On cross-odds ratio for multivariate competing risks data.
The cross-odds ratio is defined as the ratio of the conditional odds of the occurrence of one cause-specific event for one subject given the occurrence of the same or a different cause-specific event for another subject in the same cluster over the unconditional odds of occurrence of the cause-specific event. It is a measure of the association between the correlated cause-specific failure times within a cluster. The joint cumulative incidence function can be expressed as a function of the marginal cumulative incidence functions and the cross-odds ratio. Assuming that the marginal cumulative incidence functions follow a generalized semiparametric model, this paper studies the parametric regression modeling of the cross-odds ratio. A set of estimating equations are proposed for the unknown parameters and the asymptotic properties of the estimators are explored. Non-parametric estimation of the cross-odds ratio is also discussed. The proposed procedures are applied to the Danish twin data to model the associations between twins in their times to natural menopause and to investigate whether the association differs among monozygotic and dizygotic twins and how these associations have changed over time.


[Use of the Term ″Pre-Embryo″ In the Biomedical Literature From Its Origin to the Present].
In this article, we present a review about the use of the term ″preembryo″ in the scientific literature as well as Bioethics from its origin, back in June 1979, to the end of the year 2014. We analyze their evolution along the time comparing with other terms commonly used in embryology. Also, we show the relevant journals in which this term appears, (offering the impact index within their specific field), and the authors who use it the most. The term ″preembryo″ arose in the scientific literature in 1979, remaining for about 6 years without reappearing in the scientific literature. Then, after an increase of articles, that covers the 90's decade, began to decrease its use without having disappeared altogether. Our study also shows that the use of the word ″preembryo″ has not increased with the passage of time; on the contrary, it is becoming less used in the biomedical literature. This does not occur with other terms that name the embryo before implantation, which have not ceased to increase during these years, both referring to the human species and other animal species. Finally, the term ″pre-embryo″ appears very little in journals related to the reproduction biology area, but it does so in obstetrics and gynecology, where many articles on assisted reproduction are published. Our findings suggest that, instead of replacing classical embryological terms, the word ″preembryo″ does not seem to affect the use of them. Likewise, this word has a hypertrophied use in humans without an apparent reason, which would support the artificial nature of this term. Finally, the term ″pre-embryo″ appears very little in journals of reproduction biology area, but it does so in obstetrics and gynecology, where many articles on assisted reproduction are published. In conclusion, instead of substituting classical embryological terms, the word ″pre-embryo″ does not seem to affect the use of them and in the current discussions about the human condition of the embryo this term is no longer used.


Brd4 regulates the expression of essential autophagy genes and Keap1 in AML cells.
We have recently reported that activation of Brd4 is associated with the presence of autophagy in NPMc+ and MLL AML cells. In order to determine the mechanisms underlying this relationship, we have examined the role of Brd4 in regulating the expression of several genes that are central to the process of autophagy. We found that Brd4 binds to the promoters of ATG 3, 7 and CEBPβ, and expression of these genes is markedly reduced by inhibitors of Brd4, as well as by Brd4-shRNA and depletion of CEBPβ. Inhibitors of Brd4 also dramatically suppress the transcription of Keap1, thereby increasing the expression of anti-oxidant genes through the Nrf2 pathway and reducing the cytotoxicity induced by Brd4 inhibitors. Elimination of ATG3 or KEAP1 expression using CRISPR-cas9 mediated genomic editing markedly reduced autophagy. We conclude that Brd4 plays a significant role in autophagy activation through the direct transcriptional regulation of genes essential for it, as well as through the Keap1-Nrf2 axis in NPMc+ and MLL-fusion AML cells.


Transcatheter Mitral Valve Replacement in Patients with Mitral Annular Calcification: A Review.
Mitral annular calcification (MAC) is a progressive degenerative calcification of the mitral valve (MV) that is associated with mitral stenosis, regurgitation or both. Patients with MAC are poor candidates for MV surgery because of technical challenges and high peri-operative mortality. Transcatheter MV replacement (TMVR) has emerged as an option for such high surgical risk patients. This has been described with the use of the SAPIEN transcatheter heart valve (valve-in-MAC) and dedicated TMVR devices. Careful anatomic assessment is important to avoid complications of TMVR, such as left ventricular outflow tract obstruction, valve migration, embolization and paravalvular mitral regurgitation. In this review, we discuss the pathology, importance of preprocedural multimodality imaging for optimal patient selection, clinical outcomes and complications associated with TMVR in patients with MAC.


Relationship between serum total sialic acid and C-reactive protein in silicosis.
Serum total sialic acid and C-reactive protein (CRP) were studied in 68 patients with silicosis divided into 3 groups according to the evolutive stage of disease. The results were compared with the data obtained in a control group of 35 healthy subjects. The changes in serum total sialic acid levels were in parallel with those of CRP in silicosis. Patients in stage III had the highest mean values of serum total sialic acid (p < 0.01) and of CRP (p < 0.001). Linear regression analysis revealed a close positive correlation between serum total sialic acid and CRP levels in silicosis (r = 0.86, p < 0.01).


Thyroid Hormone Regulates the mRNA Expression of Small Heterodimer Partner through Liver Receptor Homolog-1.
Expression of hepatic cholesterol 7α-hydroxylase (CYP7A1) is negatively regulated by orphan nuclear receptor small heterodimer partner (SHP). In this study, we aimed to find whether thyroid hormone regulates SHP expression by modulating the transcriptional activities of liver receptor homolog-1 (LRH-1). We injected thyroid hormone (triiodothyronine, T3) to C57BL/6J wild type. RNA was isolated from mouse liver and used for microarray analysis and quantitative real-time polymerase chain reaction (PCR). Human hepatoma cell and primary hepatocytes from mouse liver were used to confirm the effect of T3 in vitro. Promoter assay and electrophoretic mobility-shift assay (EMSA) were also performed using human hepatoma cell line. Initial microarray results indicated that SHP expression is markedly decreased in livers of T3 treated mice. We confirmed that T3 repressed SHP expression in the liver of mice as well as in mouse primary hepatocytes and human hepatoma cells by real-time PCR analysis. LRH-1 increased the promoter activity of SHP; however, this increased activity was markedly decreased after thyroid hormone receptor β/retinoid X receptor α/T3 administration. EMSA revealed that T3 inhibits specific LRH-1 DNA binding. We found that thyroid hormone regulates the expression of SHP mRNA through interference with the transcription factor, LRH-1.


Multi-Parameter Quantitative Imaging of Tumor Microenvironments Reveals Perivascular Immune Niches Associated With Anti-Tumor Immunity.
Tumors are populated by a multitude of immune cell types with varied phenotypic and functional properties, which can either promote or inhibit anti-tumor responses. Appropriate localization and function of these cells within tumors is critical for protective immunity, with CD8 T cell infiltration being a biomarker of disease outcome and therapeutic efficacy. Recent multiplexed imaging approaches have revealed highly complex patterns of localization for these immune cell subsets and the generation of distinct tumor microenvironments (TMEs), which can vary among cancer types, individuals, and within individual tumors. While it is recognized that TMEs play a pivotal role in disease progression, a better understanding of their composition, organization, and heterogeneity, as well as how distinct TMEs are reshaped with immunotherapy, is necessary. Here, we performed spatial analysis using multi-parameter confocal imaging, histocytometry, and CytoMAP to study the microanatomical organization of immune cells in two widely used preclinical cancer models, the MC38 colorectal and KPC pancreatic murine tumors engineered to express human carcinoembryonic antigen (CEA). Immune responses were examined in either unperturbed tumors or after immunotherapy with a CEA T cell bispecific (CEA-TCB) surrogate antibody and anti-PD-L1 treatment. CEA-TCB mono and combination immunotherapy markedly enhanced intra-tumoral cellularity of CD8 T cells, dominantly driven by the expansion of TCF1-PD1+ effector T cells and with more minor increases in TCF1+PD1+ resource CD8 T cells. The majority of infiltrating T cells, particularly resource CD8 T cells, were colocalized with dendritic cells (DCs) or activated MHCII+ macrophages, but largely avoided the deeper tumor nest regions composed of cancer cells and non-activated macrophages. These myeloid cell - T cell aggregates were found in close proximity to tumor blood vessels, generating perivascular immune niches. This perivascular TME was present in untreated samples and markedly increased after CEA-TCB therapy, with its relative abundance positively associated with response to therapy. Together, these studies demonstrate the utility of advanced spatial analysis in cancer research by revealing that blood vessels are key organizational hubs of innate and adaptive immune cells within tumors, and suggesting the likely relevance of the perivascular immune TME in disease outcome.


Ultrastructure of the sternocleidomastoid muscle in muscular torticollis.
The sternocleidomastoid muscles from five children with muscular torticollis--examined by transmission electron microscopy, exhibited a marked increase in interstitial collagen deposition, and scattered areas of amorphous ground substance with electron dense deposits. No vascular abnormalities were observed. Ultrastructural muscle abnormalities showed various stages of immobilization degeneration including nearly complete loss of myofibrils. The muscle abnormalities ultrastructurally are consistent with immobilization degeneration, probably secondary to the marked fibrosis in the sternocleidomastoid muscle.


A non-parametric graphical representation of the relationship between survival and the occurrence of an event: application to responder versus non-responder bias.
Reports of cancer clinical trials often attempt to evaluate whether tumour response is associated with prolonged survival. Proper analysis requires accounting for the time-dependent nature of response status. We review a valid and relatively simple method of significance testing for this problem, and develop a corresponding non-parametric method for displaying the association between survival and occurrence of response. The new method applies to many other clinical problems involving representation and the association between survival and the occurrence of an event. We illustrate the method with data from two clinical trials.


[Role of total bladder resection and reconstructive surgery in children with soft tissue sarcomas--three clinical cases)].
Soft tissue tumors of the lower genitourinary tract in children require a multidisciplinary treatment. The international CWS-91 and CWS-96 protocols established the second-look operation as a control procedure. One of the surgical options is a total cystectomy followed by the subsequent genitourinary reconstruction. The article presents a short characteristic of the reconstructive method modo Studer, advantages connected with this procedure, possible complications as well as description of three clinical cases of children treated from 1994 to 2001 in the Department of Hematology and Pediatric Oncology in Wrocław. All patients were qualified as the clinical stage III and treated with primary chemotherapy and/or radiotherapy, followed by total cystectomy and subsequent genitourinary reconstruction modo Studer. This procedure led in all cases to the complete remission, which is present up to date. The regular clinical and diagnostic controls as well as the patients' compliance enable the immediate detection of any possible complication as well as the nearly unchanged life activity.


