Attenuation of intrinsic ageing of the skin via elimination of senescent dermal fibroblasts with senolytic drugs.

BACKGROUND: Skin ageing is caused by numerous factors that result in structural and functional changes in cutaneous components. Research has shown that senescent cells are known to accumulate in skin ageing, however, the role of senescent cells in skin ageing has not been defined. OBJECTIVES: To elucidate the role of the senescent cell in skin ageing, we evaluated the effect of known senolytic drugs on senescent dermal fibroblasts. METHODS: Primary human dermal fibroblasts (HDFs) were induced to senescence by long-term passaging, UV irradiation, and H2 O2 treatment. Cell viability was measured after treatment of ABT-263 and ABT-737 on HDFs. Young and aged hairless mice were intradermally injected with drugs or vehicle on the dorsal skin for 10 days. Skin specimens were obtained and reverse-transcription quantitative PCR, western blotting, and histological analysis were performed. RESULTS: We found that ABT-263 and ABT-737 induced selective clearance of senescent dermal fibroblasts, regardless of the method of senescence induction. Aged mouse skin treated with ABT-263 or ABT-737 showed increased collagen density, epidermal thickness, and proliferation of keratinocytes, as well as decreased senescence-associated secretory phenotypes, such as MMP-1 and IL-6. CONCLUSIONS: Taken together, our results indicate that selective clearance of senescent skin cells can attenuate and improve skin ageing phenotypes and that senolytic drugs may be of potential use as new therapeutic agents for treating ageing of the skin.

Ultrashort laser induced spatial redistribution of silver species and nano-patterning of etching selectivity in silver-containing glasses.

Femtosecond laser-induced spatial redistribution of silver species (ions, clusters, and hole centers) in a silver-containing phosphate glass is investigated by correlative means of near-field scanning optical microscopy (NSOM) images, numerical simulations, chemical micro-probe analysis, and nanoscale spatial profiles after soft etching. In particular, we found that the chemical etching selectivity for nanoscale patterning is strongly dependent upon the irradiation of femtosecond laser due to the spatial redistribution of silver species within the affected area. These results strongly indicate that controlling the distribution of silver species by femtosecond laser irradiation may open new routes for surface nanoscale chemical and/or spatial patterning for the fabrication of 2D surface photonic crystals.

The brain-derived neurotrophic factor Val66Met polymorphism and degeneration of the corticospinal tract after stroke: a diffusion tensor imaging study.

BACKGROUND AND PURPOSE: A common single nucleotide polymorphism, Val66Met, in the human brain-derived neurotrophic factor (BDNF) gene has a potential role in the pathogenesis and treatment of stroke. The relevance of the BDNF Val66Met polymorphism to long-term stroke outcomes was examined, specifically with respect to changes in corticospinal integrity. METHODS: Thirty-five stroke patients with unilateral motor weakness were genotyped within 2 weeks after onset (T1), and changes in the integrity of the ipsilesional corticospinal tract (CST) as well as alterations in motor function at 1 month (T2) and 3 months after onset (T3) were tracked. RESULTS: On the basis of the Fugl-Meyer assessment upper extremity score, carriers of the Met allele (Val/Met and Met/Met) showed poorer motor outcomes at T2 and T3 compared to carriers of only the Val allele (Val/Val). For both BDNF allele types, patients exhibited characteristic degeneration of the CST compared to healthy controls. There were no differences between the two genotypes with respect to time-dependent changes in diffusion-tensor-imaging-derived parameters of the CST. However, the two groups showed different relationships between motor outcomes and directional diffusivities according to the elapsed time after onset. Poorer motor function was associated with lower axial diffusivity values for the Val/Val genotype group in the sub-acute phase (T1 and T2) but with higher radial diffusivity values for the Val/Met and Met/Met genotype group in the early chronic phase (T3). CONCLUSIONS: Motor recovery in stroke patients may be affected by the BDNF Val66Met polymorphism, possibly through its effects on distinct pathological processes underlying corticospinal degeneration.

Comparison of Total Arch and Partial Arch Transposition During Hybrid Endovascular Repair for Aortic Arch Disease.

