Biotransformation of ginsenosides F4 and Rg6 in zebrafish.
Ginsenosides F4 and Rg6 (GF4 and GRg6), two main active components of steamed notoginseng or red ginseng, are dehydrated disaccharide saponins. In this work, biotransformation of ginsenosides F4 and Rg6 in zebrafish was investigated by qualitatively identifying their metabolites and then proposing their possible metabolic pathways. The prediction of possible metabolism of ginsenosides F4 and Rg6 using zebrafish model which can effectively simulate existing mammals model was early and quickly performed. Metabolites of ginsenosides F4 and Rg6 after exposing to zebrafish for 24 h were identified by Ultraperformance Liquid Chromatography/Quadrupole-Time-of-Flight Mass Spectrometry. A total of 8 and 6 metabolites of ginsenosides F4 and Rg6 were identified in zebrafish, respectively. Of these, 7 and 5, including M1, M3-M5, M7-M9 and N1 (N5), N2, N4 (N9), N7-N8 were reported for the first time as far as we know. The mechanisms of their biotransformation involved were further deduced to be desugarization, glucuronidation, sulfation, dehydroxylation, loss of C-17 and/or C-23 residue pathways. It was concluded that loss of rhamnose at position C-6 and glucuronidation at position C-3 in zebrafish were considered as the main physiologic and metabolic processes of ginsenosides F4 and ginsenosides Rg6, respectively.


[Diagnosis and treatment of endometriosis in adolescents].
To discuss the clinical feature, diagnosis and treatment options of adolescent endometriosis. The records of adolescent patients with endometriosis (11-20 years old) who were admitted to First, Second and Third Affiliated Hospital of Zhongshan University and Guangdong Provincial People's Hospital between 1990 and 2003 were retrospectively reviewed. Forty-three patients were diagnosed as endometriosis either by laparotomy or laparoscopy. The chief symptoms leading to the diagnosis were palpable pelvic mass (18/43), dysmenorrhea (15/43), chronic pelvic mass (10/43) and acute pelvic pain (4/43). The majority of patients (53%) presented with the revised AFS-r classification stage III, 8 cases (19%) presented with stage I, 3 cases (7%) with stage II and 9 cases (21%) with stage IV. Nine cases (21%) had complicated genital tract abnormalities. Conservative operations, including salpingo-oophorectomy ins cases, ovarian cystectomy in 31 cases and laparoscopic vaporization in 8 cases, were performed. Surgeries were followed by hormonal suppression using oral contraceptives in a continuous or cyclic manner. Adolescent endometriosis may occur around 4.6 years after menarche. The chief symptoms are palpable pelvic mass and dysmenorrhea. The treatment of endometriosis in adolescence does not differ principally from that in adult women. In the treatment of endometriosis and for the prevention of recurrence, it is recommended to give 3-6 months of oral contraceptives.


Growth and regrowth of an autogenous rat sarcoma: effects of nitrogen mustard.
Immediate and delayed effects of nitrogen mustard (HN2) (0.1 mg/kg/day for 4 days) on the growth and cell proliferation patterns of the 3-methylcholanthrene-induced autogenous rat sarcoma were studied. Tumor cells were labeled continuously with 0.5 muCi tritiated thymidine/g for 24 hours. The labeling index fell from 36.4 to 14.0% and the mitotic index from 0.88 to 0.67% after two treatments with HN2. At that time, tumor growth stopped and remained arrested during HN2 administration. After four injections of HN2, the labeling index was reduced further to 0.73% and the mitotic index to 0.36%. After the drug was withdrawn, tumor growth resumed at the pretreatment rate, even though the labeling index on day 3 was only 15.5% (or 40% of the control). The percent labeled mitosis curves and DNA contents, before and 4 days after HN2 was given, were similar. It was concluded that a subpopulation of cells of predominantly short intermitotic times caused tumor growth before and after drug treatment.


Influence of ultrasound on chemically induced gelation of micellar casein systems.
Gelation is a significant operation in dairy processing. Protein gelation can be affected by several factors such as temperature, pH, or enzyme addition. Recently, the use of ultrasonication has been shown to have a significant impact on the formation of whey protein gels. In this work, the effect of ultrasonication on the gelation of casein systems was investigated. Gels were formed by the addition of 7.6 mm Tetra Sodium Pyro Phosphate (TSPP) to 5 wt% micellar casein (MC) solutions. Sonication at 20 KHz and 31 W for up to 30 min changed the surface hydrophobicity of the proteins, whereas surface charge was unaltered. Sonication before the addition of TSPP formed a firm gel with a fine protein network and low syneresis. Conversely, sonication after TSPP addition led to an inconsistent weak-gel-like structure with high syneresis. Gel strength in both cases increased significantly after short sonication times, while the viscoelastic properties were less affected. Overall, the results showed that ultrasonication can have a significant effect on the final gel properties of casein systems.


'Bundle busters': who is at risk of exceeding the target payment and can they be optimized?
The Bundled Payments for Care Improvement (BPCI) initiative has identified pathways for improving the value of care. However, patient-specific modifiable and non-modifiable risk factors may increase costs beyond the target payment. We sought to identify risk factors for exceeding our institution's target payment, the so-called 'bundle busters'. Using our data warehouse and Centers for Medicare and Medicaid Services (CMS) data we identified all 412 patients who underwent total joint arthroplasty and qualified for our institution's BPCI model, between July 2015 and May 2017. Episodes where CMS payments exceeded the target payment were considered 'busters' (n = 123). Risk ratios (RRs) were calculated using a modified Poisson regression analysis. An increased risk of exceeding the target payment was significantly associated with increasing age (adjusted RR 1.04, 95% confidence interval (CI) 1.01 to 1.06) and body mass index (adjusted RR 1.03, 95% CI 1.003 to 1.06). Eight comorbid risk factors were also identified (all p < 0.05), only two of which were considered to be potentially modifiable (diabetes with complications and preoperative anaemia). An American Society of Anesthesiologist physical status classification system (ASA) score ≥ 3 (adjusted RR 2.3, 95% CI 1.67 to 3.18) and Charlson Comorbidity Index (CCI) ≥ 3 (adjusted RR 1.94, 95% CI 1.45 to 2.60) were risk factors for bundle busting. Non-modifiable preoperative risk factors can increase costs and exceed the target payment. Future bundled payment models should incorporate the stratification of risk. Cite this article: Bone Joint J 2019;101-B(7 Supple C):64-69.


Cardiac Lipoma: An Uncharacteristically Large Intra-Atrial Mass Causing Symptoms.
Primary tumours of the heart are often encountered in clinical practice. Different autopsy series estimate the incidence to be anywhere from 0.001% to 0.19%. Cardiac lipoma is a rare type of tumour of the heart and pericardium. It comprises approximately 10-19% of all cardiac tumours. We present a case of a large cardiac lipoma in a fifty-year-old female. She presented with sharp chest pains, palpitations, and dizziness. Acute coronary syndrome was ruled out. A transthoracic echocardiogram showed an abnormal, large, fixed right atrial mass. The mass was noted to be occupying most of the right atrium. It was excised due to its large size and persistent symptoms. On pathophysiology, the mass was definitively diagnosed to be an 80 mm × 70 mm cardiac lipoma. Postoperatively, the patient did well with resolution of her symptoms. This case provides evidence that even large, invasive, symptomatic cardiac lipomas can be successfully resected with good outcomes.


Knowledge, attitudes, and behavior of homeless African-American adolescents: implications for HIV/AIDS prevention.
The purpose of this pilot study was to describe the knowledge of HIV/AIDS, attitudes about condom use, and the sexual behavior of African-American adolescents who reside in a children's emergency homeless shelter. The Attitudes Toward Condom Usage Questionnaire, the AIDS Knowledge and Attitude Survey, and a Perceived Risk of HIV/AIDS Scale were modified and administered to 37 African-American male and female adolescents who reside in an emergency shelter. HIV/AIDS knowledge and attitudes about condoms among these respondents were comparable to those of other adolescents described in the literature in that there was a strong knowledge of HIV/AIDS, although sexual behavior and attitudes toward condoms were not consistent with this knowledge. Significant differences between male and female respondents were only found on three items of the Attitudes Toward Condom Usage Questionnaire and on the Perceived Risk of HIV/AIDS Scale at the 0.05 level. The knowledge, attitudes, and sexual behavior of homeless, African-American adolescents should be examined to develop and implement appropriate programs to address the specific needs of this population. Further research should focus on this population and expand on this preliminary data.


