Alternative autophagy dampens UVB-induced NLRP3 inflammasome activation in human keratinocytes.

Sunlight exposure results in an inflammatory reaction of the skin commonly known as sunburn, which increases skin cancer risk. In particular, the ultraviolet B (UVB) component of sunlight induces inflammasome activation in keratinocytes to instigate the cutaneous inflammatory responses. Here, we explore the intracellular machinery that maintains skin homeostasis by suppressing UVB-induced inflammasome activation in human keratinocytes. We found that pharmacological inhibition of autophagy promoted UVB-induced NLRP3 inflammasome activation. Unexpectedly, however, gene silencing of Atg5 or Atg7, which are critical for conventional autophagy, had no effect, whereas gene silencing of Beclin1, which is essential not only for conventional autophagy but also for Atg5/Atg7-independent alternative autophagy, promoted UVB-induced inflammasome activation, indicating an involvement of alternative autophagy. We found that damaged mitochondria were highly accumulated in UVB-irradiated keratinocytes when alternative autophagy was inhibited, and they appear to be recognized by NLRP3. Overall, our findings indicate that alternative autophagy, rather than conventional autophagy, suppresses UVB-induced NLRP3 inflammasome activation through the clearance of damaged mitochondria in human keratinocytes and illustrate a previously unknown involvement of alternative autophagy in inflammation. Alternative autophagy may be a new therapeutic target for sunburn and associated cutaneous disorders.

How emotional changes affect skin odor and its impact on others.

The gas emanating from human skin is known to vary depending on one's physical condition and diet. Thus, skin gas has been gaining substantial scholarly attention as an effective noninvasive biomarker for understanding different physical conditions. This study focuses on the relationship between psychological stress and skin gas, which has remained unclear to date. It has been deduced that when participants were subjected to interviews confirmed as stressful by physiological indicators, their skin emitted an odor similar to stir-fried leeks containing allyl mercaptan and dimethyl trisulfide. This characteristic, recognizable odor appeared reproducibly during the stress-inducing situations. Furthermore, the study deduced that individuals who perceive this stress odor experience subjective tension, confusion, and fatigue (Profile of Mood States scale). Thus, the study findings indicate the possibility of human nonverbal communication through odor, which could enhance our understanding of human interaction.

Catheter-Directed Thrombolysis for Persistent Sciatic Artery Presenting with Acute Limb Ischemia.

Persistent sciatic artery (PSA) is a rare congenital peripheral artery disorder that is usually detected incidentally on computed tomographic examination. PSA can also cause iliac aneurysm and acute thromboembolism, which are potentially associated with rest pain, claudication, and limb-threatening ischemia. Patients with PSA and leg ischemia should be treated with revascularization and appropriate management of PSA aneurysm. The authors often choose emergent bypass surgery or endovascular intervention for aneurysmal rupture and acute lower-extremity arterial occlusion. This report describes an emergency procedure using catheter-based thrombolysis for acute limb ischemia in a patient with PSA.

Open Repair of a Giant Popliteal Artery Aneurysm Presenting with Nerve Compression Symptoms.

Popliteal artery aneurysm (PAA) is a rare vascular disease, especially in women, and presents with various symptoms, ranging from being asymptomatic to rupture or acute life-threatening ischemia. We have presented a case of PAA in an 81-yearold woman complaining of tingling sensations in her leg. Computed tomography revealed a large 10-cm sized PAA. Because of the compression related symptoms, an open repair approach was selected and performed successfully via a posterior approach, including partial aneurysm resection and interposition graft with a reversed saphenous vein.

Subjective and objective refractions in eyes with extended-depth-of-focus intraocular lenses using echelette optics: clinical and experimental study.