A thermoregulatory behavior.
The existence of yawning across vertebrate species suggests important basic functions, and the spontaneous and involuntary nature of a yawn lends support for it having adaptive significance. Recent research suggests the biological function of yawning among homeotherms is central thermoregulation. Comparative research from birds, rats and humans shows that yawning reduces brain and body temperature, is influenced by the range and direction of ambient temperature change, and is inhibited by methods of behavioral cooling. This research provides strong support for the view that yawning stimulates or facilitates cortical arousal, demonstrating that a yawn is a behavioral response to transient brain hyperthermia, acting to counter intermittent increases in brain temperature and promote thermal homeostasis. This theory is powerful because it not only integrates a great deal of seemingly diverse information about yawning, but it can also be used to generate numerous testable predictions. Applications from this research range from basic physiological understanding to the improved treatment and understanding of diseases associated with thermoregulatory dysfunction.


A case of acute disseminated encephalomyelitis associated with hepatitis C virus infection.
Acute disseminated encephalomyelitis (ADEM) is a monophasic autoimmune demyelinating disease of the central nervous system, which typically follows acute viral or bacterial infection or vaccination. We report a case of ADEM associated with hepatitis C virus (HCV) infection with positive serum and cerebrospinal fluid (CSF) anti-HCV antibody. After steroid treatment, neurologic symptoms were improved. Virus triggers autoimmunity or direct viral invasion plays a part in the genesis of ADEM. This is the first reported case of ADEM with anti-HCV antibody in the CSF.


Characterization of evolution of mode coupling in a graded-index polymer optical fiber by using Brillouin optical time-domain analysis.
A narrow bandwidth (2GHz) π-phase-shift flattop fiber Bragg grating (FBG) is proposed to achieve Brillouin optical time-domain analysis (BOTDA) for perfluorinated graded-index polymer optical fibers (GI-POFs) for the first time to best of our knowledge. Using the technique of BOTDA, we explore the evolution of mode coupling in perfluorinated GI-POFs by analyzing the Brillouin frequency shift (BFS) variation along the whole fiber, and compare them with that of silica graded index multimode fibers (GI-MMFs). The characteristics of mode coupling of GI-POFs and GI-MMFs were also investigated in terms of the speckle patterns at the output face of the two fibers. The results show that compared with silica GI-MMFs, GI-POFs exhibit more efficient mode coupling and the excellent ablility of mode scrambling regardless of alignment conditions.


Sociobehavioral correlates of HIV risk among men who have sex with men in Chhattisgarh, India: analysis of sentinel surveillance data.
Men who have sex with men (MSM) in India are mostly hidden due to stigma and discrimination and are at a higher risk of acquiring human immunodeficiency virus (HIV). HIV Sentinel Surveillance (HSS) reported an increased HIV burden in Chhattisgarh, an important state in central India. This state has the distinction of having the highest HIV prevalence among MSM in India; therefore, it warrants special attention; hence, we focused on the role of MSM in the HIV epidemic in this state. Cross-sectional analysis of the most recent latest (2010-2011) HSS data of 227 MSM in Chhattisgarh revealed a HIV seropositivity of 14.98%. Older age, unemployment, and receiving money for sex with a man were associated with a higher HIV risk. Participants were mostly young (mean age, approximately 26 years), school-level educated (51.98%), urban residents (99.56%), in service (46.26%), not involved in heterosexual activity (97.36%), or paid sex (68.72%). None of the participants reported injection drug use, and almost all of them (98.68%) were kothis. Some of the observed associations lacked statistical power due to sparse data obtained during this initial surveillance among MSM in Chhattisgarh. Therefore, further studies involving a larger population are needed to understand the role of MSM in the dynamics of the HIV epidemic in this state to facilitate the planning of appropriate interventions, as the epidemic is likely to be concentrated among MSM in Chhattisgarh.


Effect of exogenous p51a gene on the growth and chemo sensitivity of human lung adenocarcinoma cell lines.
The dysfunction of p53-mediated apoptosis is the key to tumorigenesis, so most gene therapy programs concentrate on improving the expressing level of wild-type p53 in tumour cells. However, the p53 gene therapy has not yielded satisfactory results in tumours with normal p53 function. A new member of p53 gene family-p63, has provided new hopes. TAp63γ (p51A) resembles p53 the most, thus it might become a new promising therapeutic gene of tumours. We designed the primer pairs of p51A and amplified the p51A cDNA sequence from human skeletal muscle poly A + RNA to construct recombinant plasmid. It was then transfected into human lung adenocarcinoma cell lines A549 and NCI-H1299. RT-PCR, Western blot, MTT, flow cytometry and colony formation assay were used to analyse the growth and chemosensitivity of tumour cells. The recombinant plasmid was constructed and transfected into tumour cells successfully. After transfection, p51A mRNA, P51A protein and P21 protein level raised significantly. Cell proliferation capacity and colony formation rate decreased while cell apoptosis rate and chemosensitivity to cisplatin and adriamycin increased significantly. Exogenous p51A gene can increase its expression in A549 and NCI-H1299 cells, suppress cell growth and induce cell apoptosis. Moreover, it can also cooperate with chemotherapy and reduce the dose and side-effect. p51A gene can suppress tumours in spite of p53 status and p21 gene might be involved. It might become a new promising therapeutic gene of tumours, which will make up for the limitation of p53 gene therapy.


Ureteroscopy during pregnancy under local anesthesia and light sedation: Technique and video.
Ureteroscopy during pregnancy has become increasingly recognized as a safe intervention. Performing it under local anesthesia and light sedation reduces the risks associated with general or regional anesthesia, such as difficult airway scenarios, hypothermia, and hypotension. In addition, this approach reduces the total amount of fetal exposure to medications and anesthetic agents. Performing ureteroscopy in this manner requires a number of adjustments and modifications to the standard technique. This article provides a summary in a step-by-step format, as well as an accompanying video demonstration.


The Prevalence of Antenatal Depression and its Related Factors in Chinese Pregnant Women who Present with Obstetrical Complications.
The psychological status of Chinese pregnant women who present with obstetrical complications is concerning to Chinese health professionals. This study aimed to investigate the prevalence of antenatal depression and analyzed related risk factors in a population of high-risk Chinese women. A large sample size, cross-sectional study. A total of 842 pregnant women with complications completed the Chinese version of the Postpartum Depression Screen Scale (PDSS) in this cross-sectional study. t-Test, ANOVA and Binary logistic regression tests were used in data analysis of antenatal depression and risk factors. The prevalence of major or minor depression in high-risk Chinese pregnant women during antenatal period was 8.3% and 28.9%, respectively. Independent-sample t-test and two-way analysis of variance (ANOVA) indicated significant differences in age, education, occupation and the number of complications (P<0.05). Binary logistic regression analysis indicated a significant negative association between depression and education (P<0.01) with lower educational level (OR: 0.590; 95% CI: 0.424-0.820) associated with a higher risk for depression. A significant positive association was observed between depression and age (P<0.05) with higher age (OR: 1.338; 95% CI: 1.008-1.774) correlated with a higher risk for depression. Women who experienced obstetric complications presented with higher PDSS depression scores. Screening for antenatal depression in high-risk pregnant women to promote early detection of depression and reduce health risks for universal health promotion is recommended.


Contemporary surgical treatment of primary hyperparathyroidism without intraoperative parathyroid hormone measurement.
Primary hyperparathyroidism (pHPT) is usually the result of a single adenoma that can often be accurately located preoperatively and excised by a focused operation. Intraoperative parathyroid hormone (IOPTH) measurement is used occasionally to detect additional abnormal glands. However, it remains controversial as to whether IOPTH monitoring is necessary. This study presents the results of a large series of focused parathyroidectomy without IOPTH measurement. Data from 2003 to 2014 were collected on 180 consecutive patients who underwent surgical treatment for pHPT by a single surgeon. Preoperative ultrasonography and sestamibi imaging was performed routinely, with computed tomography (CT) and/or selective venous sampling in selected cases. The preferred procedure for single gland disease was a focused lateral approach guided by on-table surgeon performed ultrasonography. Frozen section was used selectively and surgical cure was defined as normocalcaemia at the six-month follow-up appointment. Focused surgery was undertaken in 146 patients (81%) and 97% of these cases had concordant results with two imaging modalities. In all cases, an abnormal gland was discovered at the predetermined site. Of the 146 patients, 132 underwent a focused lateral approach (11 of which were converted to a collar incision), 10 required a collar incision and 4 underwent a mini-sternotomy. At 6 months following surgery, 142 patients were normocalcaemic (97% primary cure rate). Three of the four treatment failures had subsequent surgery and are now biochemically cured. There were no complications or cases of persistent hypocalcaemia. This study provides further evidence that in the presence of concordant preoperative imaging, IOPTH measurement can be safely omitted when performing focused parathyroidectomy for most cases of pHPT.


Evolution of the large-subunit ribosomal RNA binding site for protein L23/25.
The region of the large-subunit rRNA encompassing the D7 divergent domain is organized within eukaryotes in a patchwork of short conservative secondary-structure features interspersed with more rapidly evolving sequences. It contains the attachment site of protein L25 (E. coli L23), which binds rRNA in the first stages of ribosome assembly, suggesting a crucial importance of this region in ribosome elaboration and functioning. A better understanding of its roles requires a good knowledge of its mode of structural variation during the course of evolution. With this aim, we sequenced the D7 region for 24 new invertebrate species belonging to annelids, molluscs, arthropods, and eight other deep-branching invertebrate phyla. Their comparison allowed us to propose refinements in previous eukaryotic folding models. A detailed analysis of the pattern of variation at each position both within the D7 region and along the L23/25 sequence by reference to previous heterologous binding experiments gives new insight into the rRNA-protein contacts. We identified in the D7 region and L23/25, respectively, six and five positions presenting a pattern of variation compatible with experimental results, three of which show coincident variations which support their possible involvement in the rRNA-L23/25 binding.