Effectiveness of a 23-valent polysaccharide vaccine in preventing pneumonia and non-invasive pneumococcal infection in elderly people: a large-scale retrospective cohort study.
This retrospective cohort study evaluated the effectiveness of a 23-valent pneumococcal polysaccharide vaccine in reducing hospital admission for pneumonia, otitis media and exacerbation of asthma or other syndromes due to Streptococcus pneumoniae in 9170 high-risk individuals. Cohort members were followed from 1 January 1998 to 31 December 2002. With regard to preventing hospitalization due to pneumonia, we observed a decrease in the incidence of 1/10000 person-months and a reduction in the relative risk of 38% in the vaccinated cohort compared with the non-vaccinated subjects. A decrease in the risk of hospital admission for asthma, acute otitis media, chronic obstructive pulmonary disease and other respiratory infections was also observed in vaccinated compared with non-vaccinated subjects. The specificity of these findings was confirmed by the lack of a protective effect from vaccination for those outcomes, such as hospitalization 'for all causes' and 'other otorhinolaryngological diagnoses', that were not directly related to pneumococcal disease.


Excessive supply of glucose elicits an NF-κB2-dependent glycolysis in lactating goat mammary glands.
During lactation, an improper glucose supply often threatens mammary gland (MG) health. However, information is limited on the metabolic trajectories and molecules that regulate lactating MGs with an excessive glucose supply. Based on the network analysis of transcriptome and microRNAs, we found that the oversupply of glucose-induced severe glucose metabolic disorders in MGs of lactating goats, shifting lactose synthesis to acute fermentative glycolysis which caused increased flux of glucose metabolism into lactate. Moreover, NF-κB2 played a key role in regulating glycolysis, exhibiting a metabolic shift when MGs had an excessive supply of glucose. In primary mammary epithelial cells, fermentative glycolysis, and intracellular concentration of reactive oxygen species (ROS) were reduced by ganoderic acid A through blocking NF-κB2, while activation of NF-κB2 with phorbol myristate acetate (PMA) upregulated fermentative glycolysis and increased cellular ROS accumulation under excessive glucose. Thus, we established an NF-κB2-targeting method to reform the metabolic shift toward glycolysis caused by glucose oversupply by integrating NF-κB2 blockade and intracellular ROS scavenging.


Renormalization Group Flows of Hamiltonians Using Tensor Networks.
A renormalization group flow of Hamiltonians for two-dimensional classical partition functions is constructed using tensor networks. Similar to tensor network renormalization [G. Evenbly and G. Vidal, Phys. Rev. Lett. 115, 180405 (2015)PRLTAO0031-900710.1103/PhysRevLett.115.180405; S. Yang, Z.-C. Gu, and X.-G. Wen, Phys. Rev. Lett. 118, 110504 (2017)PRLTAO0031-900710.1103/PhysRevLett.118.110504], we obtain approximate fixed point tensor networks at criticality. Our formalism, however, preserves positivity of the tensors at every step and hence yields an interpretation in terms of Hamiltonian flows. We emphasize that the key difference between tensor network approaches and Kadanoff's spin blocking method can be understood in terms of a change of the local basis at every decimation step, a property which is crucial to overcome the area law of mutual information. We derive algebraic relations for fixed point tensors, calculate critical exponents, and benchmark our method on the Ising model and the six-vertex model.


Comparative Biochemistry and In Vitro Pathway Reconstruction as Powerful Partners in Studies of Metabolic Diversity.
There are estimated to be >300,000 plant species, producing >200,000 metabolites. Many of these metabolites are restricted to specific plant lineages and are referred to as "specialized" metabolites. These serve varied functions in plants including defense against biotic and abiotic stresses, plant-plant and plant-microbe communication, and pollinator attraction. These compounds also have important applications in agriculture, medicine, skin care, and in diverse aspects of human culture. The specialized metabolic repertoire of plants can vary even within and between closely related species, in terms of the number and classes of specialized metabolites as well as their structural variants. This phenotypic variation can be exploited to discover the underlying variation in the metabolic enzymes. We describe approaches for using the diversity of specialized metabolites and variation in enzyme structure and function to identify novel enzymatic activities and understand the structural basis for these differences. The knowledge obtained from these studies will provide new modules for the synthetic biology toolbox.


Apoptosis induced by PGC-1β in breast cancer cells is mediated by the mTOR pathway.
The peroxisome proliferator-activated receptor-γ (PPAR-γ) coactivator-1β (PGC-1β) is a well-established regulator of mitochondrial biogenesis. However, the underlying mechanism of PGC-1β action remains elusive. This study reveals that knockdown of endogenous PGC-1β by short-hairpin RNA (shRNA) leads to a decrease in the expression of mammalian target of rapamycin (mTOR) pathway-related genes in MDA-MB-231 cells. After knockdown of PGC-1β, phosphorylation of AMP-activated protein kinase (AMPK), phosphorylation of Rictor on Thr1135, Raptor and S6 protein was inhibited. However, Akt phosphorylation on Ser473 was upregulated and cell apoptosis occurred. In particular, we demonstrate that the levels of PGC-1β and mTOR correlated with overall mitochondrial activity. These results provide new evidence that cell apoptosis is orchestrated by the balance between several signaling pathways, and that PGC-1β takes part in these events in breast cancer cells mediated by the mTOR signaling pathway.


Polymorphisms in the cytotoxic T lymphocyte antigen-4 gene region confer susceptibility to Addison's disease.
The cytotoxic T lymphocyte antigen-4 (CTLA4) gene on chromosome 2q33 encodes a key regulator in the adaptive immune system. The CTLA4 surface molecule is expressed on activated T lymphocytes and involved in down-regulation of the immune response. Previous studies on a possible association between autoimmune Addison's disease and CTLA4 polymorphisms have shown conflicting results. A recent study identified new candidate polymorphisms in the CTLA4 region, influencing gene splicing and thereby the relative abundance of soluble CTLA4. We genotyped 134 patients with Addison's disease and 413 healthy controls from Norway and United Kingdom for these newly identified polymorphisms. Our data demonstrate that the same polymorphisms that have recently been demonstrated to confer susceptibility to autoimmune thyroid disease and type 1 diabetes also confer susceptibility to Addison's disease. This finding suggests that polymorphisms in CTLA4 confer general risk to develop autoimmunity and identifies a potential therapeutic target in the prevention of autoimmune endocrine disorders.


Genetic variations alter physiological responses following heat stress in 2 strains of laying hens.
Heat stress (HS) is a major problem experienced by the poultry industry during high-temperature conditions. The ability to manage the detrimental effects of HS can be attributed to multiple factors, including genetic background of flocks. The objective of the present study was to determine the genetic variation in HS effects on laying hens' physiological homeostasis. Ninety 28-wk-old White Leghorn hens of 2 strains were used: a commercial line of individually selected hens for high egg production, DeKalb XL (DXL), and a line of group-selected hens for high productivity and survivability, named kind gentle bird (KGB). Hens were randomly paired by strain and assigned to hot or control treatment for 14 d. Physical and physiological parameters were analyzed at d 8 and 14 posttreatment. Compared with controls, HS increased hen's core body temperature (P < 0.05) and decreased BW (P < 0.05) at d 8 and 14. Heat shock protein 70 concentrations in the liver were greater in hens exposed to HS (P < 0.05). Compared with DXL hens, KGB hens had higher heat shock protein 70 concentrations (P < 0.05). The hens' liver weight decreased following HS, with less of a response in the KGB line (P < 0.05). The data indicate HS has detrimental effects on the physiology of laying hens due to genetic variations. These data provide evidence that is valuable for determining genetic interventions for laying hens under HS.


Heterogeneity of epidemic Kaposi's sarcoma. Implications for therapy.
Kaposi's sarcoma (KS) in acquired immune deficiency syndrome (AIDS) is a new manifestation of a previously rare disease, and generally has a fatal course. Variations in the clinical course and in response to treatment by patients with this disease suggest that specific immunologic or clinical parameters may be important in the prognosis. Retrospective analyses of clinical parameters with respect to survival in 96 patients with epidemic Kaposi's sarcoma indicated that earlier tumor stage, the lack of prior opportunistic infections, and the absence of systemic symptoms correlated most closely with survival. Sixteen immune parameters were also assessed for their prognostic value. Total T4 (CD-4) cell number levels and the T4: T8 ratio correlated most closely with survival. Response to treatment with recombinant alpha interferons, while not well correlated with tumor stage, was more frequent in patients without systemic symptoms or a history or prior opportunistic infections. Treatment response was associated with a greater degree of intact T-cell function. These findings emphasize the importance of cellular immunity in the pathogenesis and subsequent course of patients with epidemic Kaposi's sarcoma, suggesting that different therapeutic strategies may be necessary to address specific prognostic subgroups.


