Associations of sitting time with leisure-time physical inactivity,education, and body mass index change

We aimed to investigate the associations of long-term leisure-time physical inactivity, body mass index (BMI) change, and education with sitting time in a 35-year follow-up based on self-reports in surveys. Influences of working status in 2011 and familial confounding on the associations were tested. Data were based on the population-based Finnish Twin Cohort of 5232 twins (53-67-year-old, 41% men) with four surveys in 1975-2011. Statistical analyses were performed using linear regression with several covariates. The effect of familial confounding (genetics and shared environment) was analyzed using a co-twin control design which should be interpreted as if familial confounding plays a role, an association should be seen among all individuals but not in discordant twin pairs. Compared to those not at work, those at work had a longer total sitting time/d. For those at work, higher education was associated with more total sitting but with less non-work sitting. Long-term leisure-time physical inactivity was associated with more non-work sitting among those at work, whereas long-term weight gain with more total and non-work sitting regardless of working status. Familial confounding attenuated the associations, except for the association of increasing BMI with total and non-work sitting among women at work. To conclude, total sitting time was longer among those still at work, but it was also influenced by long-term leisure-time physical inactivity, higher education, and an increase of BMI over the years. Public health efforts should be targeted to reduce sedentary behavior by promoting life-long leisure-time physical activity and weight control.     

Inhibition of the PI3K-Akt signaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line,MKN-45

It is well known that Fas ligand and anti-Fas antibodies can induce apoptosis, although some cancer cells are resistant to their stimuli. On the other hand, phosphatidylinositol 3-kinase (PI3 K) and Akt mediate the survival signal and allow the cells to escape from apoptosis in various human cancers. Thus, we postulated that LY294002, a PI3 K inhibitor, should inactivate Akt, consequently inhibiting cell proliferation and increase apoptosis in the human gastric carcinoma cell line, MKN-45. Previously, we reported that MKN-45 was resistant against the anti-Fas antibody, CH-11, without interferon-gamma pretreatment in vitro. LY294002 caused a decrease of phosphorylated-Akt and an inhibition of cell proliferation via cell cycle arrest in the G0/G1 phase by P27/Kip1 accumulation, but there was no obvious induction of apoptosis. The simultaneous treatment of LY294002 and CH-11 significantly induced apoptosis confirmed by morphology and DNA ladder formation. Decreased phosphorylated-Akt by LY294002 treatment led to a down-regulation of Mcl-2 and phosphorylated Bad proteins, which are anti-apoptotic factors and belong to the Bcl-2 family. On the other hand, expression levels of the other anti-apoptotic factors, such as FLICE-inhibitory protein (FLIP), Bcl-2 and Bcl-XL, which are associated with the Fas-mediated apoptotic signal pathway, did not change after LY294002 treatment. We concluded that: 1) the PI3K-Akt pathway plays an important role in preventing Fas-mediated apoptosis; and 2) a PI3 K inhibitor, such as LY294002, might be a useful anti-tumoral agent for gastric carcinoma.     

Applications of Botulinum toxin in urogynaecology

Botulinum toxin (BTX) is a neurotoxin produced by bacterium clostridium. It is the most poisonous naturally occurring substance known to mankind. The neurotoxin binds to the peripheral cholinergic terminals and inhibits acetylcholine release at that junction leading to flaccid paralysis. This process appears to offer an attractive therapeutic option, filling the void between anticholinergics and surgery in cases of neurogenic and idiopathic detrusor overactivity, detrusor sphincter dyssynergia (DSD), interstitial cystitis and pelvic pain. This article reviews the application of Botulinum toxin A in these conditions.     

Ligand-based pharmacophore modeling and molecular dynamic simulation approaches to identify putative MMP-9 inhibitors

MMP-9 is a calcium-dependent zinc endopeptidase that plays a crucial role in various diseases and is a ubiquitous target for many classes of drugs. The availability of MMP-9 crystal structure in combination with aryl sulfonamide anthranilate hydroxamate inhibitor facilitates to accentuate the computer-aided screening of MMP-9 inhibitors with the presumed binding mode. In the current study, ligand-based pharmacophore modeling and 3D-QSAR analysis were performed using 67 reported MMP-9 inhibitors possessing pIC₅₀ in the range of 5.221 to 9.000. The established five-point hypothesis model DDHRR_1 was statistically validated using various parameters R² (0.9076), Q² (0.8170), and F value (83.5) at a partial least square of four. Hypothesis validation and enrichment analysis were performed for the generated hypothesis. Further, Y-scrambling and Xternal validation using mean-absolute error-based criteria were performed to evaluate the reliability of the model. Docking in the XP mode and binding free energy was calculated for 67 selected ligands to explore the key binding interactions and binding affinity against the MMP-9 enzyme. Additionally, high-throughput virtual screening was carried out for 2.3 million chemical molecules to explore the potential virtual hits, and their predicted activity was calculated. Thus, the results obtained aid in developing novel MMP-9 inhibitors with significant activity and binding affinity.