Characterization of oral in vivo films formed on different types of solid surfaces.
Studies were made of oral films formed in vivo, which had been allowed to form on fused silica and Ge-prisms during periods between 2 s and 2 h using a variety of physico-chemical methods. To produce surfaces of different qualities the silica and Ge-prisms had either been detergent-washed, glow discharge treated or covered with polydimethylsiloxane. The following simultaneous analytical techniques were performed on the adsorbed films: a. internal reflection infrared spectroscopy, b. ellipsometry, c. contact potential measurements, d. contact angle measurements, e. scanning electron microscopy and f. energy-dispersive x-ray analysis. The results of these studies show that the formation of oral films proceeds at high speed and is of a certain qualitative selectivity. The formed films were found to be stable over long periods of time, and only showed patches of adhering micro-organisms on some of the prisms which had been exposed in the oral cavity for 2 h.


Better futures: a randomized field test of a model for supporting young people in foster care with mental health challenges to participate in higher education.
The purpose of the study was to conduct a preliminary efficacy evaluation of the Better Futures model, which is focused on improving the postsecondary preparation and participation of youth in foster care with mental health challenges. Sixty-seven youth were randomized to either a control group that received typical services or an intervention group, which involved participation in a Summer Institute, individual peer coaching, and mentoring workshops. Findings indicate significant gains for the intervention group on measures of postsecondary participation, postsecondary and transition preparation, hope, self-determination, and mental health empowerment, as compared to the control group. Youth in the intervention group also showed positive trends in the areas of mental health recovery, quality of life, and high school completion. Implications for future research and practice are discussed, while emphasizing the capacities of youth in foster care with mental health conditions to successfully prepare for and participate fully in high education.


Clinical influence of neoadjuvant chemoradiotherapy on immunonutritional status in locally advanced rectal cancer.
Cancer patients receiving various anti-cancer treatments commonly experience malnutrition, and many studies have reported that nutritional status is associated with survival and prognosis. Although standard neoadjuvant chemoradiotherapy (CRT) is commonly used in patients with locally advanced rectal cancer owing to its tumor-downsizing and downstaging effects, there is a lack of research on the impact of patients' nutritional status on the efficacy of neoadjuvant CRT. We investigated the immunonutritional markers before and after long-course neoadjuvant CRT in 131 patients diagnosed with locally advanced rectal cancer from March 2013 to March 2022. We divided the patients into two groups: a low prognostic nutritional index (PNI) with a cutoff value of 50.92, and a high PNI. In both groups, significant decreases in lymphocyte count and PNI and an increase in neutrophil-to-lymphocyte ratio (NLR) were observed before and after CRT (P<0.001). Furthermore, a higher proportion of patients experienced adverse effects in the low PNI group than in the high PNI group (76.6% in low PNI vs. 54.8% in high PNI, P=0.013). The most commonly reported CRT-induced adverse effect was lower gastrointestinal tract toxicity. By measuring the PNI and NLR without additional tests prior to starting neoadjuvant CRT in patients with locally advanced rectal cancer, it is possible to predict the risk of acute adverse effects caused by CRT. Additionally, providing external nutritional support to reduce the immunonutritional changes that occur during CRT can decrease side effects and potentially increase treatment compliance.


A missense mutation in ALDH1A3 causes isolated microphthalmia/anophthalmia in nine individuals from an inbred Muslim kindred.
Nine affected individuals with isolated anophthalmia/microphthalmia from a large Muslim-inbred kindred were investigated. Assuming autosomal-recessive mode of inheritance, whole-genome linkage analysis, on DNA samples from four affected individuals, was undertaken. Homozygosity mapping techniques were employed and a 1.5-Mbp region, homozygous in all affected individuals, was delineated. The region contained nine genes, one of which, aldehyde dehydrogenase 1 (ALDH1A3), was a clear candidate. This gene seems to encode a key enzyme in the formation of a retinoic-acid gradient along the dorsoventral axis during an early eye development and the development of the olfactory system. Sanger sequence analysis revealed a missense mutation, causing a substitution of valine (Val) to methionine (Met) at position 71. Analyzing the p.Val71Met missense mutation using standard open access software (MutationTaster online, PolyPhen, SIFT/PROVEAN) predicts this variant to be damaging. Enzymatic activity, studied in vitro, showed no changes between the mutated and the wild-type ALDH1A3 protein.


Ultrafast, One-Step, Label-Based Biosensor Diagnosis Platform for the Detection of Mycobacterium tuberculosis in Clinical Applications.
Tuberculosis (TB) is a chronic infectious disease caused by the etiological agent Mycobacterium tuberculosis (MTB). Because the majority of TB patients come from poor economic backgrounds, the development of a simple, specific, low-cost, and highly sensitive detection method for the pathogen is extremely important for the prevention and treatment of this disease. In the current study, an efficient detection method for visual, rapid, and highly sensitive detection of MTB utilizing multiplex loop-mediated isothermal amplification combined with a label-based lateral flow immunoassay biosensor (mLAMP-LFIA) was developed. Three specific primer sets targeting the MTB genes IS6110 and mpb64 were successfully designed and synthesized for the LAMP assay. The optimal reaction conditions for the mLAMP-LFIA assay were confirmed to be 67 °C for 40 min. The mLAMP amplicons were intuitively verified using the LFIA biosensor within 5 min. The entire process, including clinical sample processing, amplification reaction, and product verification, was completed within 80 min. The limit of detection of the mLAMP-LFIA assay established in the current study was 100 fg per reaction for the genomic DNA of MTB H37Rv. The analytical specificity of the mLAMP-LFIA assay was one hundred percent, and no cross-reactions with non-target strains were detected. Compared with the GeneXpert test, the sensitivity of mLAMP-LFIA for 148 clinical specimens was 100% (97/97), and the specificity was 98.04% (50/51) in the preliminary evaluation of the clinical application. Hence, the mLAMP-LFIA method, targeting the IS6110 and mpb64 genes, is an ultrafast, one-step, low-cost, and highly sensitive detection method that could be used as a screening and/or diagnostic tool for MTB in the clinical setting, basic science laboratories, and especially in resource-poor regions.


G2S: a web-service for annotating genomic variants on 3D protein structures.
Accurately mapping and annotating genomic locations on 3D protein structures is a key step in structure-based analysis of genomic variants detected by recent large-scale sequencing efforts. There are several mapping resources currently available, but none of them provides a web API (Application Programming Interface) that supports programmatic access. We present G2S, a real-time web API that provides automated mapping of genomic variants on 3D protein structures. G2S can align genomic locations of variants, protein locations, or protein sequences to protein structures and retrieve the mapped residues from structures. G2S API uses REST-inspired design and it can be used by various clients such as web browsers, command terminals, programming languages and other bioinformatics tools for bringing 3D structures into genomic variant analysis. The webserver and source codes are freely available at https://g2s.genomenexus.org. email@example.com. Supplementary data are available at Bioinformatics online.


Treatment of anterior cruciate ligament injuries, part 2.
Anterior cruciate ligament tears, common among athletes, are functionally disabling; they predispose the knee to subsequent injuries and the early onset of osteoarthritis. A total of 3810 studies published between January 1994 and the present were identified and reviewed to determine the current state of knowledge regarding the treatment of anterior cruciate ligament injuries. Part 1 of this article focused on studies pertaining to the biomechanical behavior of the anterior cruciate ligament, the prevalence of and risk factors for injuries related to it, the natural history of the ligament-deficient knee, injuries associated with anterior cruciate ligament disruption, indications for the treatment of anterior cruciate ligament injuries, as well as nonoperative and operative treatments. Part 2 includes technical aspects of anterior cruciate ligament surgery, bone tunnel widening, graft healing, rehabilitation after anterior cruciate ligament reconstruction, and the effects of sex, age, and activity level on the outcome of such reconstructive surgery.


Controlled generation of vortex and vortex dipole from a Gaussian pumped optical parametric oscillator.
We report on direct generation of optical vortices from a continuous-wave (cw), Gaussian beam pumped doubly resonating optical parametric oscillator (DRO). Using a 30-mm long MgO doped periodically poled lithium tantalate (MgO:sPPLT) crystal based DRO, pumped in the green by a frequency-doubled Yb-fiber laser in Gaussian spatial profile we have generated signal and idler beams in vortex mode of order, l = 1, tunable across 970-1178 nm. Controlling the overlap between the Gaussian pump beam with the fundamental cavity mode of the resonant signal and idler beams of the DRO through the tilt of the pump beam and/or the cavity mirror in transverse plane, we have generated both signal and idler beams in vortex and vortex dipole spatial profiles. Using the theoretical formalism for the vortex beam generation through the superposition of two Gaussian beams we have numerically calculated the spatial profile of the generated beam in close agreement with our experiment results. The generic experimental scheme can be used to generate optical vortex across the electromagnetic spectrum and in all time scales (cw to ultrafast) using suitable OPO.


Quantum chemistry study on absorption spectra, electronic and electrical properties of organic dye on anatase(001).
As the most reactive surface, the stoichiometric O-bridge terminated anatase(001) surface attracted considerable attentions in many application fields. The interfacial electron transfer in dye-sensitized anatase(001) plays a principal role in a variety of photoinduced reactions. In the present work, the UV-vis absorption spectrum of TiO2 bulk and different surface models were calculated by means of tight-binding quantum chemical molecular dynamics program "Colors-excite" for the first time. The thickness dependence on electronic and electrical properties of anatase(001) surface was achieved. The anatase(001) surface with a thickness of 1.0 nm shows excellent electronic and electrical properties. Moreover, the most suitable binding mode (dissociative adsorption) and absorption spectra of perylene with acrylic acid (PAA) on the optimum anatase(001) were investigated. A significant red-shift was observed from the UV-vis absorption spectrum of PAA/anatase(001) system. The red-shift occurring when PAA adsorbed on anatase(001) surface suggests that PAA/anatase(001) may be potential candidate for dye-sensitized solar cell. This study also proposed an effective computational tool "Colors-excite" to study of the electronic excitation properties for both molecular and periodic systems.