PURPOSE: To evaluate differences in subjective and objective refractions in eyes with extended-depth-of-focus intraocular lenses (EDOF IOLs) using echelette optics, and the effect of the light wavelength used during examinations. METHODS: In the prospective study, subjective and objective refractions of 128 eyes of 64 patients were examined 3 months after implantation of the EDOF IOLs (ZXR00V, Johnson & Johnson Surgival Vision). Objective refractions were measured using an autorefractor with a near-infrared (NIR) light source. Clinical differences in the spherical, cylindrical and spherical equivalent (SE) refractions between the subjective and objective refractions were evaluated. Then, lens powers of monofocal, EDOF and diffractive bifocal IOLs in the use of a 850-nm light source were measured experimentally for using a lensmeter, and the differences from the monofocal IOLs were calculated. RESULTS: The mean objective refractions were more myopic (p < 0.001) than the subjective refractions; the differences in the spherical, cylindrical and SE refractions were -0.71, -0.26 and -0.84 dioptre, respectively. Experimental investigation resulted that there was the mean difference of 0.83 D with the EDOF from monofocal IOLs at 850 nm, while the difference was -0.20 D with bifocal IOLs. CONCLUSIONS: The diffractive EDOF IOLs using echelette gratings inherently induced constant differences in the subjective and objective refractions, which arose from the chromatic difference in IOL powers for the visible and NIR lights.

Endovenous Laser Ablation Combined with Stripping Technique for Large Saphenous Varicose Veins: The Selection of Operation Technique.

Objective: Saphenous varicose veins can be accomplished by various operative techniques that result in stripping, ablation, or ligation of the venous reflux section. Great saphenous vein (GSV) stripping is one of the standard operations for varicose veins to eliminate reflux of the sapheno-femoral junction. The goal of any treatment regimen is to eliminate the junctional varicose reflux to control congestive dysfunction. Endovenous laser ablation (EVLA) is safe and effective with less postoperative pain, bleeding, and peripheral nerve damage than open surgery. In this study, a patient with severe progression of primary saphenous varicose veins is presented. We report the outcome of combined surgical strategy and perioperative treatment for extremely swollen varicose veins of the lower limbs to improve leg symptoms and congestion and/or promote skin ulcer healing. Materials and Methods: The subjects included 42 patients (51 limbs) who underwent EVLA with stripping. The patients comprised 24 males and 18 females, who presented a maximum GSV diameter >15 mm. The Clinical-Etiological-Anatomic-Pathophysiologic classification identified 9, 20, 9, 2, 6, and 5 limbs with C2, C3, C4a, C4b, C5, and C6, respectively, among the 42 patients. Results: EVLA was used to treat GSV with a mean length of 16.1±2.8 cm. The mean of the maximum GSV diameter was 16.8±3.2 mm (14.6-21.8 mm). The preoperative visual analog scale (VAS) score was 82.1±12.1. After operation, the VAS gradually deteriorated to 31.3±17.9 (p<0.0001), 2.8±3.6 (p<0.0001), and 1.2±1.8 (p<0.0001) in 7 days, 1 month, and 3 months, respectively. Conclusion: We obtained a satisfactory outcome from our combined strategy and perioperative treatment for extremely swollen saphenous varicose veins. This approach may show the possibility that lower saphenous varicose veins can induce cosmetic and minimally invasive ameliorated intervention to avoid late-phase incompetent perforating veins.

Popliteal Venous Aneurysm and Multiple Lower Extremity Varicose Veins Presenting with a Left-Sided Inferior Vena Cava.

A venous aneurysm is a relatively rare disease defined by cystic vasodilated lesions in a general vein. Popliteal venous aneurysm (PVA) is a rare clinical entity, and the first signs may be a thromboembolic event. They can cause potentially life-threatening diseases, such as pulmonary embolism and deep venous thrombosis. A left-sided inferior vena cava (IVC) is a common anomaly associated with venous thrombus, resulting in anatomical variations in the venous return from the lower limbs. The general vascular malformation of PVA and left-sided IVC should also be preoperatively understood because of the unpredictable risk of thromboembolic complications.

Left Subclavian Artery Occlusion: Femoro-Axillary Artery Retrograde Bypass.

The treatment tactics for subclavian artery occlusion include the more commonly used endovascular therapy rather than surgical intervention. We present a case of a 61-year-old woman with dialysis-dependent chronic renal failure who experienced left finger necrosis in the left upper extremity. To salvage the limb, we performed femoro-axillary (fem-ax) artery bypass using an autologous saphenous vein graft. However, 10 months later, she experienced coldness in the left forearm. Angiography revealed chronic total occlusion of the venous bypass. Despite emergent thrombectomy, redo fem-ax artery bypass operation was performed using a prosthetic graft. Upper limb salvage can be achieved by fem-ax artery retrograde bypass.