OBJECTIVE: Total arch transposition (TAT) during hybrid endovascular repair for aortic arch disease is believed to allow a better landing zone, but also to be associated with higher peri-operative mortality than partial arch transposition (PAT). Information on this issue is limited. METHOD: This study was a retrospective analysis. All 53 consecutive patients with aortic arch disease (41 males, mean age 65.0 years) who underwent hybrid endovascular repair with TAT (zone 0, n=20) or PAT (zone 1 or 2, n=33) from 2008 to 2014 were analyzed retrospectively. The peri-operative and late outcomes of these two groups were compared. RESULTS: Baseline characteristics, including EuroSCORE II results, were similar in the two groups. After procedures, peri-operative mortalities and stroke rates were similar in the two groups (5.0% vs. 9.1%, p=1.000, and 10.0% vs. 6.1%, p=.627). Interestingly, all four strokes occurred in patients with a type III aortic arch irrespective of transposition type. Primary success rates (80.0% vs. 69.7%, p=.527) and type I endoleak incidences (20.0% vs. 27.3%, p=.744) were not significantly different. During follow up (mean duration 36.9 months), overall survival (89.7% vs. 87.4% at 1 year and 89.7% vs. 79.3% at 3 years; p=.375) and re-intervention free survival rates (78.6% vs. 92.0% at 1 year; 72.0% vs. 62.2% at 3 years, p=.872) were similar in the two groups. CONCLUSION: Morbidity and mortality were high within the first year of hybrid endovascular therapy for aortic arch disease, implying that candidates for hybrid procedures need to be selected carefully. Hybrid endovascular repair with TAT was found to have peri-operative mortality, stroke, and long-term survival rates comparable with PAT, so hybrid endovascular repair may be considered, irrespective of type of arch reconstruction, when clinically indicated.

Arterial pressure, end-tidal carbon dioxide, and central venous oxygen saturation in reflecting compression depth.

BACKGROUND: We sought to investigate the utility of arterial pressure, end-tidal carbon dioxide (ETCO2 ), and central venous oxygen saturation (SCVO2 ) to guide compression depth adjustment. Thus, in a pig model of cardiac arrest, we observed these parameters during cardiopulmonary resuscitation (CPR) with optimal and suboptimal compression depths. METHODS: Sixteen pigs underwent three experimental sessions after induction of ventricular fibrillation. First, the animals received two 4-min CPR trials with either optimal (20% of the anteroposterior diameter) or suboptimal (70% of the optimal depth) compression depth. Second, the animals received two 5-min CPR trials with optimal compression depth, in which adrenaline (0.02 mg/kg) or saline placebo was administered. Third, the animals randomly received compression with either optimal or suboptimal depth during advanced cardiovascular life support. RESULTS: The systolic arterial pressure reflected compression depth most accurately and immediately (area under the curve [AUC], 0.895-0.939 without adrenaline and 0.928-1.000 with adrenaline). Although the response of ETCO2 to the change in compression depth was 0.5 min slower than that of the systolic arterial pressure, the performance of ETCO2 was comparable with that of systolic arterial pressure. SCVO2 did not reflect compression depth. Adrenaline administration remarkably increased systolic arterial pressure, diastolic arterial pressure, and coronary perfusion pressure but did not affect the ETCO2 readings. CONCLUSION: In a pig model of cardiac arrest, systolic arterial pressure reflected compression depth immediately and accurately. The performance of ETCO2 was comparable with that of systolic arterial pressure. SCVO2 did not reflect compression depth.

LIM domain protein-3 (LMP3) cooperates with BMP7 to promote tissue regeneration by ligament progenitor cells.

Gene transfer of key regulators of osteogenesis for mesenchymal stem cells represents a promising strategy to regenerate bone. It has been reported that LMP3, a transcription variant of LIM domain mineralization protein (LMP) lacking LIM domains, can induce osteogenesis in vitro and in vivo. As little is known about the effects of LMP3 gene therapy on periodontal ligament (PDL) cell osteogenic differentiation, this study sought to explore whether gene delivery of LMP3 can promote PDL cell mineralization and bone formation. Our results showed that adenoviral mediated gene transfer of LMP3 (AdLMP3) significantly upregulated ALP (Alkaline Phosphatase), BSP (Bone Sialoprotein) and BMP2 gene expression and increased in vitro matrix mineralization in human PDL. Although AdLMP3 gene delivery to PDL cells did not induce ectopic bone formation in vivo, we found that AdLMP3 augments new bone formation, which co-delivered with AdBMP7 gene transfer. Our study provides the evidence that there is a synergistic effect between LMP3 and BMP-7 in vivo, suggesting that LMP3 delivery may be used to augment BMP-mediated osteogenesis. LMP3 and BMP-7 combinatory gene therapy may also have specific applications for oral and periodontal regenerative medicine.