Corneal aberrations before and after small-incision cataract surgery.
To study the effect of small-incision cataract surgery on the optical aberrations of the cornea. Corneal topography was measured before and after cataract surgery on 70 eyes of 70 patients. Monofocal foldable IOLs were implanted after phacoemulsification through a clear-cornea, 3.5-mm incision without suture. Corneal aberrations, up to the fifth order and 6-mm pupil, were calculated by ray-tracing from the corneal topography. Pre- and postoperative aberrations were compared in each patient and the optical changes induced by surgery investigated. The root mean square of the wave aberration slightly increased on average after surgery (pre, 0.65 +/- 0.46 microm; post, 0.85 +/- 0.63 microm). Most aberration terms were similar, averaged across the 70 patients, before and after surgery (spherical aberration: pre, 0.32 +/- 0.12 microm, and post, 0.34 +/- 0.19 microm; astigmatism: pre, 0.9 +/- 0.8 D, and post, 1.1 +/- 1.0 D; coma: pre, 0.27 +/- 0.18 microm, and post, 0.32 +/- 0.33 microm). However, in each patient, there were changes after surgery in the magnitude (either increasing or decreasing) and/or orientation of aberrations. The mean induced astigmatism was -1.0 +/- 0.9 D at the orientation of the surgical meridian. Induced trefoil also showed a predominant pattern at this direction. Patients with nasal incisions experienced larger changes. Small-incision surgery does not systematically degrade the optical quality of the anterior corneal surface. However, it introduces changes in some aberrations, especially in nonrotationally symmetric terms such as astigmatism, coma, and trefoil. The incision site plays a main role in the corneal changes after surgery.


Determination of Dyadic Adjustment, Happiness and Related Factors in Married Turkish Women Living in Anatolia.
Nowadays, divorce rate increases rapidly; therefore evaluation, of dyadic adjustment and happiness at marriage gains importance. In the study, 910 women were reached and 772 married women agreed to participate in the study. Women have a mild level for dyadic adjustment and happiness with spouses. Sociodemographic factors such as income status, age, age at first marriage, the number of children, duration of marriage, woman's and her husband's education level and type of marriage affect dyadic adjustment and relationship happiness. It is recommended that within the scope of primary healthcare, women should be followed in terms of dyadic adjustment and factors affecting dyadic adjustment, happiness and that couples who are at risk should be provided counseling services.


Characterizing patterns of DTI variance in aging brains.
As large analyses merge data across sites, a deeper understanding of variance in statistical assessment across the sources of data becomes critical for valid analyses. Diffusion tensor imaging (DTI) exhibits spatially varying and correlated noise, so care must be taken with distributional assumptions. Here we characterize the role of physiology, subject compliance, and the interaction of subject with the scanner in the understanding of variance. We analyze DTI data from 1035 subjects in the Baltimore Longitudinal Study of Aging (BLSA), with ages ranging from 22.4 to 103 years old. For each subject, up to 12 longitudinal sessions were conducted. In each session, a scan and a rescan of DTI were performed. We assess variance of DTI scalars within regions of interest (ROIs) defined by four segmentation methods and investigate the relationships between the variance and covariates, including baseline age, time from the baseline (referred to as "interval"), motion, sex, and scan-rescan pairs. Covariate effects are heterogeneous and bilaterally symmetric across ROIs. The interval is positively related to FA variance in the cuneus and occipital gyrus, but negatively in the caudate nucleus. Males show higher FA variance in the right putamen, thalamus, body of the corpus callosum, and cingulate gyrus. In certain ROIs, an increase in motion is associated with a decrease in FA variance. Head motion increases during the rescan of DTI. The effects of each covariate on DTI variance, and their relationships across ROIs are complex. Ultimately, we encourage researchers to include estimates of variance when sharing data and consider models of heteroscedasticity in analysis.


Spectrum and antibiotic resistance of catheter-associated urinary tract infections.
Catheter associated urinary tract infections (CAUTIs) are amongst the most common nosocomial infections and are also considered among the most common complications associated with indwelling urinary catheters. Most catheter associated infections are derived from the patient's own perineal flora, however the presence of a catheter increases the chance of being colonised by cross transmission of nosocomial bacteria as well. Most episodes of short-term catheter-associated bacteriuria are asymptomatic and are caused by single organisms, while long-term catheterisation promotes multibacterial infections and colonization. With prolonged duration of catheterization bacteriuria is considered universal because of the formation of biofilms on the surface of the catheter. Chronic indwelling catheters are an important reservoir of different multiresistant gram-negative organisms, therefore they are frequently isolated from CAUTIs. Treatment of catheter associated asymptomatic bacteriuria is not recommended because it will only promote the emergence of resistant organisms without effectively clearing the urine of catheterised patients.


[Mutual Influence Between Microbial Community, Wastewater Characteristics, and Antibiotic Resistance Genes During Spiramycin Production Wastewater Treatment].
Wastewater from antibiotic production usually contains a huge amount of antibiotic resistance genes (ARG). Therefore, it is essential to study the dissemination and control of antibiotic resistance during the treatment of antibiotic production wastewater. The mutual influence between microbial community evolution, wastewater characteristics, and ARG was investigated using high-throughput sequencing and a variety of statistical analysis methods. Results showed that the influent characteristics had only a marginal influence on the microbial community of each treatment section. Methanogenic bacteria and sulfate-reducing bacteria were the dominant microbes in the anaerobic and anoxic tank. Chemical oxygen demand (COD), NO2--N, and PO43--P exhibited an intimate relationship with the microbial community, whereas biomass, NH4+-N, and COD showed a strong correlation with ARG and mobile genetic elements (MGE). In the sludge, more genera (including pathogenic bacteria) were significantly correlated with ARG and MGE than that in the wastewater, indicating that bacteria in the sludge had a greater chance of acquiring pathogenicity and resistance. Therefore, more attnetion should be given to waste sludge from the treatment plants of antibiotic production wastewater. This research could provide further understanding of antibiotic resistance dissemination and control during wastewater treatment, especially for antibiotic production wastewater.


Inhibin B plasma concentrations in infertile patients with DAZ gene deletions treated with FSH.
The DAZ (deleted in azoospermia) gene family on the Y chromosome long arm is the major candidate for the AZFc (azoospermia factor c) phenotype of male infertility and it is expressed only in germ cells. The aim of the study was to assess Sertoli cell function in subjects with AZFc deletions. Case-control, prospective study. We have studied six severely oligozoospermic subjects with AZFc-DAZ deletions, and looked whether they responded in terms of inhibin B production to a 1 month FSH treatment. These patients were compared with three groups of patients affected by different spermatogenic alterations not related to deletions on the Y chromosome. Although affected by severe testiculopathy, patients with AZFc-DAZ deletions had only slightly elevated FSH, and normal inhibin B plasma concentrations. Inhibin B responded normally during FSH treatment, supporting the hypothesis that Sertoli cells are not altered. On the contrary, other severe testiculopathies not related to Y chromosome deletions showed high FSH and low inhibin B concentrations, with no response to FSH treatment. In these cases the cause of the spermatogenic defect probably damaged both germ and Sertoli cells. Finally, idiopathic patients with a hormonal status similar to Y-deleted patients (slightly elevated FSH and normal inhibin B concentrations) did not respond to FSH treatment, suggesting that Sertoli cells were already at their maximal functional capability. These data confirm that Sertoli cell function is not damaged in patients with AZFc-DAZ deletions and that the strong reduction of germ cells does not affect the FSH-inhibin B feedback loop.


Affective Temperaments and Meteoropathy Among Women: A Cross-sectional Study.
The main goal of the study was to assess the relationship between affective temperaments and meteoropathy among women and examine meteorosensitivity as a mediator in this relationship. The issue of affective temperaments and meteoropathy has not been considered in the literature. The sample consisted of 450 Caucasian women gathered via the online recruitment platform. The participants' ages ranged from 18 to 70 years (M = 30.01; SD = 9.10). The Polish version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire was used to assess affective temperaments (depressive, cyclothymic, hyperthymic, irritable and anxious). Meteorosensitivity and meteoropathy were assessed using the Polish adaptation of the METEO-Q questionnaire. A large positive correlation was found between meteorosensitivity and meteoropathy. Medium positive correlations were found between meteorosensitivity/meteoropathy and cyclothymic and anxious temperaments. Small positive correlations were revealed between depressive and irritable temperaments and both meteorosensitivity and meteoropathy scales. No correlation was found between hyperthymic temperament and meteorosensitivity/meteoropathy. Mediation analyses indicated cyclothymic and anxious temperaments affected meteoropathy both directly and indirectly through meteorosensitivity as a mediator. The most severe meteoropathy symptoms in the studied sample were asthenia, an indefinite feeling of malaise and irritability. The results suggest affective temperaments may be related to meteoropathy symptoms in women.


Structure and expression in Escherichia coli of canine interferon-alpha genes.
Using a human interferon-alpha (IFN-alpha) cDNA probe, several recombinant phages containing type I IFN genes were isolated from a canine genomic library. One of these phages contains two complete CaIFN-alpha genes with identical coding sequences, and a second one a slightly different IFN-alpha gene. The IFN-alpha protein sequences contain six cysteine residues as well as two or three potential N-glycosylation sites. Expression of mature CaIFN-alpha 1 in E. coli results in antiviral activity on dog cells. Genomic analysis using an equine IFN-omega probe and DNA sequencing suggests the deletion of IFN-omega genes from canine genome.


Antiviral assays on phytochemicals: the influence of reaction parameters.
Investigations of phytochemicals for antiviral activities are assuming greater importance; but little attention has been given to the influence of various reaction parameters. We found that the activities of several known antiviral phytochemicals were profoundly affected by the presence of serum components, but in different ways. Thus, the terthiophene, alpha-terthienyl (alpha-T), was inhibited in a concentration-dependent manner by serum. In the case of a carboxylic acid derivative of alpha-T, the compound appeared to have no antiviral activity at all in the presence of serum, yet in its absence this compound was as effective as alpha-T. In contrast the complex anthraquinone hypericin required a small amount of serum for maximal antiviral activity, although too much was inhibitory. The reactions were also strongly affected by the order of incubation of the components: virus, compound, serum, and light. The antiviral effects were not influenced significantly by temperature, in contrast to a report by other workers, provided the light exposures were controlled. These effects are significant because serum is commonly used in virus assays, and plant extracts often contain polypeptides. Furthermore, when phytochemicals are used in vivo, their effects could be modulated by components of tissues and body fluids.