MMP-9 is a calcium-dependent zinc endopeptidase that plays a crucial role in various diseases and is a ubiquitous target for many classes of drugs.     

Using digital technology to create a custom esthetic bandage for patients after rhinectomy

Patients undergoing partial or total rhinectomy surgeries are left with a lifelong facial defect that poses psychosocial and functional challenges. The extended postoperative healing period after rhinectomy can delay the timely restoration of a patient’s nose by definitive prosthesis when conventional impression methods are used. The treatment workflow for fabricating a custom esthetic nasal bandage with the use of digital technology is introduced to avoid the conventional preoperative impression, as well as to allow for immediate delivery at the postoperative follow-up visit.     

Radiosensitivity of permanent human bone marrow stromal cell lines: effect of dose rate

In contrast to the dose-rate independent X ray killing observed with human bone marrow hematopoietic stem cells, bone marrow adherent stromal cells from the same fresh marrow harvests demonstrate increased radiation resistance at low dose rate (LDR) (5 cGy/min), compared to high dose rate (HDR) irradiation (120-200 cGy/min). Physiologic changes observed in plateau phase bone marrow cells after LDR irradiation in vivo and in vitro suggested that marrow stromal cells might be heterogeneous in LDR irradiation repair. Five permanent clonal bone marrow stromal lines were derived from a single human marrow donor. Each cell line was positive for markers of fibroblasts including: immunohistochemically detectable fibronectin, collagen, acid phosphatase, and nonspecific esterase, and was negative for Factor VIII, alkaline phosphatase, lysozyme and several markers of marrow macrophages. The x-irradiation survival curve of each cell line was determined at LDR and HDR in vitro. Cell lines KM102, KM103, KM104, and KM105 each demonstrated a significant (p less than .05) increase in radioresistance at LDR (D0 = 142, n = 2.9; D0 = 131, n = 2.5; D0 = 145, n = 2.1 and D0 = 127, n = 2.1 respectively) compared to HDR: (D0 = 111, n = 2.1; D0 = 94, n = 3.5; D0 = 99, n = 3.5 and D0 = 95, n = 2.1 respectively). In contrast, cell line KM101 demonstrated no significant change in radiosensitivity relative to dose rate at LDR (D0 = 113, n = 3.3) compared to HDR, D0 = 114, n = 3.3. Cell line KM101 was more supportive than the other lines of cocultivated hemopoietic cells in vitro. Subclones of KM101 and KM104 selected by retroviral vector transfer of the neor gene for growth in the antibiotic neomycin-analogue G418, maintained the stably associated radiobiologic properties of each parent clonal line. These data indicate significant heterogeneity in the LDR irradiation response of clonal stromal cell lines derived from human bone marrow.     

Microphthalmia and lack of vitreous body in transgenic mice expressing the first immunoglobulin-like domain of nectin-1

Background Nectins are Ca²⁺-independent immunoglobulin (Ig)-like cell-cell-adhesion molecules. We have generated transgenic mice expressing a series of soluble forms of nectin-1, and investigated special effects of each soluble form of nectin-1 in vivo. In the course of generating transgenic mice expressing a soluble form of nectin-1 consisting of the first Ig-like domain of nectin-1 and the Fc portion of human IgG1 (PHveC-VhIg), we found that all of the transgenic founder mice showed a microphthalmia. The purpose of this study is to examine functions of the extracellular domains of nectin-1 in eye development using transgenic technology. Methods Eyes of four different transgenic mouse lines expressing each soluble form of nectin-1 were analyzed histologically. Tissue sections were processed with hematoxylin-eosin staining and indirect immunoperoxidase technique. Results All of five transgenic mouse founders expressing PHveC-VhIg, and of three lines expressing PHveC-VpIg made of the first Ig-like domain fused to porcine Fc portions at 5 weeks showed a microphthalmia, but not all of the transgenic mouse lines expressing PHveCIg or PHveCpIg made of the entire ectodomain fused to human or porcine Fc portions. In the abnormal eyes, the vitreous body was almost absent. In PHveC-VhIg-expressing mice at postnatal day 6, each vitreous space was very small. In the neonatal transgenic mice, the vitreous body was almost the same as that of control mice, and PHveC-VhIg was expressed in the optic nerve, conjunctival epithelium, ciliary body, corneal and lens epithelium. At this stage, nectin-1, -3 and -4 were stained in the optic nerve of control mice as well as in that of the transgenic mice. Nectin-1 is faintly stained in the epithelium of the cornea and lens epithelium, but not in the ciliary body. Conclusion Soluble forms of the first Ig-like domain of nectin-1 (PHveC-VhIg and PHveC-VpIg), but not those of the entire ectodomain (PHveCIg and PHveCpIg), lead to microphthalmia and lack of vitreous body in the transgenic mice. Transgenic mice generating group: Keiko Amagai, Minako Kuramochi, Yuki Watanabe and Shigeto Kouda (Sankyo Labo Service Corporation, Tokyo 132-0023, Japan).