Wall mediated transport in confined spaces: exact theory for low density.
We present a theory for the transport of molecules adsorbed in slit and cylindrical nanopores at low density, considering the axial momentum gain of molecules oscillating between diffuse wall reflections. Good agreement with molecular dynamics simulations is obtained over a wide range of pore sizes, including the regime of single-file diffusion where fluid-fluid interactions are shown to have a negligible effect on the collective transport coefficient. We show that dispersive fluid-wall interactions considerably attenuate transport compared to classical hard sphere theory.


Prevalence and determinants of the precursor stages of heart failure: results from the population-based STAAB cohort study.
Prevention of heart failure relies on the early identification and control of risk factors. We aimed to identify the frequency and characteristics of individuals at risk of heart failure in the general population. We report cross-sectional data from the prospective Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study investigating a representative sample of residents of Würzburg, Germany. Sampling was stratified 1:1 for sex and 10:27:27:27:10 for age groups of 30-39/40-49/50-59/60-69/70-79 years. Heart failure precursor stages were defined according to American College of Cardiology/American Heart Association: stage A (risk factors for heart failure), stage B (asymptomatic cardiac dysfunction). The main results were internally validated in the second half of the participants. The derivation sample comprised 2473 participants (51% women) with a distribution of 10%/28%/25%/27%/10% in respective age groups. Stages A and B were prevalent in 42% and 17% of subjects, respectively. Of stage B subjects, 31% had no risk factor qualifying for stage A (group 'B-not-A'). Compared to individuals in stage B with A criteria, B-not-A were younger, more often women, and had left ventricular dilation as the predominant B qualifying criterion (all P < 0.001). These results were confirmed in the validation sample (n = 2492). We identified a hitherto undescribed group of asymptomatic individuals with cardiac dysfunction predisposing to heart failure, who lacked established heart failure risk factors and therefore would have been missed by conventional primary prevention. Further studies need to replicate this finding in independent cohorts and characterise their genetic and -omic profile and the inception of clinically overt heart failure in subjects of group B-not-A.


Voiding dysfunction in patients with spastic paraplegia: urodynamic evaluation and response to continuous intrathecal baclofen.
Patients with hereditary spastic paraplegia (HSP), a degenerative central nervous system disorder characterized by progressive lower extremity spasticity, frequently experience symptoms of voiding dysfunction. Urodynamic evaluation of patients with HSP has not been reported, and the etiology of voiding dysfunction remains unexplained. We present our evaluation of three men (ages 42-62 years) with this rare syndrome. Urgency of urination was a uniform and dominant complaint, and two patients regularly experienced urge incontinence. Other symptoms included frequency (n = 3), nocturia (n = 3), and diminished force of stream (n = 1). Postvoid residual volumes were less than 25 ml in all patients. On urodynamic evaluation the two patients with urge incontinence displayed cystometric evidence of involuntary detrusor contractions. Pelvic floor EMG recordings suggested detrusor-sphincter dyssynergia (DSD). In addition, one patient exhibited markedly diminished bladder compliance (1.0 ml/cm H2O) and capacity (50 ml). All patients reported marked symptomatic improvement when treated with continuous intrathecal baclofen. Evaluation during baclofen treatment revealed increases in bladder compliance and capacity, with apparent resolution of DSD in one patient. Voiding symptoms in these patients most likely arise from a neurogenic etiology; however, a contributory role for chronic outlet obstruction from striated muscle spasticity may also exist.


A network approach to decentralized coordination of energy production-consumption grids.
Energy grids are facing a relatively new paradigm consisting in the formation of local distributed energy sources and loads that can operate in parallel independently from the main power grid (usually called microgrids). One of the main challenges in microgrid-like networks management is that of self-adapting to the production and demands in a decentralized coordinated way. Here, we propose a stylized model that allows to analytically predict the coordination of the elements in the network, depending on the network topology. Surprisingly, almost global coordination is attained when users interact locally, with a small neighborhood, instead of the obvious but more costly all-to-all coordination. We compute analytically the optimal value of coordinated users in random homogeneous networks. The methodology proposed opens a new way of confronting the analysis of energy demand-side management in networked systems.


Parenteral lipids shape gut bile acid pools and microbiota profiles in the prevention of cholestasis in preterm pigs.
Multi-component lipid emulsions, rather than soy-oil emulsions, prevent cholestasis by an unknown mechanism. Here, we quantified liver function, bile acid pools, and gut microbial and metabolite profiles in premature parenterally fed pigs given a soy-oil lipid emulsion, Intralipid (IL), a multi component lipid emulsion, SMOFlipid (SMOF), a novel emulsion with a modified fatty-acid composition [experimental emulsion (EXP)], or a control enteral diet (ENT) for 22 days. We assayed serum cholestasis markers, measured total bile acid levels in plasma, liver, and gut contents, and analyzed colonic bacterial 16S rRNA gene sequences and metabolomic profiles. Serum cholestasis markers (i.e., bilirubin, bile acids, and γ-glutamyl transferase) were highest in IL-fed pigs and normalized in those given SMOF, EXP, or ENT. Gut bile acid pools were lowest in the IL treatment and were increased in the SMOF and EXP treatments and comparable to ENT. Multiple bile acids, especially their conjugated forms, were higher in the colon contents of SMOF and EXP than in IL pigs. The colonic microbial communities of SMOF and EXP pigs had lower relative abundance of several gram-positive anaerobes, including Clostridrium XIVa, and higher abundance of Enterobacteriaceae than those of IL and ENT pigs. Differences in lipid and microbial-derived compounds were also observed in colon metabolite profiles. These results indicate that multi-component lipid emulsions prevent cholestasis and restore enterohepatic bile flow in association with gut microbial and metabolomic changes. We conclude that sustained bile flow induced by multi-component lipid emulsions likely exerts a dominant effect in reducing bile acid-sensitive gram-positive bacteria.


Covalent interactions of acetaldehyde with the actin/microfilament system.
The covalent binding of [14C]acetaldehyde to purified rabbit skeletal muscle actin was characterized. As we have found for other cytoskeletal proteins, actin formed stable covalent adducts under reductive and non-reductive conditions. Under non-reductive conditions, individual and competition binding studies versus albumin both showed that the G-form of actin is more reactive toward acetaldehyde than the F-form. When proteins were compared on an 'equi-lysine' basis under non-reducing conditions, G-actin was found to preferentially compete with albumin for binding to acetaldehyde. Time-course dialysis studies indicated that acetaldehyde-actin adducts become more stable with prolonged incubation at 37 degrees C. These data raise the possibility that actin could be a preferential target for adduct formation in cellular systems and will serve as the basis for ongoing studies aimed at defining the role of acetaldehyde-protein adducts in ethanol-induced cell injury.


Toward the development of virtual surgical tools to aid orthopaedic FE analyses.
Computational models of joint anatomy and function provide a means for biomechanists, physicians, and physical therapists to understand the effects of repetitive motion, acute injury, and degenerative diseases. Finite element models, for example, may be used to predict the outcome of a surgical intervention or to improve the design of prosthetic implants. Countless models have been developed over the years to address a myriad of orthopaedic procedures. Unfortunately, few studies have incorporated patient-specific models. Historically, baseline anatomic models have been used due to the demands associated with model development. Moreover, surgical simulations impose additional modeling challenges. Current meshing practices do not readily accommodate the inclusion of implants. Our goal is to develop a suite of tools (virtual instruments and guides) which enable surgical procedures to be readily simulated and to facilitate the development of all-hexahedral finite element mesh definitions.


