Here we present a sound production mechanism where the fundamental and overtone frequencies of blue whale B calls can be well modeled using a series of short-duration (<1 s) wavelets. We propose that the likely source of these wavelets are pneumatic pulses caused by opening and closing of respiratory valves during air recirculation between the lungs and laryngeal sac. This vocal production model is similar to those proposed for humpback whales, where valve open/closure and vocal fold oscillation is passively driven by airflow between the lungs and upper respiratory spaces, and implies call frequencies could be actively changed by the animal to center fundamental tones at different frequency bands during the call series.

IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype.

BACKGROUND: Genetic markers of susceptibility to asthma exacerbations in adults remain unclear. OBJECTIVE: To identify genetic markers of asthma exacerbations, particularly in patients with type-2 inflammatory endotype. METHODS: In this observational study of patients enrolled in the Kinki Hokuriku Airway disease Conference multicenter study, frequency of exacerbations requiring systemic corticosteroids during 2 years after enrolment and associated risk factors was determined. For genetic marker analysis, interleukin-4 receptor α (IL4RA) rs8832 and a disintegrin and metalloprotease 33 (ADAM33) S_2 (rs528557), T_1 (rs2280091), T_2 (rs2280090), and V_4 (rs2787094) variants were included. Elevated serum periostin levels at enrolment (≥95 ng/mL, defined as type-2 inflammatory endotype) were considered in the analysis. RESULTS: Among 217 patients who were successfully followed up for 2 years after enrolment, 60 patients showed at least one asthma exacerbation during the 2 years. Airflow limitation (%FEV1 <80%) and recent exacerbations but not genetic variants were identified as risk markers of exacerbations. A total of 27 patients showed type-2 inflammatory endotype (serum periostin ≥95 ng/mL at enrolment) and subsequent exacerbations; risk factors in these patients were airflow limitation (odds ratio, 6.51; 95% confidence interval (CI): 2.37-18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% CI: 1.47-11.0; P=.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% CI: 1.05-7.67; P=.04) by multivariate analysis. In addition, GG genotype of IL4RA rs8832 was associated with type-2 endotype, whereas A allele of ADAM33 T_2 was associated with mixed type of eosinophilic/type-2 and neutrophilic inflammations. CONCLUSIONS AND CLINICAL RELEVANCE: IL4RA and ADAM33 variants may be risk markers of asthma exacerbations in type-2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.

Phenytoin-induced gingival overgrowth caused by death receptor pathway malfunction.

OBJECTIVE: In this study, we investigated the role of phenytoin (PHT) in death receptor-induced apoptosis of gingival fibroblasts to clarify the mechanism of PHT-induced gingival overgrowth. METHODS: Human gingival fibroblasts were cultured to semiconfluence and treated with PHT (0.025, 0.1, 0.25, and 1.0 µM) for 48 h, and then, the apoptotic cell numbers were relatively determined by absorptiometry. After 24 h of 0.25 µM PHT treatment, caspase activity was measured by absorptiometry, apoptotic and cell cycle phase distribution was analyzed by flow cytometry, expression levels of apoptotic genes were quantified by real-time qPCR, and expression of apoptotic proteins was detected by Western blot analysis. After 48 h of 0.25 µM PHT treatment, appearance of apoptotic cells was detected by TUNEL assay. RESULTS: PHT treatment decreased the proportion of apoptotic cells in gingival fibroblasts compared to a serum-free control culture in response to the protein changes as follows: PHT upregulated c-FLIP and, in turn, downregulated FADD, caspase-8, and caspase-3; PHT upregulated c-IAP2 and downregulated TRAF2; PHT downregulated caspase-9 and caspase-3 via decreased RIPK1 activity and increased Bcl-2 activity. CONCLUSION: PHT-induced gingival overgrowth may result from the above-mentioned mechanisms involving apoptosis inhibition in gingival fibroblasts.

Usefulness of dyssynchrony indices based on two-dimensional speckle tracking echocardiography in a canine model of left bundle branch block.

INTRODUCTION: Determine the usefulness of dyssynchrony indices derived from two-dimensional speckle tracking echocardiography for the detection of mechanical dyssynchrony in a canine model of left bundle branch block. ANIMALS: Ten healthy beagles. MATERIALS AND METHODS: Segmental, time-radial strain curves were obtained using two-dimensional speckle tracking echocardiography. The maximum difference and standard deviation of the time to peak radial strain for six predefined segments (MaxD-TpSR and 6SD-TpSR) were calculated, together with the left ventricular dyssynchrony by radial strain (DysSR), before and after ablation of the left bundle branch block. Receiver operating characteristic curve analysis was performed using dogs after ablation as positive controls. RESULTS: After ablation, all dogs showed multiple peaks in at least one segment on the time-radial strain curve, while all dyssynchrony indices increased significantly (MaxD-TpSR from 16.25 ± 16.04 [mean ± standard deviation] to 44.4 ± 26.18 ms, 6SD-TpSR from 7.59 ± 7.40 to 19.62 ± 11.91 ms, and DysSR from 4.20 ± 2.12 to 10.87± 2.92%, p<0.05). In receiver operating characteristic curve analysis, the areas under the curve for MaxD-TpSR, 6SD-TpSR, and DysSR were 0.825, 0.800, and 0.980, respectively. CONCLUSIONS: Left ventricular dyssynchrony by radial strain can detect mechanical dyssynchrony with higher sensitivity and specificity than dyssynchrony indices, based on the time to peak radial strain.

Myocardial torsional deformations in cats with hypertrophic cardiomyopathy using two-dimensional speckle-tracking echocardiography.