Efficacy and safety of pharmacotherapy for smoking cessation among pregnant smokers: a meta-analysis.

BACKGROUND: The efficacy and safety of pharmacotherapy for smoking cessation among pregnant smokers has not yet been established. OBJECTIVE: To investigate the efficacy and safety of pharmacotherapy for smoking cessation among pregnant smokers. SEARCH STRATEGY: A search was made of PubMed, Embase and CENTRAL in June 2011. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs and retrospective or prospective controlled studies were included. DATA COLLECTION AND ANALYSIS: The main analyses were designed to examine the efficacy of pharmacotherapy for smoking cessation among pregnant smokers based on the longest follow-up data available and from data obtained at the latest available time-point in pregnancy in each study. MAIN RESULTS: Of 74 articles identified from the databases, seven studies (five RCTs, one quasi-RCT and one prospective study) involving a total of 1386 pregnant smokers, 732 in the intervention groups and 654 in the control groups, were included in the final analyses. In a fixed-effects meta-analysis of all seven studies based on the longest follow-up data available, pharmacotherapy had a significant effect on smoking cessation (relative risk [RR] 1.80; 95% confidence interval [CI] 1.32-2.44). Subgroup meta-analysis by type of study design also showed similar findings for RCTs (RR 1.48; 95% CI 1.04-2.09) and other types of studies (RR 3.25; 95% CI 1.65-6.39). The abstinence rate at late pregnancy in the intervention ranged from 7 to 22.6% (mean abstinence rate 13.0%; 95% CI 10.9-15.2%). A few minor adverse effects and serious adverse effects were reported in several studies. AUTHOR'S CONCLUSIONS: This study indicates that there may be clinical evidence to support the use of pharmacotherapy for smoking cessation among pregnant smokers. Further RCTs are needed.

A cluster of Teflon pledgets manifesting as an intrathoracic cavitary mass following lung resection.

Teflon pledgets are widely used for hemostasis and the reinforcement of friable tissue in surgery. However, rare but serious complications caused by the erosion of Teflon pledgets have been reported. We present an unusual case of an intrathoracic cavitary mass that was formed by the erosion of a cluster of Teflon pledgets into the lung parenchyma eight years after a lung resection.

Epithelial-Myoepithelial Carcinoma in a Canine Salivary Gland.

A 7-year-old male cavalier King Charles spaniel was presented with a cervical subcutaneous mass. The mass had a multilobular growth pattern and each individual lobule contained ductal epithelial cells and myoepithelial cells surrounding the ductal cells. Immunohistochemically, the ductal epithelial cells were positive for cytokeratin (CK) 7 and CAM5.2 and the myoepithelial cells were positive for α-smooth muscle actin and p63. Both types of cells were positive for CK14, a myoepithelial cell marker. Ultrastructurally, the ductal epithelial cells were attached by desmosomes and contained abundant intracytoplasmic tonofilaments. Some ductal epithelial cells contained myofilaments characteristic of myoepithelial cells. Based on these findings, a diagnosis of epithelial-myoepithelial carcinoma was made. It is presumed that the tumour originated from an intercalated duct in a parotid salivary gland.

Changes in blood and urinary cadmium levels and bone mineral density according to osteoporosis medication in individuals with an increased cadmium body burden.

The aim of this study was to assess changes in bone mineral density (BMD) and cadmium (Cd) levels in blood and urine in individuals living in a Cd-contaminated area according to the type of osteoporosis medication over a three-year period. This follow-up study included 204 residents living in the vicinity of a closed copper refinery, who had been found to have elevated urinary or blood Cd levels. Cd levels in the blood and urine, as well as BMD, were measured every 6 months. After the first BMD measurement, individuals were prescribed antiresorptives such as alendronate or vitamin D and calcium, according to their BMD. Subjects were classified according to the type of medicine provided over the previous 6 months. General linear models controlling for other factors were used to evaluate the effects of each type of medication on the participants' Cd levels and BMD. Spinal BMD showed a significant increase in the antiresorptive group compared to the nontreatment group. Significant decreases in blood Cd levels were found in the vitamin D and calcium group, in comparison to the nontreatment group, as well as a marginally significant decrease in the antiresorptive group. The vitamin D and calcium group showed a significantly greater decrease in urinary Cd levels than the nontreatment group. In contrast, antiresorptive medication was found to have a negative effect on urinary Cd excretion. These results suggest that vitamin D and calcium treatment for osteoporosis lowers blood Cd levels more effectively and improves urinary Cd excretion.