Clinical results of bioresorbable drug-eluting scaffolds in short and long coronary artery lesions using the PSP technique.
Data on bioresorbable vascular scaffolds (BVS) for the treatment of long lesions are limited. We studied the use of BVS-Absorb in routine clinical practice and compared the outcome of long lesions with short lesions. Implantation of drug-eluting scaffolds without PSP-technique (predilation, proper sizing and postdilation) is associated with an increased thrombotic risk. We compared the long-term outcome up to 36 months of patients with short (< 20 mm) and long (≥20 mm) coronary artery lesions after implantation of bioresorbable vascular scaffolds (BVS) via PSP-technique. Three hundred twenty-six patients with 424 lesions were enrolled in this prospective study and underwent percutaneous coronary intervention with the Absorb BVS. Clinical follow-up was scheduled after 12, 24 and 36 months. In all lesions the PSP-technique was used. The device oriented composite endpoint (DOCE) was defined as cardiac death, myocardial infarction (MI) not clearly related to a non-target vessel and target lesion revascularization (TLR). Kaplan-Meier estimates for DOCE after 12 months were 2.63% for short lesions and 8.09% for long lesions (p = 0.0131), 5.51% vs. 11.35% (p = 0.0503) after 24 months and 8.00% vs. 18.00% (p = 0.0264) after 36 months of clinical follow-up. Kaplan-Meier estimates for TLR after 12 months were 1.46% for short and 7.69% for long lesions (p = 0.0012), 2.06% vs. 8.75% after 24 months (p = 0.0027) and 4.96% vs. 9.59% after 36 months of follow-up (p = 0.0109). Scaffold thrombosis rates were low. In long lesions compared to short ones the bioresorbable scaffold Absorb implanted with the proper PSP technique Absorb has significant higher rates of DOCE. Is 3 (non-random sample).


Protective effect of Sargussum vulgare sulfated polysaccharide against molecular, biochemical and histopathological damage caused by alloxan in experimental diabetic rats.
Diabetes is a serious condition that is linked to the development of oxidative stress. In the context of enhancing the biodiversity of Tunisia's flora, this study aimed to evaluate the effect of Sargussum vulgare sulfated polysaccharide (SVSP) on hyperglycemia and diabetes complications in the alloxan-induced diabetic rats. Our results showed a disturbance of carbohydrate, lipid, hematological and histopathological parameters, an increase in the α-amylase enzyme activity and damage to the pancreatic, hepatic and renal tissues in rats rendered diabetic by alloxan. In contrast, treatment with SVSP resulted in a correction of fasting and postprandial blood glucose and HbA1c through inhibition of pancreatic α-amylase. We also noticed an improvement in hemogram parameters and an attenuation of the pancreatic oxidative stress markers as well as histological protections. On the other hand, the administration of SVSP to diabetic rats caused, besides the correction of glycemic and lipid parameters, a good defense against hepatotoxicity and nephrotoxicity of diabetes as well as good antioxidant status and histological protections.


Collective effect of personal behavior induced preventive measures and differential rate of transmission on spread of epidemics.
In the present work, the effect of personal behavior induced preventive measures is studied on the spread of epidemics over scale free networks that are characterized by the differential rate of disease transmission. The role of personal behavior induced preventive measures is parameterized in terms of variable λ, which modulates the number of concurrent contacts a node makes with the fraction of its neighboring nodes. The dynamics of the disease is described by a non-linear Susceptible Infected Susceptible model based upon the discrete time Markov Chain method. The network mean field approach is generalized to account for the effect of non-linear coupling between the aforementioned factors on the collective dynamics of nodes. The upper bound estimates of the disease outbreak threshold obtained from the mean field theory are found to be in good agreement with the corresponding non-linear stochastic model. From the results of parametric study, it is shown that the epidemic size has inverse dependence on the preventive measures (λ). It has also been shown that the increase in the average degree of the nodes lowers the time of spread and enhances the size of epidemics.


Synthesis and evaluation of novel N-substituted-6-methoxynaphthalene-2-carboxamides as potential chemosensitizing agents for cancer.
A novel class of molecules with structure N-[3-(heteroaryl)propyl]-6-methoxynaphthalene-2-carboxamides 8-13 were synthesized by condensing 6-methoxy-2-naphthoyl chloride 1 with 3-(heteroaryl)propyl amines 2-7. Compounds 8-12 were evaluated in vitro, in P388 murine lymphocytic leukemia cell line (P388) using SRB assay for cytotoxicity and in adriamycin resistant P388 murine lymphocytic leukemia cell line (P388/ADR) using MTT assay for resistant reversal activity. Compounds 8-12 were non-toxic at lower dose of 20 microg/ml, and effectively reversed adriamycin resistance. However, at higher doses (40, 80 microg/ml) they showed significant cytotxicity and hence reversal potency was not determined at these concentrations.


Determination of variable region sequences from hybridoma immunoglobulins that target Mycobacterium tuberculosis virulence factors.
Mycobacterium tuberculosis (Mtb) infects one-quarter of the world's population. Mtb and HIV coinfections enhance the comorbidity of tuberculosis (TB) and AIDS, accounting for one-third of all AIDS-associated mortalities. Humoral antibody to Mtb correlates with TB susceptibility, and engineering of Mtb antibodies may lead to new diagnostics and therapeutics. The characterization and validation of functional immunoglobulin (Ig) variable chain (IgV) sequences provide a necessary first step towards developing therapeutic antibodies against pathogens. The virulence-associated Mtb antigens SodA (Superoxide Dismutase), KatG (Catalase), PhoS1/PstS1 (regulatory factor), and GroES (heat shock protein) are potential therapeutic targets but lacked IgV sequence characterization. Putative IgV sequences were identified from the mRNA of hybridomas targeting these antigens and isotype-switched into a common immunoglobulin fragment crystallizable region (Fc region) backbone, subclass IgG2aκ. Antibodies were validated by demonstrating recombinant Ig assembly and secretion, followed by the determination of antigen-binding specificity using ELISA and immunoblot assay.


Ceftriaxone in the treatment of bacterial meningitis in adults.
Twenty-six adults with acute bacterial meningitis were enrolled in an open randomized comparative study. The organisms isolated from CSF were Streptococcus pneumoniae, Staphylococcus epidermidis, Haemophilus influenzae, Escherichia coli and Salmonella typhi. 13 patients (group A) were treated once daily with intravenous ceftriaxone (Rocephin). The 13 patients in group B received ampicillin or ampicillin plus chloramphenicol in 4 doses/day. The mean duration of therapy in groups A and B was 9.9 and 12.3 days, respectively. This difference in the duration of therapy was statistically significant. All patients from group A showed clinical improvement and all were bacteriologically cured. In group B only 12 patients were clinically and bacteriologically cured; 1 patient had to be withdrawn from the therapy because CSF culture remained positive after 48 h of therapy. Ceftriaxone was well tolerated in all patients; ampicillin or ampicillin plus chloramphenicol were associated with diarrhea and skin rash in 6 patients.


Anatomical and functional assessment of the intra-atrial lateral tunnel in the Fontan circulation.
In patients after completion of the total cavopulmonary connection (TCPC) with an intra-atrial lateral tunnel, deviations of the tunnel from an ideal straight tubular shape were observed. However, little is known about frequency and adverse effects of such shape deviations. We sought to analyse tunnel anatomy, dimensions and blood flow using cardiac magnetic resonance imaging (CMR). Fifty-four patients with hypoplastic left heart syndrome (HLHS; mean age 6.0 ± 2.4 years) underwent CMR with gradient-echo cine sequences, 2D- and 3D-phase-contrast imaging. We analysed anatomy, diameters, cross-sectional areas, volumes and blood flow of the tunnel. Twenty-five patients had a tubular tunnel. In 29 patients, bulging and/or narrowing of the tunnel were present. Cross-sectional areas and volumes of the tunnel were not significantly different between the two groups. There were also no differences for the mean blood flow and the mean and maximal flow velocity (P = 0.05-0.6). In all the patients, the normalized tunnel volume was related to age (r = 0.44; P = 0.002) and body surface area (BSA; r = 0.42; P = 0.005). The mean tunnel blood flow correlated with age (r = 0.73; P = 0.001) and BSA (r = 0.83; P < 0.0001). A considerable percentage of patients with an intra-atrial lateral tunnel develop mild deviations of the tunnel from ideal tubular shape. The correlation between tunnel volume and mean blood flow with age and BSA suggests that the capacity of the tunnel adjusts to body growth, independent of tunnel shapes that deviate from a fluid-dynamically favourable shape. Follow-up CMRs are needed to detect long-term effects of irregular tunnel shapes on flow dynamics.