Nuclear DNA damage-triggered NLRP3 inflammasome activation promotes UVB-induced inflammatory responses in human keratinocytes.

Ultraviolet (UV) radiation in sunlight can result in DNA damage and an inflammatory reaction of the skin commonly known as sunburn, which in turn can lead to cutaneous tissue disorders. However, little has been known about how UV-induced DNA damage mediates the release of inflammatory mediators from keratinocytes. Here, we show that UVB radiation intensity-dependently increases NLRP3 gene expression and IL-1ß production in human keratinocytes. Knockdown of NLRP3 with siRNA suppresses UVB-induced production of not only IL-1ß, but also other inflammatory mediators, including IL-1α, IL-6, TNF-α, and PGE2. In addition, inhibition of DNA damage repair by knockdown of XPA, which is a major component of the nucleotide excision repair system, causes accumulation of cyclobutane pyrimidine dimer (CPD) and activation of NLRP3 inflammasome. In vivo immunofluorescence analysis confirmed that NLRP3 expression is also elevated in UV-irradiated human epidermis. Overall, our findings indicate that UVB-induced DNA damage initiates NLRP3 inflammasome activation, leading to release of various inflammatory mediators from human keratinocytes.

Troubleshooting OptEase inferior vena cava filter retrieval.

For treatment of deep vein thrombosis and prevention of pulmonary thromboembolism, a retrievable inferior vena cava filter is commonly utilized as an effective bridge to anticoagulation. However, we have experienced difficulties in retrieving inferior vena cava filters. Endovascular retrieval assisted by disposable biopsy forceps is an appropriate approach because it provides a less-invasive low-cost way to remove a migrated filter. We suggest this troubleshooting technique to deal with filter hook migration into the caval wall.

Successful cases of difficult inferior vena cava filter retrieval with the use of biopsy forceps: Biopsy forceps technique.

OBJECTIVES: For treatment and prevention of deep vein thrombosis(DVT) and pulmonary embolism(PE), retrievable inferior vena cava(IVC) filters have commonly been used as an effective bridge to anticoagulation. However, we experienced unexpected difficulty in endovascular retrieval of some IVC filters. Most problems were due to endovascular treatment devices issues, filter intimal migration, filter disintegration, filter-associated thrombosis, and right atrium/ventricle migration. METHODS: Disposable biopsy forceps was used to engage the filter hook and reform the shape of the filter struts. Endovascular retrieval assisted by use of the biopsy forceps via a similar vein was effective and provided a less-invasive, low cost method for removal of problematic IVC filters. RESULTS: We described easily performed methods that uses disposable biopsy forceps for the retrieval of IVC filters that are difficult to remove because of filter hook migration into the caval wall. CONCLUSION: We developed an easily performed method that uses intestine biopsy forceps for the retrieval of IVC filter that are difficult to remove.

Chafuroside B, an Oolong tea polyphenol, ameliorates UVB-induced DNA damage and generation of photo-immunosuppression related mediators in human keratinocytes.

Chafuroside B was recently isolated as a new polyphenolic constituent of oolong tea leaves. However, the effects of chafuroside B on skin function have not been examined. In this study, we investigated the protective effects of chafuroside B against UVB-induced DNA damage, apoptosis and generation of photo-immunosuppression related mediators in cultured normal human epidermal keratinocytes (NHEK). Chafuroside B at 1 µM attenuated both UVB-induced apoptosis, evaluated in terms of caspase-3/7 activity, and UVB-induced DNA damage, evaluated in terms of formation of cyclobutane pyrimidine dimers (CPD), in NHEK exposed to UVB (20 mJ/cm2). In addition, chafuroside B at 0.3 or 1 µM suppressed the UVB-induced production of interleukin (IL)-10, tumor necrosis factor (TNF)-α, and prostaglandin E2 (PGE2), as determined by ELISA, and conversely enhanced IL-12 mRNA expression and production, as measured by RT-PCR and ELISA. Further, chafuroside B at 1 µM also suppressed UVB-induced expression of receptor activator of nuclear factor κB ligand (RANKL) mRNA. These results indicate that chafuroside B promotes repair of UVB-induced DNA damage and ameliorates the generation of IL-10, TNF-α, PGE2, and RANKL, all of which are UVB-induced immunosuppression related mediators. These effects of chafuroside B may be mediated at least in part through induction of IL-12 synthesis in human keratinocytes. Because chafuroside B might have practical value as a photoprotective agent, a further study of the in vivo effects of chafuroside B seems warranted.