[Clinical observation on treatment of hypertension (yin-deficiency with sthenic-yang syndrome type) with Zhongfu Hypotension Capsule].
To observe the efficacy and safety of zhongfu hypotension capsule (ZHC) in treating hypertension of yin-deficiency with sthenic-yang syndrome type. Adopting the stratified, block randomized, double-blinded, double-dummy, positive parallel controlled, multi-centered clinical trial method, the tested group was treated by orally taken 3 capsules of ZHC (0.5 g/capsule) twice a day, and the control group was treated by orally taken Lotensin Tablet 1 tablet (10 mg/tab.) once a day. And all received the adiaphorous drug with the dosage-form mimic to that used in the tested group. The therapeutic course was 4 weeks for both groups. The markedly effective rate and the total effective rate in reducing blood pressure was 58.65% and 79.81% respectively in the tested group, and 60.51% and 78.34% respectively in the control group; while the markedly effective rate and the total effective rate for alleviating TCM syndrome was 21.15% and 78.85% in the tested group, and 25.48% and 86.62% in the control group respectively. Comparisons between the two groups showed insignificant difference (P > 0.05). ZHC has good efficacy and is safety in treating hypertension.


Assessment of the skin dose for aircrew.
Epidemiological studies are a useful instrument for investigating the influence of environmental factors on human health. In this context, the determination and quantification of the corresponding exposure is a demanding challenge. With regard to the investigation of the potential health effects in aircrew due to cosmic radiation, their occupational exposure at aviation altitudes is usually assessed in terms of the radiation protection quantity effective dose, which is stored in and available from official dose registers in many countries. However, when biological effects on a particular organ are investigated, knowledge of the corresponding exposure of that particular organ is necessary. In this study, we investigate the differences between the skin dose and the effective dose for the exposure of aircrew to cosmic radiation using a mathematical model for the radiation field at aviation altitudes. Furthermore, we present a method to deduce skin dose values from the officially registered effective doses.


MMM1D: a method for calculating electrostatic interactions in one-dimensional periodic geometries.
We present a new method to accurately calculate the electrostatic energy and forces on charges in a system with periodic boundary conditions in one of three spatial dimensions. We transform the Coulomb sum via a convergence factor into a series of fast decaying functions similar to the Lekner method. Rigorous error bounds for the energies and the forces are derived and numerically verified. The method has a computational complexity of O(N(2)), but is faster and easier to use than previously reported methods.


Plant Derived Inhibitor Sulforaphane in Combinatorial Therapy Against Therapeutically Challenging Pancreatic Cancer.
Pancreatic cancer is one of the most aggressive human cancers and is expected to surpass breast cancer to become the third chief cause of cancer-related deaths in the United States. While conventional treatment approaches such as surgery and classic chemotherapy have slightly improved the relative five year survival rate to 8% yet it is the lowest survival rate for any major cancer. This emphasizes the serious need of more effective and well tolerated therapies to reverse the poor prognosis of the defined neoplasm. Aberrant expression of histone deacetylase (HDAC) enzymes has been implicated in pancreatic cancer signalling. The inhibitors of these enzymes namely HDAC inhibitors (HDACi) are the novel agents which are currently being tested. These inhibitors modulate both histone and nonhistone proteins and have shown multiple biological effects including cell cycle arrest, differentiation and apoptosis in several cancer models. This article focuses on plant-derived HDAC inhibitor Sulforaphane (SFN) as a promising antipancreatic cancer agent. Moreover, we discuss the distinct molecular mechanisms triggered by SFN to exert cytotoxic effect in the predefined cancer models. Finally we describe the combinatorial therapeutic strategy involving SFN with other anticancer agents. This novel approach circumvents herculean cancer chemoresistance and alleviates toxicity, the main drawbacks of monotherapy.


β-arrestin 2 attenuates lipopolysaccharide-induced liver injury via inhibition of TLR4/NF-κB signaling pathway-mediated inflammation in mice.
To study the role and the possible mechanism of β-arrestin 2 in lipopolysaccharide (LPS)-induced liver injury in vivo and in vitro. Male β-arrestin 2+/+ and β-arrestin 2-/- C57BL/6J mice were used for in vivo experiments, and the mouse macrophage cell line RAW264.7 was used for in vitro experiments. The animal model was established via intraperitoneal injection of LPS or physiological sodium chloride solution. Blood samples and liver tissues were collected to analyze liver injury and levels of pro-inflammatory cytokines. Cultured cell extracts were collected to analyze the production of pro-inflammatory cytokines and expression of key molecules involved in the TLR4/NF-κB signaling pathway. Compared with wild-type mice, the β-arrestin 2 knockout mice displayed more severe LPS-induced liver injury and significantly higher levels of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-10. Compared with the control group, pro-inflammatory cytokines (including IL-1β, IL-6, TNF-α, and IL-10) produced by RAW264.7 cells in the β-arrestin 2 siRNA group were significantly increased at 6 h after treatment with LPS. Further, key molecules involved in the TLR4/NF-κB signaling pathway, including phospho-IκBα and phosho-p65, were upregulated. β-arrestin 2 can protect liver tissue from LPS-induced injury via inhibition of TLR4/NF-κB signaling pathway-mediated inflammation.


Developing support programs for dentists with infectious disease.
The American Dental Association (ADA) has developed many resources to address growing concerns regarding HIV (human immunodeficiency virus) issues in dental practice, including continuing education courses, workshops, journal articles, and monographs. In addition, the ADA Council on Dental Practice has established a network for dentists with HIV/AIDS (acquired immune deficiency syndrome). The network has been named PEERS, which stands for Prevention, Education, Ethics, Resources, and Support. This paper provides guidelines for developing programs in each state to address the needs of dentists with HIV/AIDS.


Nondestructive measurement of core radius, numerical aperture, and cutoff wavelength for single-mode fibers.
A method is proposed for determining the core diameter, numerical aperture, and cutoff wavelength of single-mode fibers using the end separation loss measured at two light wavelengths. A spacer with adequate end separation is used to reduce the fluctuation in connection losses caused by multiple Fresnel reflections between the fiber end faces and by small lateral offsets. The cutoff wavelengths of four 2-m long fibers measured by this method agreed with those in which abrupt changes in the near-field patterns were observed.


Kinesiology taping and ankle foot orthosis equivalent therapeutic effects on gait function in stroke patients with foot drop: A preliminary study.
An ankle foot orthosis (AFO) is a standard type of orthosis applied to immediately treat foot drop symptoms. Kinesiology taping (KT) is a therapeutic method used in patients with neurological diseases, such as stroke, as well as in patients after orthopedic and sports injuries. This study aimed to compare outcomes of AFO treatment with those of KT to investigate the effect on gait ability in patients with foot drop after stroke. We recruited 18 patients exhibiting foot drop from stroke. Gait ability was assessed under 2 conditions: treatment with KT and that with AFO using the GAITRite system according to the following parameters: cadence, velocity, swing time, stance time, step length, and stride length. As a result, gait ability after treatment with KT and that after treatment with AFO showed no significant differences in cadence (P = .851), velocity (P = .865), swing time (P = .289 and .123), stance time (P = .255 and .711), step length (P = .955 and .975), and stride length (P = .711 and .690) of the affected and less-affected limbs. This study demonstrated that KT and AFO use have similar effects on gait function in patients with foot drop after stroke. Thus, treatment of foot drop with KT may be an alternative in patients for whom AFO use is contraindicated.


[Application of 99Tc(m)-annexinV in predicting the therapeutic effect of chemical agent on lung cancer].
To prepare 99Tcm-annexinV and evaluate its application in the early prediction of therapeutic effect of chemical agent on lung cancer. Annexin V was obtained by recombinant pichia pastoris expression, ammonium sulfate precipitation, and size-exclusion chromatography. The purified protein was labeled with 99Tc(m) at the N-terminal site by stannous chloride reduction and purified by desalting. The labeling yield and radiochemical purity of 99Tc(m)-annexinV were determined by instant thin-layer chromatography. The biological activity of 99Tc(m)-annexinV was tested by phosphatidylserine-exposed erythrocytes bound radioactivity counting. The lung cancer mice models were established by inoculating LA795 cells to right flank of 615 mice subcutaneously and tumor tissue transplantation. The biodistribution of 99Tc(m)-annexinV in lung cancer mice models were investigated at 6, 12, 24, and 48 h after cyclophosphamide administration. The annexin V was secreted from pichia pastoris and purified by ammonium sulfate precipitation and size-exclusion chromatography with high yield. The annexin V could be labeled at room temperature with 50.2% radioactivity yield. The radiochemical purity of 99Tc(m)-annexinV reached up to 93.9% with intact biological activity. The biodistribution analysis demonstrated that 99Tc(m)-annexinV was excreted from kidney. The uptake of 99Tc(m)-annexinV at tumor reached maximum 48 h after cyclophosphamide administration while tumor to muscle ratio was 6.34 and tumor to blood ratio was 4.09. 99Tc(m)-annexinV derived from pichia pastoris was successfully prepared. It is useful in predicting the therapeutic effect of chemical agent on lung cancer.


Suitable ultrasound screening method for older adults with disability to identify low muscle mass.
This study aimed to investigate the accuracy and consistency of different ultrasound protocols for the measurement of gastrocnemius muscle (GM) thickness and to identify a suitable ultrasound scheme that can be used to detect the low muscle mass in older with disability. In this cross-sectional study, each participant underwent three different ultrasound protocols for the measurement of the GM thickness, and each measurement was repeated three times. The three measurement schemes were as follows: method A, lying on the examination bed in a prone position with legs stretched and relaxed and feet hanging outside the examination bed; method B, lateral right side lying position with legs separated (left leg flexed and right leg in a relaxed state); and method C, right side lying position with legs together and lower limb muscles in a relaxed state. The low muscle mass was determined by averaging two or three measurements of the GM thickness determined using different sonographic protocols. The study included 489 participants. The difference in the prevalence of low muscle mass identified between two and three replicates of the same measurement protocol ranged from 0 to 1.3%. Considering the three repeated measurements of the method A as the reference, the area under the curve (AUC) in different measurement schemes were 0.977-1 and 0.973-1 in males and females, respectively. Furthermore, male and female Kappa values from low to high were 0.773, 0.801, 0.829, 0.839, and 0.967 and 0.786, 0.794, 0.804, 0.819, and 0.984, respectively. Different ultrasound measurement protocols showed high accuracy and consistency in identifying low muscle mass. Repeating the measurements two or three times was found to be feasible.