[Effect of Long-Term Application of Agrotechnical Techniques and Crops on Soil Microbial Communities].
Effects of long-term application ofvarious fertilizers and crops on soil microbiomes an a long-term field experiment were investigated using the library of the 16S rRNA gene sequences obtained by high-throughput sequencing of the total DNA. The communities exhibited high diversity, with 655 microbial genera belonging to 34 phyla detected (31 bacterial and 3 archaeal ones). For analysis of the effect of the studied factors on community structure, a linear model was developed in order to simplify interpretation of the data of high-throughput sequencing and to obtain biologically important information. Liming was shown to modulate the effect of mineral fertilizers on the structure of microbial populations. The differences in the structure and alpha-diversity of microbial communities were shown to depend more on the crops and liming, rather than on the fertilizers applied. Interaction between the crop factor and liming expressed as an ambiguous effect of liming on the microbiome in the presence of different plants was reliably demonstrated. Thus, in the case of barley and clover, liming resulted in increased taxonomic diversity of the community, while in the case of potato and flax it had an opposite effect.


Learning a high-precision locomotor task in patients with Parkinson's disease.
We evaluated the acquisition and performance of a high-precision locomotor task in patients with Parkinson's disease (PD) and healthy subjects. All subjects walked on a treadmill and had to step repetitively as low as possible over an obstacle without touching it. During blocks 1 and 2, the subjects had full vision and received additional acoustic warning and feedback signals. During block 3, vision became restricted. Changes in foot clearance and the number of obstacle hits were evaluated. Initially, PD patients performed poorer and improved foot clearance slower. After task repetition, the groups performed similarly. Restricting vision deteriorated performance in both groups. The similar performance of PD patients after task repetition might indicate that adequate training could improve adaptive locomotor behavior in PD patients.


The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level.
It is evident that the gut microbiota and factors that influence its composition and activity effect human metabolic, immunological and developmental processes. We previously reported that extreme physical activity with associated dietary adaptations, such as that pursued by professional athletes, is associated with changes in faecal microbial diversity and composition relative to that of individuals with a more sedentary lifestyle. Here we address the impact of these factors on the functionality/metabolic activity of the microbiota which reveals even greater separation between exercise and a more sedentary state. Metabolic phenotyping and functional metagenomic analysis of the gut microbiome of professional international rugby union players (n=40) and controls (n=46) was carried out and results were correlated with lifestyle parameters and clinical measurements (eg, dietary habit and serum creatine kinase, respectively). Athletes had relative increases in pathways (eg, amino acid and antibiotic biosynthesis and carbohydrate metabolism) and faecal metabolites (eg, microbial produced short-chain fatty acids (SCFAs) acetate, propionate and butyrate) associated with enhanced muscle turnover (fitness) and overall health when compared with control groups. Differences in faecal microbiota between athletes and sedentary controls show even greater separation at the metagenomic and metabolomic than at compositional levels and provide added insight into the diet-exercise-gut microbiota paradigm.


Distribution of localized states from fine analysis of electron spin resonance spectra in organic transistors.
We developed a novel method for obtaining the distribution of trapped carriers over their degree of localization in organic transistors, based on the fine analysis of electron spin resonance spectra at low enough temperatures where all carriers are localized. To apply the method to pentacene thin-film transistors, we proved through continuous wave saturation experiments that all carriers are localized at below 50 K. We analyzed the spectra at 20 K and found that the major groups of traps comprise localized states having wave functions spanning around 1.5 and 5 molecules and a continuous distribution of states with spatial extent in the range between 6 and 20 molecules.


The Clinical Efficacy of Suture-Button Fixation and Trans-Syndesmotic Screw Fixation in the Treatment of Ankle Fracture Combined With Distal Tibiofibular Syndesmosis Injury: A Retrospective Study.
Twenty percent of ankle fractures present with concomitant syndesmosis injury which results in poor clinical outcomes. Surgical stabilization of the syndesmosis can be achieved with either trans-syndesmotic screws or a suture button device. The aim of this study is to investigate the clinical efficacy of suture button fixation and trans-syndesmotic screw fixation in the treatment of ankle fracture combined with distal tibiofibular syndesmosis injury. A retrospective analysis was conducted by enrolling 76 patients with ankle fractures combined with distal tibiofibular syndesmosis injury who were admitted in our trauma center from January 2018 to January 2019, including 34 cases of suture button group and 42 cases of the syndesmotic screw group with a mean follow-up period of 16 ± 7 (range 12-21) months. The demographic data included gender, age, injury mechanism, AO classification and the operation duration were recorded, the radiographic and clinical outcomes were determined by tibiofibular clear space, tibiofibular overlap distance, complications, and the Olerud-Molander Ankle Score at the last follow-up. All the indexes were compared between the 2 groups to discover the related statistical differences. With the numbers available, no significant difference could be detected in the surgical duration, tibiofibular clear space, tibiofibular overlap distance, total complication rate, and middle-term Olerud-Molander Ankle scores between the 2 groups. However, the suture button fixation group showed higher early stage Olerud-Molander Ankle scores (p = .027) and shorter full weightbearing time (p = .018) than that of syndesmotic screw fixation group. Considering the outcomes, we conclude that the suture button fixation not only shows equivalent efficacy to the traditional syndesmotic screw, but also has advantages of allowing early weightbearing, low requirements for routine removal.


The N-terminal domain of human GABA receptor rho1 subunits contains signals for homooligomeric and heterooligomeric interaction.
gamma-Aminobutyric acid type C (GABAC) receptors identified in retina appear to be composed of GABA rho subunits. The purpose of this study was to localize signals for homooligomeric assembly of rho1 subunits and to investigate whether the same region contained signals for heterooligomeric interaction with rho2 subunits. In vitro translated human rho1 was shown to be membrane-associated, and proteinase K susceptibility studies indicated that the N terminus was oriented in the lumen of ER-derived microsomal vesicles. This orientation suggested the involvement of the N terminus of rho1 in the initial steps of subunit assembly. To test this hypothesis, mutants were created containing only N-terminal sequences (N-rho1) or C-terminal sequences (C-rho1) of rho1. Co-immunoprecipitation studies revealed that N-rho1, but not C-rho1, interacted with rho1 in vitro. When coexpressed in Xenopus oocytes, N-rho1 interfered with rho1 receptor formation. Together, these data suggested that signals for rho1 homooligomeric assembly reside in the N-terminal half of the subunit. Sequential immunoprecipitations were then performed upon cotranslated rho1 and rho2 subunits which demonstrated that rho1 and rho2 interacted in vitro. Co-immunoprecipitation indicated that N-rho1 specifically associated with rho2. Therefore, the N-terminal regions of rho subunits contain the initial signals for both homooligomeric and heterooligomeric assembly into receptors with GABAC properties.


Pathogenesis of measles virus infection: an hypothesis for altered immune responses.
Measles virus causes a severe systemic illness. The rash occurs simultaneously with the onset of the effector phase of the antiviral immune response and substantial evidence of immune activation. This immune response is effective in clearing virus and in establishing long-term resistance to reinfection but is associated with immune suppression, autoimmune encephalomyelitis, and increased susceptibility to secondary infections. This apparent paradox may be explained in part by preferential long-term activation of type 2 CD4+ T cells by measles virus infection. Preferential stimulation of type 1 CD4+ T cells by inactivated virus vaccines is hypothesized to play a role in subsequent development of atypical measles.


Transient receptor potential channel-dependent myogenic responsiveness in small-sized resistance arteries.
It is well documented that the inherent ability of small arteries and arterioles to regulate intraluminal diameter in response to alterations in intravascular pressure determines peripheral vascular resistance and blood flow (termed myogenic response or pressure-induced vasoconstriction/dilation). This autoregulatory property of resistance arteries is primarily originated from mechanosensitive vascular smooth muscle cells (VSMCs). There are diverse biological apparatuses in the plasma membrane of VSMCs that sense mechanical stimuli and generate intracellular signals for the contractility of VSMCs. Although the roles of transient receptor potential (TRP) channels in pressure-induced vasoconstriction are not fully understood to date, TRP channels that are directly activated by mechanical stimuli (e.g., stretch of VSMCs) or indirectly evoked by intracellular molecules (e.g., inositol trisphosphate) provide the major sources of Ca2+ (e.g., Ca2+ influx or release from the sarcoplasmic reticulum) and in turn, evoke vascular reactivity. This review sought to summarize mounting evidence over several decades that the activation of TRP canonical, TRP melastatin, TRP vanilloid, and TRP polycystin channels contributes to myogenic vasoconstriction.