PBN fails to suppress in delayed neuronal death of hippocampal CA1 injury following transient forebrain ischemia in gerbils.

Free radicals have been suggested to be involved in the genesis of ischemic brain damage, as shown by the protective effects of alpha-phenyl-N-tert-butyl nitrone (PBN), a spin trapping agent, in ischemic cerebral injury. However, the involvement of free radicals in transient ischemic-induced delayed neuronal death is not fully understood. To clarify this, in the present study, we evaluated the effect of PBN on delayed neuronal death and on the levels of free radicals in hippocampal CA1 region in the gerbil. The administration of PBN (10 mg/kg, i.v.) failed to show any preventive effect on the delayed neuronal death, examined by hematoxylin and eosin staining and the TUNEL method. Furthermore, we observed no free radical formation in delayed neuronal death, determined immunohistochemically using a specific 8-OHdG antibody, after transient ischemic insult. These results suggest that free radical formation may not contribute to the formation of delayed neuronal death.

Increase of galectin-3 expression in microglia by hyperthermia in delayed neuronal death of hippocampal CA1 following transient forebrain ischemia.

The ischemic damage in the hippocampal CA1 region following transient forebrain ischemia, delayed neuronal death, is a typical apoptotic response, but the underlying mechanisms are not fully understood. We have reported that mild hyperthermia (38 °C) accelerates DNA fragmentation of the gerbil CA1 pyramidal neurons following transient forebrain ischemia. Recently, we reported that galectin-3, a ß-galactosidase-binding lectin, is spatio-temporally expressed only by activated microglial cells located within CA1 region following transient forebrain ischemia in gerbils. Furthermore, expression of galectin-3 and Iba-1 (a specific microglial cell marker) are strongly reduced by hypothermia during ischemic insult. To further elucidate the effect of hyperthermia on the expression of galectin-3 by micloglia in delayed neuronal death, we examined immunohistochemical expression of galectin-3 and Iba-1, in situ terminal dUTP-biotin nick end labeling of DNA fragmentation (for determination of cell death) and hematoxylin and eosin staining (for morphological observation). We observed that between 37 °C and 39 °C, there was a temperature-dependent enhancement of galectin-3 expression in microglial cells in the CA1 region following transient ischemia. Apoptotic DNA fragmentation, detected by TUNEL staining, was observed in CA1 region in normothermia. This TUNEL staining was enhanced by hyperthermia at 37.5 °C and 38 °C, but not at 39 °C. Ischemia-induced neuronal degeneration in CA1 region in gerbil hippocampus subjected to hyperthermia (37.5 °C, 38 °C and 39 °C) observed by HE staining is similar to that in normothermic gerbils. These findings imply that galectin-3 expression in microglia may influence the survival of CA1 pyramidal neurons in cases such as hyperthermia-related neuronal injury.

Dietary glucosylceramide enhances cornified envelope formation via transglutaminase expression and involucrin production.

In this study, we investigated whether dietary glucosylceramide (GlcCer) and its metabolite sphingoid bases, sphingosine (SS), phytosphingosine (PS), sphingadienine (SD) and 4-hydroxysphingenine (4HS), influence cornified envelope (CE) formation. CE is formed during terminal differentiation of the epidermis through crosslinking of specific precursor proteins by transglutaminases (TGases), and is essential for the skin's barrier function. Oral administration of GlcCer (0.25 mg/day) for 14 consecutive days dramatically reduced transepidermal water loss, an indicator of the skin barrier condition, in hairless mice with barrier perturbation induced by single-dose ultraviolet B (UVB) irradiation. The GlcCer treatment also increased the level of TGase-1 mRNA in UVB-irradiated murine epidermis approximately 1.6-fold compared with the control. Further, all four sphingoid bases at 1 µM concentration enhanced CE formation of cultured normal human keratinocyte cells. Among them, SS, PS and SD, but not 4HS, stimulated production of involucrin, one of the CE major precursor proteins. SD increased the expression of TGase-1 mRNA, while SS increased the expression of TGase-3 mRNA. These results indicate that the skin barrier improvement induced by oral GlcCer treatment might be at least partly due to a reinforcement of CE formation in the epidermis mediated by sphingoid bases metabolically derived from GlcCer.