Human serum albumin modifications associated with reductive radical stress.
Radiation-induced modifications of human serum albumin mainly occurring at S-containing residues were investigated by Raman spectroscopy and mass spectrometry techniques. When HO˙ radicals were scavenged by t-BuOH, the H˙ atom and hydrated electron (e(aq)(-)) attack led to the chemical transformation of Cys into Ala residues and the conversion of Met residues into α-aminobutyric acid residues. Mapping experiments demonstrated that desulfurization selectively affects Cys34, Met123, Met298, Cys514, Met548 and Cys567 since the first stages of reaction. Generation of thiol functionality was also detected at specific residues involved in disulfide bonds, namely Cys200, Cys392 and Cys514, together with partial oxidation at Met87, Met123, Met298, Met329 and Met548, forming sulfoxides. When HO˙ radicals were not scavenged, lesser amounts of the previous modifications were observed, whereas some residues (Cys34, Cys461, Pro486, Phe488 and Phe502) resulted to be oxidatively modified. Based on the known cystine pairing in native albumin, no relationships were observed between desulfurization and disulfide reduction processes at Cys residues involved in disulfide bonds, thus suggesting either independent reactivities or, more probably, reactions at the same amino acids that then underwent quick disulfide scrambling events toward more stable disulfide/thiol populations. When these reactions were performed on protein species added to large unilamellar vesicles, desulfurization yielded sulfur radicals able to induce a cis-trans isomerization of lipids at the onset of irradiation. This study provides a description of the human albumin modifications resulting from reductive radical stress, thus suggesting the need for specific assays and future investigations to detect these events in proteins and lipids within challenged cells.


Esthetic and functional rehabilitation of missing anterior teeth with a conservative treatment approach: a clinical case series.
The current scenario in dentistry proposes several treatment modalities for the esthetic and functional replacement of a congenitally or traumatically missing anterior tooth in young and adult patients which includes implant supported single crown, conventional FPD, Resin Bonded FPD (RBFPD) or RPD. However when certain clinical conditions or unwillingness of the patient preclude the replacement of missing tooth with any of these prostheses, in such cases, a more conservative treatment modality, fiber reinforce composite resin fixed partial denture with composite resin, porcelain fused to metal, all ceramic or natural tooth pontic can be consider as a definitive treatment alternative in certain clinical conditions. This article describes successful rehabilitation of three different patients with three types of pontics by this technique.


A LC-MS/MS method for simultaneous determination of seven alkaloids in rat plasma after oral administration of Phellodendri chinensis cortex extract and its application to a pharmacokinetic study.
A sensitive and rapid liquid chromatography with tandem mass spectrometry method has been developed for simultaneous determination of berberine (I), jateorhizine (II), palmatine (III), tetrahydropalmatine (IV), phellodendrine (V), protopine (VI) and columbamine (VII) in rat plasma after oral administration of Phellodendri chinensis cortex extraction. The plasmas were extracted by liquid-liquid extraction. The tandem mass spectrometric detection was performed in the multiple reaction monitoring mode in the positive ionization. The intra- and interday precisions and accuracies were in range from -12.18 to 13.21%. Mean absolute recoveries of all analytes and internal standard were between 78.6 and 98.9%. The seven alkaloids were proven to be stable during sample storage and analysis procedures. The established method was validated and successfully applied to pharmacokinetics study in rat plasma after oral administration of Phellodendri chinensis cortex extract. The t1/2 of palmatine, columbamine, pellodendrine, berberine, tetrahydropalmaine, jatrorrhizine, and protopine were 5.16, 5.96, 7.18, 19.84, 6.28, 7.08, 6.90 h, respectively. The seven compounds could be rapidly absorbed into blood (time for maximal concentration, 1.80-1.93 h). This study could establish a foundation for further research of Phellodendri chinensis cortex and might provide more useful information to guide the clinical usage.


Top Differential Diagnosis Should Be Microscopic Polyangiitis in ANCA-Positive Patient with Diffuse Pulmonary Hemorrhage and Hemosiderosis.
A rat model of antineutrophil cytoplasmic antibody (ANCA) associated vasculitides reveals crescentic glomerulonephritis as seen in human renal biopsies and diffuse lung hemorrhage that is not well documented in human lung biopsies. A 64-year-old male, with shortness of breath and mild elevation of serum creatinine, was found to have a positive serum test for ANCA, but negative antiglomerular basement membrane antibody. A renal biopsy showed pauci-immune type of crescentic glomerulonephritis and focal arteritis. The prior lung wedge biopsy was retrospectively reviewed to show diffuse hemorrhage and hemosiderosis with focal giant cells. In addition, small arteries revealed subtle neutrophil aggregation, and margination along vascular endothelium, but no definitive vasculitis. The pathology of ANCA associated vasculitides results from activated neutrophils by ANCA and subsequent activation of the alternative complement cascade with endothelial injury, neutrophil aggregation and margination. Our findings, after the correlation between lung biopsy and renal biopsy, imply that the top differential diagnosis in the lung biopsy should be microscopic polyangiitis when diffuse pulmonary hemorrhage and hemosiderosis are present in this ANCA-positive patient.


Double vital staining of corneal epithelium after corneal transplantation with a rose bengal-fluorescein mixture.
Longitudinal double vital staining with 1% rose bengal (RB) and 1% fluorescein (Flu) has been carried out on 33 eyes subjected to penetrating corneal transplantation. At the conclusion of the operation pronounced desiccation of both donor's and recipient's epithelium was seen in a scant 50%, but abrasion in only 8%. the desiccation subsided during the first post-operative day, but the donor's epithelium was rejected in the majority (91%). Healing started on the third day, manifesting itself by Flu-punctate whorl-shaped epithelium invading or gliding across the wound. By the fifth day nearly complete healing had occurred. In 9% no renewal of epithelium was noticed. Subsequent control examinations revealed loose sutures (RB-stained mucous adhesions), evanescent cicatricial defects, and open suture canals (Flu). Graft rejection occurred in 8 cases. In 5 of these, well-defined massive peripheral staining of donor epithelium was seen (RB most widespread and sharply outlined), and in the remaining 3, uncharacteristic, diffuse, punctate staining.


Fibroblast growth factor (FGF)-23 inhibits renal phosphate reabsorption by activation of the mitogen-activated protein kinase pathway.
The homeostasis of the plasma phosphate level is essential for many biological processes including skeletal mineralization. The reabsorption of phosphate in the kidney is a major determinant of the plasma levels of phosphate. Phosphatonin is a hormone-like factor that specifically inhibits phosphate uptake in renal proximal epithelial cells. Recent studies on tumor-induced osteomalacia suggested that phosphatonin was potentially identical to fibroblast growth factor (FGF)-23. However, as purified recombinant FGF-23 could not inhibit phosphate uptake in renal proximal epithelial cells, the mechanism of action of FGF-23 remains to be elucidated. Therefore, we examined the mechanism of action of FGF-23 in cultured renal proximal epithelial cells, opossum kidney cells. FGF-23 was found to require heparin-like molecules for its inhibitory activity on phosphate uptake. FGF-23 binds to the FGF receptor 3c, which is mainly expressed in opossum kidney cells, with high affinity. An inhibitor for tyrosine kinases of the FGF receptor, SU 5402, blocked the activity of FGF-23. FGF-23 activated the mitogen-activated protein kinase (MAPK) pathway, which is the major intracellular signaling pathway of FGF. Inhibitors of the MAPK pathway, PD98059 and SB203580, also blocked the activity of FGF-23. The present findings have revealed a novel MAPK-dependent mechanism of the regulation of phosphate uptake by FGF signaling.


Formation of 3-hydroxy-2,3-dihydrovitamin K1 in vivo: relationship to vitamin K epoxide reductase and warfarin resistance.
Hydroxy vitamin K [3(2)-hydroxy-2,3- dihydrovitamin K1] has been identified as a quantitatively important metabolite of injected vitamin K epoxide in vivo. The metabolite has been isolated and identified by comparison of its UV, mass spectra and high-performance liquid chromatography (HPLC) retention times with those of synthetic standards, and by its characteristic conversion to vitamin K quinone on treatment with the base triethylamine. This metabolite is formed from the vitamin K epoxide, not from the vitamin K quinone and can represent up to 3.5% of dose and 13% of hexane-extractable metabolites present in liver 1 hour after injection of 330 micrograms vitamin K1 epoxide per kilogram body weight. It is formed in both normal and warfarin-resistant rat strains, but to a significantly greater extent in the latter. Unlike the hydroxy vitamin K formed by warfarin-resistant rat liver microsomes in vitro, the metabolite formed from racemic vitamin K epoxide in vivo was not optically active, nor was its formation inhibited by coumarin anticoagulants under conditions that completely blocked vitamin K epoxide reduction in vivo. On this basis, hydroxy vitamin K formation in vivo differs from its formation in vitro; it is not a product of vitamin K epoxide reductase in vivo, but of some other possibly non-enzymatic reaction.


High Precision Imaging of Microscopic Spread of Glioblastoma with a Targeted Ultrasensitive SERRS Molecular Imaging Probe.
The dismal prognosis of patients with malignant brain tumors such as glioblastoma multiforme (GBM) is attributed mostly to their diffuse growth pattern and early microscopic tumor spread to distant regions of the brain. Because the microscopic tumor foci cannot be visualized with current imaging modalities, it remains impossible to direct treatments optimally. Here we explored the ability of integrin-targeted surface-enhanced resonance Raman spectroscopy (SERRS) nanoparticles to depict the true tumor extent in a GBM mouse model that closely mimics the pathology in humans. The recently developed SERRS-nanoparticles have a sensitivity of detection in the femtomolar range. An RGD-peptide-conjugated version for integrin-targeting (RGD-SERRS) was compared directly to its non-targeted RAD-SERRS control in the same mice via Raman multiplexing. Pre-blocking with RGD peptide before injection of RGD-SERRS nanoparticles was used to verify the specificity of integrin-targeting. In contrast to the current belief that the enhanced permeability and retention (EPR) effect results in a baseline uptake of nanoparticles regardless of their surface chemistry, integrin-targeting was shown to be highly specific, with markedly lower accumulation after pre-blocking. While the non-targeted SERRS particles enabled delineation of the main tumor, the RGD-SERRS nanoparticles afforded a major improvement in visualization of the true extent and the diffuse margins of the main tumor. This included the detection of unexpected tumor areas distant to the main tumor, tracks of migrating cells of 2-3 cells in diameter, and even isolated distant tumor cell clusters of less than 5 cells. This Raman spectroscopy-based nanoparticle-imaging technology holds promise to allow high precision visualization of the true extent of malignant brain tumors.