[The daily life of patients at the Hôtel-Dieu in Lyon in the nineteenth century].
In 1802 the Hôtel-Dieu in Lyons was incorporated in the so-called Hospices Civils de Lyon. This allowed the expansion and renovation of buildings, as well as the improvement of the conditions of hygiene and comfort of the patients. This hospital was devoted only to the most severely ill or injured adults. 1100 patients were treated by seven doctors, a main surgeon and his deputy, residents and sisters. Broadly speaking the evolution of surgery can be divided into two periods: that of before anesthesia and septic surgery and that of antiseptic and aseptic surgery. We have to mention Gensoul and the resection of the maxillary before anesthesia, Bonnet and Ollier who were devoted to osteo-articular surgery (Ollier's disease), Poncet who built the first aseptic theater, Jaboulay and the resident Carrel who were transplantation's pioneers, Bouveret (paroxysmal tachycardia and Bouveret syndrome), Destot who did the first medical use of X-rays in 1895.


Vitamin D status in Algerian Behçet's disease patients: an immunomodulatory effect on NO pathway.
Behçet's disease (BD) is an inflammatory multisystemic disorder associated with orogenital ulcers, uveitis and skin lesions with unpredictable episodes of exacerbations and remissions. Even though several immunological and environmental factors contribute to BD progression, its ethiopathogenesis remains uncertain and elusive. Considered as one of the potent environmental factors that can increase prevalence of some autoimmune and inflammatory disorders, vitamin D deficiency has been linked to several diseases as BD. The aim of this study is to assess vitamin D status in Algerian BD patients and its relationship with disease activity. Immunomodulatory effect of this vitamin on nitric oxide (NO), inflammatory mediator, was also undertaken. Serum 25(OH) vitamin D levels were measured in healthy controls (HC), active and inactive BD patients with an electrochemiluminescence method. After treatment of HCs' and patients' peripheral blood mononuclear cells with different concentrations of vitamin D3, NO production was evaluated with Griess method, while inducible nitric oxide synthase (iNOS) and NF-κB expression with immunofluorescence test. A high decrease of vitamin D levels was noted in active BD patients compared to those of inactive stage and HC. However, a higher NO production was observed during active stage of BD compared to inactive one. In inactive BD, vitamin D levels correlates negatively with NO. Interestingly, vitamin D3 inhibits ex vivo NO production, iNOS and NF-κB expression in BD patients. In conclusion, vitamin D deficiency was associated with active BD. This vitamin down-modulates NO production in BD patients, suggesting that it may be considered as promising therapy modulating inflammation during BD.


Dye removal by eco-friendly physically cross-linked double network polymer hydrogel beads and their functionalized composites.
Hydrogels have attracted large attention in wastewater treatment fields due to their low-cost and good interaction with pollutants, among which novel double network hydrogel is an outstanding class. To expand the application of double network hydrogel in water treatment, in this study, eco-friendly physically cross-linked double network polymer hydrogel beads (DAP) are prepared and studied in depth on the mechanism of Methylene Blue (MB) adsorption; and then the polymer hydrogels are further functionalized by inorganic materials. MB adsorption on DAP favors alkaline condition which is due to the increase of electrostatic attraction and adsorption site, and it reaches equilibrium within 10 hr, which is faster than that of the single network hydrogel beads (SAP). Through thermodynamics study, the process shows to be an exothermic and spontaneous process. The adsorption isotherms are well fitted by Langmuir model, with a maximum monolayer adsorption capacity of 1437.48 mg/g, which is larger than SAP (1255.75 mg/g). After being functionalized with common inorganic materials including activated carbon, Fe3O4 and graphene oxide (GO), the composites show to have larger pore sizes and have obvious increases in adsorption capacity especially the one contains GO. Then the composites contains Fe3O4 are used as heterogeneous Fenton catalyst which shows to have excellent performance in MB degradation. The results indicate the potential of polymer double network to be functionalized in environmental areas.


Protective effects of 2-aminoethylthiosulfuric acid and structurally analogous organosulfur compounds against ionizing radiation.
High efficacy and minimal toxicity radioprotectors are desirable options for the hazards posed by nuclear medical and energy technologies and the dangers presented by nuclear weapons in an unstable global situation. Although cysteamine is an effective radioprotector, it has considerable toxicity. In this study, the protective effects of the less toxic organosulfur compounds 2-aminoethylthiosulfate (AETS), thiotaurine (TTAU), and hypotaurine (HTAU) against X-ray damage in mice were compared with that of cysteamine. Intraperitoneal injection of either AETS or cysteamine (2.2 mmol/kg body weight) 30 min before X-ray irradiation (7.0 Gy) provided 100% survival for 30 days, limited the decrease in erythrocytes and neutrophils over 9 days, and reduced damage to bone marrow and spleen over 9 days. Neither TTAU nor HTAU provided any protection. In mice, 30 min after AETS administration, non-protein thiol content increased in the spleen, indicating cysteamine generation by AETS hydrolysis, the active protective species of AETS. All examined compounds scavenged •OH under diffusion control in aqueous solution, which is inconsistent with the difference in the protective effects among the compounds. The results indicate that AETS protects animals from ionizing radiation by several mechanisms, including scavenging •OH as cysteamine.


Antioxidant and Cytoprotective Effects of the Di-O-Caffeoylquinic Acid Family: The Mechanism, Structure-Activity Relationship, and Conformational Effect.
In this study, a series of di-O-caffeoylquinic acids (di-COQs) were systematically investigated for their antioxidant and cytoprotective effects towards •OH-damaged bone marrow-derived mesenchymal stem cells (bmMSCs). Five di-COQs were measured using a set of antioxidant assays. The results show that adjacent 4,5-Di-O-caffeoylquinic acid (4,5-COQ) and 3,4-di-O-caffeoylquinic acid (3,4-COQ) always gave lower IC50 values than did non-adjacent di-COQs. In the Fe2+-chelating assay, 4,5-COQ and 3,4-COQ presented greater UV-Vis spectra and darker colors than did non-adjacent di-COQs. In the UPLC-ESI-MS/MS analysis, no corresponding radical adduct formation (RAF) peak was found in the reaction products of di-COQs with PTIO•. In the MTT assay, all di-COQs (especially 1,5-COQ, 1,3-COQ, and 4,5-COQ) dose-dependently increased the cellular viabilities of •OH-damaged bmMSCs. Based on this evidence, we conclude that the five antioxidant di-COQs can protect bmMSCs from •OH-induced damage. Their antioxidant mechanisms may include electron-transfer (ET), H⁺-transfer, and Fe2+-chelating, except for RAF. Two adjacent di-COQs (4,5-COQ and 3,4-COQ) always possessed a higher antioxidant ability than the non-adjacent di-COQs (1,3-COQ, 1,5-COQ, and 3,5-COQ) in chemical models. However, non-adjacent 1,3-COQ and 1,5-COQ exhibited a higher cytoprotective effect than did adjacent di-COQs. These differences can be attributed to the relative positions of two caffeoyl moieties and, ultimately, to the conformational effect from the cyclohexane skeleton.


From bevacizumab to tasquinimod: angiogenesis as a therapeutic target in prostate cancer.
It was first posited in the 1970s that angiogenesis may prove to be a useful target for anticancer therapies. Since then, a number of agents have been developed and tested across a range of tumor types; however, to date, there have unfortunately been more failures than successes. Prostate cancer (PCa) is no exception in this regard, and despite a strong preclinical rationale for targeting angiogenesis in men with PCa, there has yet to be an antiangiogenic therapy proven to prolong survival in this group of patients. Drugs have been developed to target a host of angiogenesis mediators. These include vascular endothelial growth factor (VEGF), the VEGF receptors, antiangiogenic factors (e.g., thrombospondin-1), and downstream mediators of angiogenesis (e.g., hypoxia-inducible factor-1α and MET). At present, there are 2 drugs being tested in the phase III setting for men with PCa: cabozantinib and tasquinimod. Cabozantinib, a dual VEGF receptor-2/MET inhibitor, has shown dramatic beneficial effects on radiographically evident bone metastases and pain in the phase II setting. There are currently 2 large phase III trials underway to further investigate cabozantinib's role in treating men with PCa. Both trials randomize subjects to cabozantinib versus mitoxantrone: one is designed to evaluate overall survival, and the other, pain response durability. The other drug, tasquinimod, has a somewhat poorly understood mechanism of action. It is thought to exert an antiangiogenic effect through the inhibition of myeloid-derived suppressor cells, key to the support of an angiogenic environment, and down-regulation of hypoxia-inducible factor-1α. A phase II trial randomizing men to tasquinimod versus placebo revealed a median progression-free survival advantage in the experimental arm (7.6 vs. 3.3 months with placebo; P = 0.0042). Based on these encouraging phase II results, a randomized, double-blind, placebo-controlled trial in men with metastatic castration-resistant PCa was launched. That trial is powered for a primary endpoint of progression-free survival and is expected to enroll 1200 men.