OBJECTIVES: The objective of our study was to quantitatively measure systolic torsional deformations in cats with hypertrophic cardiomyopathy (HCM) and in controls. ANIMALS: Twenty-six client-owned cats with HCM and 14 healthy cats. HCM cats were categorized based on their symptoms (asymptomatic and symptomatic) and with or without left ventricular outflow tract obstruction (obstructive and non-obstructive). METHODS: The cats were examined for myocardial deformations using two-dimensional speckle-tracking echocardiography and were evaluated for peak systolic rotation and the rotation rate at each basal and apical view. Cats were also evaluated for the peak systolic torsion and torsion rate. RESULTS: The peak systolic apical rotation and torsion were higher in asymptomatic and symptomatic cats with HCM than in control cats. Also, the peak systolic apical rotation, apical rotation rate, torsion, and torsion rate were higher in cats with obstructive HCM than in control cats. CONCLUSIONS: Myocardial torsional deformations assessed by two-dimensional speckle-tracking echocardiography may be useful for evaluating compensatory myocardial function of HCM.

Utility of serum periostin and free IgE levels in evaluating responsiveness to omalizumab in patients with severe asthma.

BACKGROUND: Omalizumab, a humanized anti-IgE monoclonal antibody, has demonstrated efficacy in patients with severe allergic asthma. However, treatment responses vary widely among individuals. Despite a lack of data, free serum IgE levels following omalizumab treatment have been proposed as a marker of treatment responsiveness. METHODS: In this prospective, observational study, we assessed the utility of biomarkers of type 2 inflammation in predicting omalizumab treatment responses, as determined by the absence of asthma exacerbation during the first year of treatment. Free serum IgE levels were monitored for 2 years to examine their association with baseline biomarker levels and the number of exacerbations. RESULTS: We enrolled thirty patients who had been treated with omalizumab for at least 1 year, of whom 27 were treated for 2 years. Baseline serum periostin levels and blood eosinophil counts were significantly higher in patients without exacerbations during the first year of treatment than in patients with exacerbations. Baseline serum periostin levels, but not eosinophil counts, were negatively associated with free serum IgE levels after 16 or 32 weeks of treatment. Reduced free serum IgE levels during treatment from those at baseline were associated with reduced exacerbation numbers at 2 years. In 14 patients who continued to have exacerbations during the first year of treatment, exacerbation numbers gradually and significantly decreased over the 2-year study period, with concurrent significant reductions in free serum IgE levels. CONCLUSION: Baseline serum periostin levels and serum free IgE levels during treatment follow-up may be useful in evaluating responses to omalizumab treatment.

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.

Possible pharmacotherapy for nifedipine-induced gingival overgrowth: 18α-glycyrrhetinic acid inhibits human gingival fibroblast growth.

BACKGROUND AND PURPOSE: This investigation aimed to establish the basis of a pharmacotherapy for nifedipine-induced gingival overgrowth. Gingival overgrowth has been attributed to the enhanced growth of gingival fibroblasts. In this study, we investigated the effects of 18-α-glycyrrhetinic acid (18α-GA) on growth, the cell cycle, and apoptosis and on the regulators of these processes in gingival fibroblasts isolated from patients who presented with nifedipine-induced gingival overgrowth. EXPERIMENTAL APPROACH: Gingival fibroblasts were cultured in medium containing 1% FBS with/without 10 µM 18α-GA for 24 or 48 h, and the cell number, cell cycle phase distribution, relative DNA content, apoptotic cell number and morphological characteristics of the cells undergoing apoptosis were measured together with the levels of proteins that regulate these processes and the level of caspase activity. KEY RESULTS: 18α-GA significantly decreased cell numbers and significantly increased the percentage of cells in the sub-G1 and G0 /G1 phases of the cell cycle and the number of apoptotic cells. Nuclear condensation and fragmentation of cells into small apoptotic bodies appeared in the fibroblasts treated with 18α-GA. In addition, 18α-GA significantly decreased the protein levels of cyclins A and D1, CDKs 2 and 6, phosphorylated Rb (ser(780) and ser(807/811)), Bcl-xL and Bcl-2 and increased the protein levels of p27, cytosolic cytochrome c, pro-caspase-3, and cleaved caspase-3 and the activities of caspases 3 and 9. CONCLUSIONS AND IMPLICATIONS: 18α-GA inhibited gingival fibroblast growth by suppressing the G1 /S phase transition and inducing apoptosis. In conclusion, 18α-GA may be used as a pharmacotherapy for nifedipine-induced gingival overgrowth.

Membrane-bound and soluble Fas ligands have opposite functions in photoreceptor cell death following separation from the retinal pigment epithelium.

Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-induced cell death of Fas-positive photoreceptors following a retinal detachment. However, as FasL exists in membrane-bound (mFasL) and soluble (sFasL) forms, and is expressed on resident microglia and infiltrating monocyte/macrophages, the current study examined the relative contribution of mFasL and sFasL to photoreceptor cell death after induction of experimental retinal detachment in wild-type, knockout (FasL-/-), and mFasL-only knock-in (ΔCS) mice. Retinal detachment in FasL-/- mice resulted in a significant reduction of photoreceptor cell death. In contrast, ΔCS mice displayed significantly more apoptotic photoreceptor cell death. Photoreceptor loss in ΔCS mice was inhibited by a subretinal injection of recombinant sFasL. Thus, Fas/FasL-triggered cell death accounts for a significant amount of photoreceptor cell loss following the retinal detachment. The function of FasL was dependent upon the form of FasL expressed: mFasL triggered photoreceptor cell death, whereas sFasL protected the retina, indicating that enzyme-mediated cleavage of FasL determines, in part, the extent of vision loss following the retinal detachment. Moreover, it also indicates that treatment with sFasL could significantly reduce photoreceptor cell loss in patients with retinal detachment.