Behavioral Responses of Cattle to Naturally Occurring Seasonal Populations of Horn Flies (Diptera: Muscidae) Under Rangeland Conditions.
The behavioral responses of cattle under the influence of naturally occurring seasonal horn fly, Haematobia irritans (L.), populations were evaluated under rangeland conditions. This study was replicated four times using 10 cows as the subsampling unit equipped with GPS collars scheduled to receive locational fixes every 5 min for 6 d prior to, and 6 d following horn fly insecticidal control application. Data derived from GPS collars were used to evaluate potential horn fly-induced behavioral modifications expressed during predawn, daytime, and nighttime periods. These data were used to analyze variables, which included distance travelled, daily area explored, vertical and horizontal head movements, and inferred activities such as resting, grazing, and walking. Horn fly populations were estimated using daily visual counts and were reduced significantly on animals following insecticidal application. There was no significant difference between treatment periods in any of the aforementioned analyzed variables. During the night-time hours estimated differences (pretreatment minus posttreatment) for distance travelled, area explored, and vertical head movements were 0.81 ± 0.46 km/d, 0.35 ± 0.21 km(2)/d, and 7.25 ± 5.30 counts/d, respectively. The implications of these observations are discussed.


Application of drug delivery technologies in lead candidate selection and optimization.
Formulation development during early drug discovery and lead optimization, involves several challenges including limited drug supply, the need for rapid turnaround, and limited development time. It is also desirable to develop initial formulations that will be representative of final commercial formulations. Nanoparticles offer a unique platform for the formulation of poorly soluble drugs - such formulations can be injected (intravenous, subcutaneous, intramuscular), as well as administered through other routes, such as oral, ocular and inhalation. Thus, a single formulation can be used to test and eventually develop multiple dosage forms. Furthermore, nanoparticles offer the opportunity for high drug loading, for low potency compounds, and thus support toxicological evaluation of such compounds.


Transcriptional bypass of regioisomeric ethylated thymidine lesions by T7 RNA polymerase and human RNA polymerase II.
Alkylative damage to DNA can be induced by environmental chemicals, endogenous metabolites and some commonly prescribed chemotherapeutic agents. The regioisomeric N3-, O(2)- and O(4)-ethylthymidine (N3-, O(2)- and O(4)-EtdT, respectively) represent an important class of ethylated DNA lesions. Using nonreplicative double-stranded vectors containing an N3-EtdT, O(2)-EtdT or O(4)-EtdT at a defined site in the template strand, herein we examined the effects of these lesions on DNA transcription mediated by single-subunit T7 RNA polymerase or multisubunit human RNA polymerase II in vitro and in human cells. We found that O(4)-EtdT is highly mutagenic and exclusively induces the misincorporation of guanine opposite the lesion, whereas N3-EtdT and O(2)-EtdT display promiscuous miscoding properties during transcription. In addition, N3-EtdT and O(2)-EtdT were found to inhibit strongly DNA transcription in vitro and in certain human cells. Moreover, N3-EtdT, but not O(2)-EtdT or O(4)-EtdT, is an efficient substrate for transcription-coupled nucleotide excision repair. These findings provide new important insights into how these alkylated DNA lesions compromise the flow of genetic information, which may help to understand the risk of these lesions in living cells.


Defining criteria used to evaluate response to treatment of acne vulgaris.
Results from controlled studies form the basis of overall perceptions regarding the efficacy and safety of specific treatments. In acne vulgaris, determining statistical significance related to mean percentage reduction in inflammatory and noninflammatory lesion counts, investigator global assessment, and patient (subject) global assessment have formed the basis of most studies. Results may be impacted by several mitigating factors related to inclusion and exclusion criteria and variations in study "power." Recently, standards for evaluation of response to acne treatment have been reconsidered, with new methodologies suggested throughout the approval process. For example, the standard of "complete clearance" has been introduced. How the new methodologies compare with previous standards, and how new criteria will impact the reporting and interpretation of trial results are reviewed in this article. Specific study outcomes, including those reported in more recent trials with topical adapalene, are utilized as illustrative examples.


Acquisition of bile salt resistance promotes antibiotic susceptibility changes in bifidobacterium.
The effect of acquired resistance to bile on the antimicrobial sensitivity of two Bifidobacterium strains (Bifidobacterium animalis IPLA4549 and Bifidobacterium longum NIZO B667) was studied. The MICs of 23 different antibiotics belonging to the most clinically important groups were determined by using the Etest method, which comprises nonporous plastic strips calibrated with a predefined gradient of antibiotic concentrations covering 15 twofold dilutions. The strains were sensitive to most antibiotics assayed, although they tolerated relatively high concentrations of gentamicin, kanamycin, streptomycin, polymyxin B, and ciprofloxacin (from 32 to more than 1,024 microg/ml). One of the bile-adapted strains was more strongly resistant to ceftazidime than was its parent bile-sensitive strain, and the other bile-adapted strain had increased resistance to tetracyclines. Therefore, to test the possibility that the acquisition of stable resistance to bile could be associated with a general increase in resistance to some antibiotics, we analyzed the sensitivities of four additional pairs of parent strains and their bile-adapted derivatives to ceftazidime and three tetracyclines (doxycycline, minocycline, and tetracycline). Three of the bile-resistant derivatives had increased resistance to ceftazidime (more than 256-fold) compared with their parents, and two had enhanced resistance to tetracyclines (at least 12-fold). Thus, the acquisition of bile salts resistance in Bifidobacterium induced modifications of the antibiotic resistance patterns. These results suggest that adaptation of probiotics to bile could also change their potential impact on intestinal microbiota, and this possibility deserves further attention.


Validation of the femoral anteversion measurement method used in imageless navigation.
Total hip arthroplasty restores lost mobility to patients suffering from osteoarthritis and acute trauma. In recent years, navigated surgery has been used to control prosthetic component placement. Furthermore, there has been increasing research on what constitutes correct placement. This has resulted in the definition of a safe-zone for acetabular cup orientation. However, there is less definition with regard to femoral anteversion and how it should be measured. This study assesses the validity of the femoral anteversion measurement method used in imageless navigation, with particular attention to how the neutral rotation of the femur is defined. CT and gait analysis methodologies are used to validate the reference which defines this neutral rotation, i.e., the ankle epicondyle piriformis (AEP) plane. The findings of this study indicate that the posterior condylar axis is a reliable reference for defining the neutral rotation of the femur. In imageless navigation, when these landmarks are not accessible, the AEP plane provides a useful surrogate to the condylar axis, providing a reliable baseline for femoral anteversion measurement.


Defining the role of ab externo Xen gel stent in glaucomatous eyes with prior failed surgical intervention.
To evaluate the safety and efficacy of Xen45 Gel stent (Xen; Allergan) in eyes that have failed prior surgical intervention, compared to traditional glaucoma drainage device (GDD) or continuous-wave cyclophotocoagulation (CPC). Since this population has low expected success rates with additional surgery, it is vital to compare to standard-of-care surgical options. Retrospective, single-center, case-control study of ab externo transconjunctival Xen shunt in eyes that have previously undergone trabeculectomy and/or GDD surgery. Postoperative data were collected for 18 months. Failure was defined as no light perception, additional glaucoma surgery required, or intraocular pressure (IOP) of < 6 mmHg after 6 weeks postoperatively. Eighteen Xen eyes and 36 control eyes matched on both glaucoma type and previous glaucoma surgeries were included. Seventy-two percent had primary open angle glaucoma, 11% uveitic, 6% primary angle closure, 6% pseudoexfoliation, and 6% pigmentary glaucoma. Fifty-six percent of eyes in each group had prior trabeculectomy, 28% of Xen and 31% of control eyes had prior GDD, and 17% of Xen and 14% of control eyes had both. Baseline medicated IOP was lower in the Xen group (21.8 ± 7.2) compared to controls (27.5 ± 9.4, P = 0.043). The cumulative failure rate at year 1 was 17% for Xen and 20% for controls (P = 0.57). Mean survival time was 14.1 (± 1.5) months and 11.4 (± 0.6) months for controls. There was no difference in minor complication rates between groups (P = 0.65), but the Xen group had a significantly lower rate of serious complications (P = 0.043) defined as vision threatening or requiring surgical intervention in the operating room. When censored for additional glaucoma procedures, there were no differences at year 1 in IOP, change in IOP, number of IOP-lowering medications, or number of medications reduced from baseline. The Xen shunt provides a reasonable alternative to current standard of care, with a similar failure rate at year 1, with a noninferior IOP reduction compared to GDD and CPC, and a preferred safety profile.


Hexokinase 3 dysfunction promotes tumorigenesis and immune escape by upregulating monocyte/macrophage infiltration into the clear cell renal cell carcinoma microenvironment.
Purpose: This study aimed to identify the potential prognostic role of HK3 and provide clues about glycolysis and the microenvironmental characteristics of ccRCC. Methods: Based on the Cancer Genome Atlas (TCGA, n = 533) and Gene expression omnibus (GEO) (n = 127) databases, real-world (n = 377) ccRCC cohorts, and approximately 15,000 cancer samples, the prognostic value and immune implications of HK3 were identified. The functional effects of HK3 in ccRCC were analyzed in silico and in vitro. Results: The large-scale findings suggested a significantly higher HK3 expression in ccRCC tissues and the predictive efficacy of HK3 for tumor progression and a poor prognosis. Next, the subgroup survival and Cox regression analyses showed that HK3 serves as a promising and independent predictive marker for the prognosis and survival of patients with ccRCC from bioinformatic databases and real-world cohorts. Subsequently, we found that HK3 could be used to modulate glycolysis and the malignant behaviors of ccRCC cells. The comprehensive results suggested that HK3 is highly correlated with the abundance of immune cells, and specifically stimulates the infiltration of monocytes/macrophages presenting surface markers, regulates the immune checkpoint molecules PD-1 and CTLA-4 of exhaustive T cells, restrains the immune escape of tumor cells, and prompts the immune-rejection microenvironment of ccRCC. Conclusion: In conclusion, the large-scale data first revealed that HK3 could affect glycolysis, promote malignant biologic processes, and predict the aggressive progression of ccRCC. HK3 may stimulate the abundance of infiltrating monocytes/macrophages presenting surface markers and regulate the key molecular subgroups of immune checkpoint molecules of exhaustive T cells, thus inducing the microenvironmental characteristics of active anti-tumor immune responses.