Expression of key prostaglandin synthases in equine endometrium during late diestrus and early pregnancy.
Luteolysis in domestic species is mediated by the release of luteolytic pulses of prostaglandin (PG) F(2alpha) by the uterus at the end of diestrus, which must be suppressed by the conceptus to permit maternal recognition of pregnancy. In many species, including the horse, both the conceptus and the endometrium also synthesize PGE(2), which may antagonize PGF(2alpha) by playing a luteotropic and/or antiluteolytic role. While the release of PGE(2) and PGF(2alpha) by the equine endometrium in late diestrus and early pregnancy has been previously studied, the underlying prostaglandin synthase gene regulatory mechanisms remain poorly defined. To resolve this issue, cyclooxygenase-2 (COX-2), microsomal PGE(2) synthase (PGES), and PGF(2alpha) synthase (PGFS) expression were examined in a series of endometrial biopsies obtained from cycling mares on Days 10, 13, and 15 postovulation, as well as from pregnant mares on Day 15. Quantification of COX-2 expression revealed significant (P < 0.01) increases in both mRNA and protein levels at Day 15 in cycling endometrium relative to other timepoints. Importantly, the level of COX-2 expression in Day 15 pregnant endometrium was found to be comparable with that observed in Day 10 and Day 13 cycling animals, suggesting that the presence of the conceptus blocks the induction of COX-2. Immunohistochemistry demonstrated that the induction of COX-2 expression on Day 15 occurs specifically in surface epithelial cells in cycling animals only. As equine PGFS had not been previously characterized, a 1380-base pair (bp) cDNA transcript was cloned by a combination of reverse transcription-PCR techniques and found to be highly homologous to bovine liver-type PGFS. The pattern of expression observed for the terminal PG synthases was distinct from that of COX-2, as PGES and PGFS mRNA and protein levels were found to be invariant throughout the timecourse and unaffected by pregnancy. Similar to COX-2, however, the PGES and PGFS proteins were found to localize mainly to the surface epithelium. Thus, this study describes for the first time the regulation and spatial distribution of COX-2, PGES, and PGFS expression in equine endometrium in late diestrus, with a marked induction of COX-2 but not of PGES and PGFS expression in uterine epithelial cells at Day 15. Furthermore, the presence of the conceptus was shown to block the induction of COX-2 expression at Day 15, suggesting an important mechanism by which it may suppress uterine PGF(2alpha) release and prevent luteolysis during early pregnancy.


Improvement of immunomagnetic separation for Escherichia coli O157:H7 detection by the PickPen magnetic particle separation device.
Conventional immunomagnetic separation (IMS) procedures, which use an external magnetic source to capture magnetic particles against the side of a test tube, are labor-intensive and can have poor sensitivity for the target organism because of high background microflora that is not effectively washed away during the IMS process. This report compares the conventional IMS procedure to a new IMS procedure with an intrasolution magnetic particle transfer device, the PickPen. The IMS target for the majority of these studies is Escherichia coli O157:H7 in various types of samples, including cattle feces, hides, carcasses, and ground beef. Comparison of the two IMS methods showed a significant difference (P < 0.05) in the efficiency of detecting E. coli O157:H7 from cattle carcass surface, cattle hide, and cattle fecal samples. No significant improvement (P > 0.05) in E. coli O157:H7 detection was observed when the PickPen IMS procedure was used to isolate this pathogen from ground beef samples. Use of the PickPen IMS greatly increases the throughput of the IMS procedure and may be more compatible with various emerging technologies for pathogen detection. In addition, the efficacy of sequential IMS for multiple pathogens is reported herein.


Wnt-4 activates the canonical beta-catenin-mediated Wnt pathway and binds Frizzled-6 CRD: functional implications of Wnt/beta-catenin activity in kidney epithelial cells.
The Wnt signaling pathway is central to the development of all animals and to cancer progression, yet largely unknown are the pairings of secreted Wnt ligands to their respective Frizzled transmembrane receptors or, in many cases, the relative contributions of canonical (beta-catenin/LEF/TCF) versus noncanonical Wnt signals. Specifically, in the kidney where Wnt-4 is essential for the mesenchymal to epithelial transition that generates the tissue's collecting tubules, the corresponding Frizzled receptor(s) and downstream signaling mechanism(s) are unclear. In this report, we addressed these issues using Madin-Darby Canine Kidney (MDCK) cells, which are competent to form tubules in vitro. Employing established reporter constructs of canonical Wnt/beta-catenin pathway activity, we have determined that MDCK cells are highly responsive to Wnt-4, -1, and -3A, but not to Wnt-5A and control conditions, precisely reflecting functional findings from Wnt-4 null kidney mesenchyme ex vivo rescue studies. We have confirmed that Wnt-4's canonical signaling activity in MDCK cells is mediated by downstream effectors of the Wnt/beta-catenin pathway using beta-Engrailed and dnTCF-4 constructs that suppress this pathway. We have further found that MDCK cells express the Frizzled-6 receptor and that Wnt-4 forms a biochemical complex with the Frizzled-6 CRD. Since Frizzled-6 did not appear to transduce Wnt-4's canonical signal, data supported recently by Golan et al., there presumably exists another as yet unknown Frizzled receptor(s) mediating Wnt-4 activation of beta-catenin/LEF/TCF. Finally, we report that canonical Wnt/beta-catenin signals cells help maintain cell growth and survival in MDCK cells but do not contribute to standard HGF-induced (nonphysiologic) tubule formation. Our results in combination with work from Xenopus laevis (not shown) lead us to believe that Wnt-4 binds both canonical and noncanonical Frizzled receptors, thereby activating Wnt signaling pathways that may each contribute to kidney tubulogenesis.


[Programmed diagnosis].
Diagnostics is still a problem not completely solved. The progress is not only in the possibilities of making use of better improved laboratory and technique for the examination of the patient but in mastering of improved methodology, of new operational ability of the physician of programmed work and better organization--in his activities and mentally.


Pediatric highly active antiretroviral therapy in Mozambique: an integrated model of care.
To test the impact of a public health model to implement HIV pediatric care in Limited Resource Settings. A retrospective study on the clinical files of 679 Mozambican children (mean age 4.4 years; SD 3.2), has been carried out. The pediatric patients received HAART (Highly Active Anti-Retroviral Therapy) in the framework of DREAM, a nationwide public health program offering an integrated model of care to HIV patients including free-of-charge HAART and monitoring, nutritional assessment and supplementation, peer-to-peer education, active tracing of the dropped out patients. HAART was started in 297 subjects out of 679. The median time of treatment was 286 (IQ 25-75:125-465). Mortality rate was lower in the sub-sample receiving HAART (8.4%; CI 95%: 5.2-11.6 vs 13.1%; CI 95%: 9.7-16.5). After 6 months of treatment the percentage of viral load lower than 400 copies/mL rose from 4.9% to 46.3%. The percentage of patients with less than 15% of CD4 cells out of the total lymphocyte count and the percentage of patients below the 2 z-score decreased from 56.4% and 58.1% to 8.8% and 38.1% respectively. Pediatric HAART in limited resource settings often face difficulties to handle complex treatment schemes, but the implemented model seems to be an effective tool to reduce mortality rate in HIV positive pediatric population.


Autosomal dominant inheritance of hereditary canine spinal muscular atrophy.
Hereditary canine spinal muscular atrophy ( HCSMA ) is a motor neuron disease in Brittany spaniels. Three phenotypes are recognized (accelerated, intermediate, and chronic) and are distinguished on the basis of rate of progression and age at onset. Breeding studies within a kindred of more than 125 dogs (Brittany spaniel and beagle-Brittany outcrosses ) have established an autosomal dominant inheritance for HCSMA . Pups homozygous for the trait have accelerated disease whereas heterozygous dogs have intermediate or chronic disease. The reason for the two phenotypes in heterozygotes is under study. HCSMA provides a unique opportunity to study the genetic and pathophysiological mechanisms of a motor neuron disease, and findings may have broad relevance to investigations of autosomal dominant degenerative disorders of the central nervous system.