Endophytic and endolichenic fungal diversity in maritime Antarctica based on cultured material and their evolutionary position among Dikarya.

Fungal endophytes comprise one of the most ubiquitous groups of plant symbionts. They live asymptomatically within vascular plants, bryophytes and also in close association with algal photobionts inside lichen thalli. While endophytic diversity in land plants has been well studied, their diversity in lichens and bryophytes are poorly understood. Here, we compare the endolichenic and endophytic fungal communities isolated from lichens and bryophytes in the Barton Peninsula, King George Island, Antarctica. A total of 93 fungal isolates were collected from lichens and bryophytes. In order to determine their identities and evolutionary relationships, DNA sequences of the nuclear internal transcribed spacer (ITS), nuclear ribosomal small subunit (nuSSU), nuclear large subunit (nuLSU), and mitochondrial SSU (mtSSU) rDNA were obtained and protein coding markers of the two largest subunit of RNA polymerase II (RPB1 and RPB2) were generated. Multilocus phylogenetic analyses revealed that most of the fungal isolates were distributed in the following six classes in the phylum Ascomycota: Dothideomycetes, Eurotiomycetes, Lecanoromycetes, Leotiomycetes, Pezizomycetes and Sordariomycetes. For the first time we report the presence of subphylum Mortierellomycotina that may belong to an undescribed order in endophytic fungi. Taken together, our results imply that lichens and bryophytes provide similar niches and harbour a selection of these fungi, indicating generalists within the framework of evolutionary adaptation.

Endotoxin-induced injury of the central, autonomic and enteric nervous systems and intestinal muscularis in Thoroughbred horses.

To evaluate the effects of endotoxin on the morphology of the equine central, autonomic and enteric nervous system and intestinal muscularis, six Thoroughbred horses with experimentally induced endotoxaemia were examined. The lesions in the central nervous system consisted of perivascular oedema around arterioles, suggesting brain oedema, and ring haemorrhages around veins, similar to those in human patients with septic shock. In the cranial mesenteric ganglia, neuronal cell bodies became pink or red, with shrinkage of cytoplasm indicative of ischaemic changes; intramural and perivascular infiltration by erythrocytes and neutrophils occurred around arterioles in the epineurium (acute focal interstitial inflammation). In addition, transmission electron microscopy revealed oedema of the endoneurium and mesoaxon in the nerve fascicles running inside or outside the ganglia. Myenteric neurons showed shrinkage of the cytoplasm with multiple cytoplasmic vacuoles, suggesting ischaemic changes. Oedematous degeneration and coagulation necrosis of smooth muscle cells, with dissociation of the cells, were prominent in the tunica muscularis. It is suggested that arterionecrosis elicited by endotoxin and frequently observed in the autonomic and enteric nervous system and intestinal muscularis, was the result of vasoconstriction or vasospasm.

Developmental stage-dependent self-regulation of embryonic cortical precursor cell survival and differentiation by leukemia inhibitory factor.

Cortical precursor cells secrete soluble factors for their own survival and self-renewal. We show here that neural precursor cells isolated from embryonic rat cortices abundantly secrete leukemia inhibitory factor (LIF) and express its receptor components, gp130 and LIF receptor. LIF signaling is responsible for cortical precursor cell survival. As described previously, LIF caused astrocytic differentiation of cultured embryonic cortical precursor cells. LIF-mediated survival and astrocytic differentiation of cortical precursor cells were differentially regulated, depending on the developmental ages of embryos from which cortical precursors were isolated. LIF did not enhance the survival of cortical precursor cells isolated from later embryos (embryonic day 16, E16). Moreover, LIF-mediated astrocytic differentiation was not observed in early (E12) cortical precursors. Inhibition studies revealed that Janus-activated kinase/signal transducer and activator of transcription and phosphatidylinositol 3 kinase/Akt pathways participate in both the LIF-mediated effects. However, mitogen-activated protein kinase, another signal pathway activated by LIF, was specifically responsible for astrocytic differentiation. These findings collectively indicate that precursor cells self-regulate the sequential processes of brain development, such as early maintenance of the precursor cell population and later differentiation into astrocytes, via common LIF signaling.