Connective tissue growth factor and cardiac fibrosis.
Cardiac fibrosis is a major pathogenic factor in a variety of cardiovascular diseases and refers to an excessive deposition of extracellular matrix components in the heart, which leads to cardiac dysfunction and eventually overt heart failure. Evidence is accumulating for a crucial role of connective tissue growth factor (CTGF) in fibrotic processes in several tissues including the heart. CTGF orchestrates the actions of important local factors evoking cardiac fibrosis. The central role of CTGF as a matricellular protein modulating the fibrotic process in cardiac remodelling makes it a possible biomarker for cardiac fibrosis and a potential candidate for therapeutic intervention to mitigate fibrosis in the heart.


A histological comparison of a new pulp capping material and mineral trioxide aggregate in rat molars.
Recent investigations have attempted to improve regenerative endodontics with the help of stem cell therapy. In vitro studies have shown the ability of different agents to stimulate the differentiation of dental pulp stem cells (DPSC) into odontoblast-like cells. A combination of dexamethasone, β-glycerophosphate and Vitamin D has been proven to induce a successful differentiation. The aim of this animal study was to evaluate the effect of this combination, named odontoblastic differentiating material (ODM), on pulp tissue when used as a capping material. Sixty maxillary right and left molars of 30 Sprague-dawley rats were selected for this study. The teeth were exposed under sterile condition. Half of the teeth were capped with mineral trioxide aggregate (MTA) and the other half with ODM. All cavities were restored with glass ionomer. The rats were sacrificed at post-operative intervals of 2 weeks and 2 months. Samples were histologically evaluated for the degree of inflammation and reparative dentin formation. Finally the data was analyzed with Mann-Whitney and Chi-Square tests. Reparative dentin formed in all groups within both time periods and there was no statistically significant difference between the groups in the mentioned time periods. The MTA group, however, showed a statistically significant reduction in inflammation at both time intervals (P<0.05). Compared to MTA, ODM samples showed a greater amount of inflammation in the pulp tissue. ODM, as a pulp capping material, can induce dentinal bridge formation.


Steel syndrome: dislocated hips and radial heads, carpal coalition, scoliosis, short stature, and characteristic facial features.
A syndrome of children with short stature, bilateral hip dislocations, radial head dislocations, carpal coalitions, scoliosis, and cavus feet in Puerto Rican children, was reported by Steel et al in 1993. The syndrome was described as a unique entity with dismal results after conventional treatment of dislocated hips. The purpose of this study is to reevaluate this patient population with a longer follow-up and delineate the clinical and radiologic features, treatment outcomes, and the genetic characteristics. This is a retrospective cohort study of 32 patients in whom we evaluated the clinical, imaging data, and genetic characteristics. We compare the findings and quality of life in patients with this syndrome who have had attempts at reduction of the hips versus those who did not have the treatment. Congenital hip dislocations were present in 100% of the patients. There was no attempt at reduction in 39% (25/64) of the hips. In the remaining 61% (39/64), the hips were treated with a variety of modalities fraught with complications. Of those treated, 85% (33/39) remain dislocated, the rest of the hips continue subluxated with acetabular dysplasia and pain. The group of hips that were not treated reported fewer complaints and limitation in daily activities compared with the hips that had attempts at reduction. Steel syndrome is a distinct clinical entity characterized by short stature, bilateral hip and radial head dislocation, carpal coalition, scoliosis, cavus feet, and characteristic facial features with dismal results for attempts at reduction of the hips. Prognostic Study Level II.


Limiting potential infectious risks of transplanting insulin-producing pig cells into humans.
Prior to commencing a study of grafting foetal/neonatal pig islet-like cell clusters into type I diabetic human subjects, the microbiological risks of transplanting porcine pancreatic tissue were assessed. An exclusion list for screening donor animals and graft tissue in Australia was compiled following evaluation of the disease risks posed by 121 organisms, including 36 bacteria, 12 fungi, four mycoplasma, 31 parasites and 38 viruses. The list of evaluated agents was derived from the literature, interviews with veterinarians and physicians, and a survey of laboratories. The exclusion list contains 35 organisms (including 20 bacteria, four fungi, one mycoplasma, one parasite and nine viruses) that are zoonotic, pathogens of immunocompromised hosts (including human allograft recipients), pathogens resistant to antibiotics or potentially able to recombine with the human genome. These 35 agents can be detected by culture (e.g., Actinomyces), serological testing (e.g., influenza viruses) or nucleic acid amplification (e.g., Mycobacteria). It is recommended that: (i) source pigs designated for use in human xenotransplantation trials should be tested regularly for the 35 organisms; (ii) the mothers of donor foetal/neonatal pigs and, when possible, the foetal/ neonatal pigs themselves should be tested immediately prior to the grafting of tissue into humans; and (iii) the exclusion list be modified for designated source pig herds in countries other than Australia.


Wilms Tumor NCAM-Expressing Cancer Stem Cells as Potential Therapeutic Target for Polymeric Nanomedicine.
Cancer stem cells (CSC) form a specific population within the tumor that has been shown to have self-renewal and differentiation properties, increased ability to migrate and form metastases, and increased resistance to chemotherapy. Consequently, even a small number of cells remaining after therapy can repopulate the tumor and cause recurrence of the disease. CSCs in Wilms tumor, a pediatric renal cancer, were previously shown to be characterized by neural cell adhesion molecule (NCAM) expression. Therefore, NCAM provides a specific biomarker through which the CSC population in this tumor can be targeted. We have recently developed an NCAM-targeted nanosized conjugate of paclitaxel bound to a biodegradable polyglutamic acid polymer. In this work, we examined the ability of the conjugate to inhibit Wilms tumor by targeting the NCAM-expressing CSCs. Results show that the conjugate selectively depleted the CSC population of the tumors and effectively inhibited tumor growth without causing toxicity. We propose that the NCAM-targeted conjugate could be an effective therapeutic for Wilms tumor. Mol Cancer Ther; 16(11); 2462-72. ©2017 AACR.


Emerging New Therapeutics for Retinoblastoma.
Background: Over the last few decades, chemotherapy has become the main treatment of retinoblastoma, delivered through various routes: intravenous, intra-arterial, and intravitreal. Despite its efficacy, chemotherapy-related toxicity (ocular and systemic) and recurrences due to resistant tumor clones are common, highlighting the need for novel therapeutic agents. Summary: Recent advances in our understanding of the molecular drivers of Rb1 tumorigenesis and mechanisms of tumor resistance have afforded opportunities to explore novel targets such as the MDMX-p53 pathway (nutlin-3), histone deacetylase inhibitors, spleen tyrosine kinase inhibitors, and genetic and immune modulatory drugs. In this review, we discuss the limitations of current therapeutic strategies, candidate cellular pathways, current evidence for newer targeted drugs, and offer a look toward the future. Key Messages: Advances in the understanding of the molecular drivers of the RB pathway have provided opportunities to explore novel drugs with targeted effects, improved bioavailability, and reduced chemotoxicity.


Not later, but longer: sleep, chronotype and light exposure in adolescents with remitted depression compared to healthy controls.
The relationship between sleep and adolescent depression is much discussed, but still not fully understood. One important sleep variable is self-selected sleep timing, which is also referred to as chronotype. Chronotype is mostly regulated by the circadian clock that synchronises the internal time of the body with the external light dark cycle. A late chronotype as well as a misalignment between internal time and external time such as social jetlag has been shown to be associated with depressive symptoms in adults. In this study, we investigated whether adolescents with remitted depression differ from healthy controls in terms of chronotype, social jetlag and other sleep-related variables. For this purpose, we assessed chronotype and social jetlag with the Munich ChronoType Questionnaire (MCTQ), subjective sleep quality with the Pittsburgh Sleep Quality Index (PSQI) and used continuous wrist-actimetry over 31 consecutive days to determine objective sleep timing. Given the potentially mediating effect of light on chronotype and depressive symptoms, we measured light exposure with a light sensor on the actimeter. In our sample, adolescents with remitted depression showed similar chronotypes and similar amounts of social jetlag compared to controls. However, patients with remitted depression slept significantly longer on work-free days and reported a worse subjective sleep quality than controls. Additionally, light exposure in remitted patients was significantly higher, but this finding was mediated by living in a rural environment. These findings indicate that chronotype might be modified during remission, which should be further investigated in longitudinal studies.


[Establishment and characterization of a melanoma cell line HME1].
To establish a melanoma cell line and identify its characteristics in vitro. The tissues from biopsies of melanoma were performed primary culture. After growing to 90% confluence, the cells were detached and transferred to another flask for subculture, and then we identified their characteristics including growth kinetic, morphology and tumorigenecity. This cell line was cultivated for more than 90 times. Its characteristics were as follows:The pathological morphology of the tumor transplanted in nude mice were similar to that of the original lesion;The growth curves of the 20th passage were determined, and the population doubling time calculated was 56.9 h; The cloning efficiency in soft agar was 19.1%; Karyo-type analysis showed aneuploidy with the modal chromosomal number 85-102; Electronmicroscopical observation showed that there were rich microvilli on the surface of the cells, abundant ribosomes and melanoid grain; SP immunohistochemical staining showed that the cells expressed HMB-45. The Melanoma cells were immortalized after being cultured in vitro and a new melanoma cell line was established.


Prognostic Significance of Preoperative NLR, MLR, and PLR Values in Predicting the Outcome of Primary Cytoreductive Surgery in Serous Epithelial Ovarian Cancer.
(1) The degree of cytoreduction achieved during primary debulking surgery (PDS) is an important prognostic factor for the survival of patients with epithelial ovarian cancer (EOC). Our aim was to investigate the prognostic value of preoperative laboratory parameters for the outcome of PDS. (2) We analyzed the preoperative laboratory parameters of 150 serous EOC patients who underwent PDS between 2006 and 2013. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off values of the variables for predicting the PDS outcome. We used binary logistic regression to examine the independent predictive value of the factors for incomplete cytoreduction. (3) Among the parameters, we established optimal cut-off values for cancer antigen (Ca)-125, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) to predict the outcome of PDS. The results of binary logistic regression showed that stage (FIGO III-IV), MLR (>0.305), and Ca-125 (>169.15 kU/L) were independent significant predictors of the degree of tumor reduction achieved during PDS. (4) In the future, MLR, especially in combination with other parameters, may be useful in determining prognosis and selecting the best treatment option (PDS or neoadjuvant chemotherapy + interval debulking surgery) for ovarian cancer patients.