Galectin-3 expression in delayed neuronal death of hippocampal CA1 following transient forebrain ischemia, and its inhibition by hypothermia.

The ischemic damage in the hippocampal CA1 sector following transient ischemia, delayed neuronal death, is a typical apoptosis, but the mechanism underlying the delayed neuronal death is still far from fully understood. Galectin-3 is a ß-galactosidase-binding lectin which is important in cell proliferation and apoptotic regulation. Galectin-3 is expressed by microglial cells in experimental models of adult stroke. It has been reported that activated microglial cells are widely observed in the brain, including in the hippocampal CA1 region after transient ischemic insult. In the present study, time course expression of galectin-3 following transient forebrain ischemia in gerbils was examined by immunohistochemistry, combined with Iba-1 immunostaining (a specific microglial cell marker), hematoxylin and eosin staining (for morphological observation), and in situ terminal dUTP-biotin nick end labeling of DNA fragments method (for determination of cell death). Following transient ischemia, we observed a transient increase of galectin-3 expression in CA1 region, which was maximal 96h after reperfusion. Galectin-3 expression was predominately localized within CA1 region and observed only in cells which expressed Iba-1. The galectin-3-positive microglial cells emerge after the onset of neuronal cell damage. Expressions of galectin-3 and Iba-1 were strongly reduced by hypothermia during ischemic insult. Prevention of galectin-3 and Iba-1 expression in microglia by hypothermia has led us to propose that hypothermia either inhibits microglial activation or prevents delayed neuronal death itself. Our results indicate that galectin-3 might exert its effect by modulating the neuronal damage in delayed neuronal death.

The evaluation of surgical reconstruction for intermittent claudication by the Walking Impairment Questionnaire / Avaliação da reconstrução cirúrgica para claudicação intermitente pelo Walking Impairment Questionnaire

BACKGROUND: No standards reflecting the quality of life (QOL) and activity of daily living (ADL) in postoperative clinical course have been validated in the area of vascular disease. The Walking Impairment Questionnaire (WIQ) is a disease-specific questionnaire that evaluates patients with intermittent claudication due to arteriosclerosis obliterans (ASO). The WIQ uses four subscales: pain severity, walking distance, walking speed, and stair climbing while walking. OBJECTIVE: To evaluate the correlation between postoperative arterial blood flow and the Japanese edition of the WIQ. METHODS: Thirty-one patients (47 limbs) with intermittent claudication who had been subjected to lower limb surgical arterial reconstruction were assessed by WIQ, and compared with Ankle-Brachial Pressure Index (ABPI) and angiography. RESULTS: A significant increase in the WIQ score was identified in walking pain (26 versus 89.5, p<0.001), walking distance (13.1 versus 83.3, p<0.001), walking speed (10 versus 46, p<0.001), and stair climbing (6.2 versus 79, p<0.001). The correlation coefficient between the increase in postoperative ABPI and the WIQ score was R²=0.1889, which shows weak correlation. The correlation between blood flow obstruction due to the postoperative bypass that was scored by angiography and WIQ score was R²=0.3894, which shows moderate correlation. CONCLUSION: An improvement in the Japanese edition of the WIQ score was correlated not only with the patients' QOL after bypass revascularization but also with the rate of increase of postoperative ABPI and image findings, such as the postoperative angiography.