Effect of interstitial hydrogen impurities on ferroelectric polarization in PbTiO3

We investigate the electronic and atomic structure of interstitial hydrogen impurities in PbTiO3 and investigate their effect on ferroelectric polarization through first-principles total-energy calculations. Interstitial H in PbTiO3 is found to bond to oxygen and to act as a shallow donor impurity. At equilibrium, H does not much affect nearby Ti-O bonds and the H-O dipole increases the polarization. The barrier for reversing the defect dipole can give rise to imprint (extra stabilization of one of the two polarization modes).

A comparison of proximal and distal chevron osteotomy for the correction of moderate hallux valgus deformity.

The purpose of this study was to compare the results of proximal and distal chevron osteotomy in patients with moderate hallux valgus. We retrospectively reviewed 34 proximal chevron osteotomies without lateral release (PCO group) and 33 distal chevron osteotomies (DCO group) performed sequentially by a single surgeon. There were no differences between the groups with regard to age, length of follow-up, demographic or radiological parameters. The clinical results were assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) scoring system and the radiological results were compared between the groups. At a mean follow-up of 14.6 months (14 to 32) there were no significant differences in the mean AOFAS scores between the DCO and PCO groups (93.9 (82 to 100) and 91.8 (77 to 100), respectively; p = 0.176). The mean hallux valgus angle, intermetatarsal angle and sesamoid position were the same in both groups. The metatarsal declination angle decreased significantly in the PCO group (p = 0.005) and the mean shortening of the first metatarsal was significantly greater in the DCO group (p < 0.001). We conclude that the clinical and radiological outcome after a DCO is comparable with that after a PCO; longer follow-up would be needed to assess the risk of avascular necrosis.

Insulin concentration is critical in culturing human neural stem cells and neurons.

Cell culture of human-derived neural stem cells (NSCs) is a useful tool that contributes to our understanding of human brain development and allows for the development of therapies for intractable human brain disorders. Human NSC (hNSC) cultures, however, are not commonly used, mainly because of difficulty with consistently maintaining the cells in a healthy state. In this study, we show that hNSC cultures, unlike NSCs of rodent origins, are extremely sensitive to insulin, an indispensable culture supplement, and that the previously reported difficulty in culturing hNSCs is likely because of a lack of understanding of this relationship. Like other neural cell cultures, insulin is required for hNSC growth, as withdrawal of insulin supplementation results in massive cell death and delayed cell growth. However, severe apoptotic cell death was also detected in insulin concentrations optimized to rodent NSC cultures. Thus, healthy hNSC cultures were only produced in a narrow range of relatively low insulin concentrations. Insulin-mediated cell death manifested not only in all human NSCs tested, regardless of origin, but also in differentiated human neurons. The underlying cell death mechanism at high insulin concentrations was similar to insulin resistance, where cells became less responsive to insulin, resulting in a reduction in the activation of the PI3K/Akt pathway critical to cell survival signaling.

Effects of low-level arsenic exposure on urinary N-acetyl-ß-D-glucosaminidase activity.

This study was aimed to evaluate whether renal tubular function is impaired by exposure to relatively low concentrations of arsenic. Mean urinary arsenic concentrations and N-acetyl-ß-D-glucosaminidase (NAG) activities were compared among 365 and 502 Korean men and women, respectively, in relation to gender, smoking, alcohol consumption, and recent seafood consumption. The study subjects were divided into 4 groups according to urinary NAG activity and seafood consumption prior to urine sampling, and the correlation between arsenic concentration and urinary NAG activity was tested for each group. The mean urinary arsenic level was higher in women, non-smokers, and non-drinkers in comparison to men, smokers, and drinkers, respectively. Individuals who consumed seafood within 3 days prior to urine sampling showed a higher mean urinary arsenic level than those who did not. The correlation between urinary arsenic concentration and NAG activity in urine was significant only in subjects who did not consume seafood within 3 days prior to urine sampling and whose urinary NAG activity was 7.44 U/g creatinine (75th percentile) or higher. The urinary arsenic concentration was a significant determinant of urinary NAG activity in subjects with NAG activity higher than 7.44 U/g creatinine and especially in those who had not consumed seafood recently. These facts suggest that a relatively low-level exposure to inorganic arsenic produces renal tubular damage in humans.