INTRODUÇÃO: Nenhum padrão de qualidade de vida e atividades diárias no período pós-operatório já foi validado na área de doenças vasculares. O Walking Impairment Questionnaire (WIQ) é um questionário específico para pacientes com claudicação intermitente devido à aterosclerose obliterante. O WIQ se baseia em quatro subescalas: intensidade da dor, distância caminhada, velocidade de caminhada e subir degraus durante caminhada. OBJETIVO: Avaliar a correlação entre fluxo sanguíneo periférico pós-operatório e a edição japonesa do WIQ. MÉTODOS: Trinta e um pacientes (totalizando 47 membros inferiores) com claudicação intermitente que se submeteram à reconstrução arterial cirúrgica foram avaliados pelo WIQ e comparados por meio do índice de pressão tornozelo-braço (ITB) e angiografia. RESULTADOS: Um aumento significativo no escore do WIQ foi observado em relação à dor durante caminhada (26 versus 89,5, p<0,001), distância caminhada (13,1 versus 83,3, p<0,001), velocidade da caminhada (10 versus 46, p<0,001) e ato de subir escadas (6,2 versus 79, p<0,001). O coeficiente de correlação entre o aumento no ITB pós-operatório e o escore WIQ foi R²=0,1889, demonstrando correlação baixa. A correlação entre obstrução do fluxo sanguíneo devido ao bypass pós-operatório avaliado por angiografia e WIQ foi R²=0,3894, o que revela uma correlação moderada. CONCLUSÃO: Uma melhora na edição japonesa do escore WIQ esteve correlacionada não apenas com a qualidade de vida dos pacientes após revascularização com bypass, mas também com a taxa de aumento no ITB pós-operatório e achados imaginológicos, como a angiografia pós-operatória.

Distribution and metabolism of sphingosine in skin after oral administration to mice.

In this study, (3)H- or (13)C(2),D(2)-sphingosine (SPH) was orally administered to mice to assess absorption, mass balance, tissue distribution, and metabolites in the skin. The blood concentration of (3)H-SPH showed a Tmax of 10.7 hr. The radioactivity in the skin reached 763.4 ng eq./g tissue at 12 hr, and decreased to 181.7 ng eq./g tissue at 168 hr. The concentration of radioactivity at 12 hr was 577.6 and 100.7 ng eq./g tissue in the dermis and epidermis, respectively. Thereafter, the dermis concentration decreased to 158.5 ng eq./g tissue, while the epidermis concentration increased to 298.8 ng eq./g tissue, suggesting that radioactivity moves from the dermis to the epidermis. Unchanged SPH along with lipophilic metabolites was detected in the skin of mice exposed orally to (3)H- or (13)C(2),D(2)-SPH. Moreover, in an in vitro study using human skin keratinocytes, a (13)C(2),D(2)-SPH-treatment resulted in the intracellular production of glucosylceramides (GlcCer) and ceramides (Cer) containing labeled-SPH. These results indicate the followings: first, that SPH is absorbed through the digestive tract and distributed to the skin; second, it is transferred from the dermis to the epidermis; and third, SPH is partly distributed to the skin in an unchanged form, and some of the distributed compounds are converted into GlcCer and Cer by biosynthesis.

The treatment of infectious aneurysms in the thoracic aorta; our experience in treating five consecutive patients.

The surgical strategy for infected thoracic aortic aneurysms (ITAA) remains controversial. Effective antibiotic therapy is mandatory and surgical intervention is indicated only to prevent an aneurysmal rupture. In-situ reconstruction through an aseptic route is ideal; however, urgent surgery is often required in the uncontrolled infectious phase. Five patients were recently treated surgically for ITAA. They were all males with a mean age of 61.2 (range: 58-66) years. Two patients were operated on urgently in the active infectious phase due to impending aneurysmal rupture. A total arch reconstruction with an extra-anatomical bypass between the ascending aorta and both femoral arteries in one and an extended aortic arch resection with an in-situ graft reconstruction were performed in the other. The other three patients underwent in-situ graft reconstructions in the controlled infectious phase. Four patients had multiple aneurysms, including nine saccular or nodular aneurysms. Short-interval computed tomography (CT) re-examinations revealed a rapid enlargement of the aneurysms and confirmed the diagnosis. All patients successfully survived and are doing well without any evidence of a recurrent aortic infection. The surgical strategy for ITAA should be determined on a case-by-case basis under a careful follow-up with short-interval CT re-examinations.