Development of a New Microextraction Fiber Combined to On-Line Sample Stacking Capillary Electrophoresis UV Detection for Acidic Drugs Determination in Real Water Samples.
A new analytical method coupling a (off-line) solid-phase microextraction with an on-line capillary electrophoresis (CE) sample enrichment technique was developed for the analysis of ketoprofen, naproxen and clofibric acid from water samples, which are known as contaminants of emerging concern in aquatic environments. New solid-phase microextraction fibers based on physical coupling of chromatographic supports onto epoxy glue coated needle were studied for the off-line preconcentration of these micropollutants. Identification and quantification of such acidic drugs were done by capillary zone electrophoresis (CZE) using ultraviolet diode array detection (DAD). Further enhancement of concentration sensitivity detection was achieved by on-line CE "acetonitrile stacking" preconcentration technique. Among the eight chromatographic supports investigated, Porapak Q sorbent showed higher extraction and preconcentration capacities. The screening of parameters that influence the microextraction process was carried out using a two-level fractional factorial. Optimization of the most relevant parameters was then done through a surface response three-factor Box-Behnken design. The limits of detection and limits of quantification for the three drugs ranged between 0.96 and 1.27 µg∙L-1 and 2.91 and 3.86 µg∙L-1, respectively. Recovery yields of approximately 95 to 104% were measured. The developed method is simple, precise, accurate, and allows quantification of residues of these micropollutants in Genil River water samples using inexpensive fibers.


Properties of 42S and 26S Sindbis viral ribonucleic acid species.
Two species of ribonuclease-sensitive Sindbis viral ribonucleic acids which sedimented at 42S and 26S were studied. 42S RNA, derived either from virions or from viral nucleoids extracted from infected cultures, was converted by heating to an RNA which sedimented at 26S. The sedimentation patterns of 42S RNA and "derived" 26S RNA were similarly affected in low ionic strength buffers. 42S RNA ran as a homogeneous fraction on polyacrylamide gels; the "derived" 26S RNA as well as "natural" 26S RNA from infected cultures showed similar electrophoretic patterns of heterogeneity. A doubling of 3' polynucleotide termini was observed when 42S RNA was heated. Two possibilities concerning the structure of 42S RNA are considered. (i) It may consist of an aggregate of subunits, joined by means of hydrogen bonds to form a complex molecule. (ii) A heat-labile covalent bond of unknown type may link viral RNA subunits. Although 26S RNA from infected cultures and "derived" 26S RNA from 42S RNA behaved in a similar qualitative manner on gels, their sedimentation characteristics were affected differently in low ionic strength buffers. "Natural" and "derived" 26S RNA appear to consist of a population of fragments. and their behavior in gradients and in gels is probably dictated by the experimental conditions of the analytical methods used.


[Development and use of the ICF from the nursing point of view--a position statement of the German speaking working group "ICF and Nursing"].
The International Classification of Functioning, Disability and Health (ICF) provides a comprehensive and internationally acknowledged framework for the description of human functional health, which covers all aspects of health and some health-related elements of well-being. The ICF is part of the classification family of the World Health Organisation (WHO) and can be used by different health care disciplines as well as for different purposes. In order to promote the discussion about ICF within the nursing profession, the German speaking working group "ICF and Nursing" developed a position statement that critically reflects both the potentials and the restrictions of the ICF for use in nursing care, particularly for diagnostical purposes.


[Effect of hyaluronic acid on promoting bone marrow-derived mesenchymal stem cells to differentiate into neural cells in vitro].
To determine the effect of hyaluronic acid (HA) on promoting bone marrow-derived mesenchymal stem cells (BMSCs) to differentiate into neural cells. BMSCs were purified and monitored. NSE+/NF+ cells and nestin+ cells were detected by immunocytochemistry. The mRNA levels of NSE, NF and nestin were determined by RT-PCR. The BMSCs adhered to HA hydrogel, with many surface projections, branches or crossing (Group A). Those cultured in brain tissue culture medium grew projections with fewer branches (Group B). Group A had more NSE+ cells (92.58 +/- 15.84) than Group B (80.26 +/- 16.47), and more NF+ cells (71.25 +/- 17.44) than Group B (52.37 +/- 14.75) (P < 0.05). At day 2 post-stimulation, more nestin+ cells were found in Group A (48.3 +/- 7.7) compared with Group B (34.6 +/- 5.2) (P < 0.05). At day 7, the mRNA levels of NSE and NF increased in both groups, but more in Group A. Nestin mRNA increased at day 2 post-stimulation and dropped at day 7 in both groups, where more significant in Group A. HA hydrogel provides structural support and proper microenvironment for the growth, proliferation and differentiation of BMSCs, and promotes BMSCs to differentiate into neuron cells.


TAT peptide-modified liposomes provide enhanced gene delivery to intracranial human brain tumor xenografts in nude mice.
In this study, we have investigated the potential of trans-activating transcriptional activator peptide (TATp)-modified liposomes to enhance the delivery of the model gene, plasmid encoding for the green fluorescent protein (pEGFP-N1), to human brain tumor U-87 MG cells in vitro and in an intracranial model in nude mice. The TATp-lipoplexes were characterized at lipid/DNA (+/-) charge ratios of 0.2, 5, 10, and 20 for size analysis and DNA complexation. The size distribution of DNA-loaded TATp-liposomes was narrow and the DNA complexation was firm at lipid/DNA (+/-) charge ratios of 5 and higher. TATp-lipoplexes had demonstrated an enhanced delivery of pEGFP-N1 to U-87 MG tumor cells in vitro at lipid/DNA (+/-) charge ratios of 5 and 10. In vivo transfection of intracranial brain tumors by intratumoral injections of TATp-lipoplexes showed an enhanced delivery of pEGFP-N1 selectively to tumor cells and subsequent effective transfection compared to plain plasmid-loaded lipoplexes. No transfection (green fluorescence of the GFP) was noted in the normal brain adjacent to tumor.


Squamous cell carcinoma of the tongue in a patient with Rothmund-Thomson syndrome.
Rothmund-Thomson syndrome is a rare autosomal recessive genodermatosis characterised by poikilodermatous skin changes that appear in childhood. Patients exhibit variable additional features including juvenile cataracts, skeletal abnormalities and a higher than expected incidence of malignancies. We report a case of squamous cell carcinoma of the tongue in a 37-year-old Rothmund-Thomson syndrome patient and review the natural history of this rare disease, given that the patient was diagnosed with Rothmund-Thomson syndrome at the age of 8 years and was first reported in 1975.


Adult B-Cell Acute Lymphoblastic Leukemia Dominated by Osteolytic Bone Involvement on CT But Less Impressive PET on FDG PET/CT Images.
A 47-year-old man presented with abdominal pain, vomiting, and bone pain. Laboratory findings revealed severe hypercalcemia, anemia, and renal insufficiency with decreased serum parathyroid hormone. FDG PET/CT was performed for characteristics suggestive of multiple myeloma and other occult malignancy. The images revealed widespread osteolytic lesions with only 1 focus of definite abnormal FDG uptake. B-cell acute lymphoblastic leukemia was confirmed by pathological examination following bone marrow biopsy.


Pharmacogenetics of inflammatory bowel disease: a focus on Crohn's disease.
Crohn's disease is an inflammatory bowel disease showing a high heterogeneity in phenotype and a strong genetic component. The treatment is complex, due to different severity of clinical parameters and to the fact that therapies only permit to control symptoms and to induce remission for short periods. Moreover, all categories of drugs present a great interindividual variability both in terms of efficacy and side effects appearance. For this reason, the identification of specific genomic biomarkers involved in drugs response will be of great clinical utility in order to foresee drug's efficacy and to prevent adverse reactions, permitting a more personalized therapeutic approach. In this review, we focus the attention on the pharmacogenetic studies regarding drugs commonly utilized in Crohn's disease treatment.


[The role of aromatase inhibitors in the treatment of breast neoplasms. An evaluation of clinical efficacy and the tolerability profile].
Constant acquisitions regarding endocrine pathogenesis and the biology of breast neoplasms have led to the evolution of hormone manipulation as a therapeutic option in patients suffering from this disease. There has been a shift from ablative surgical procedures to the use of drugs offering greater clinical efficacy and an improved tolerability profile. Since the late 1970s tamoxifen has been regarded as the gold standard for hormone treatment in hormone-responsive breast neoplasm, but promising new endocrine agents are now being compared in random trials. Of these, the latest generation of aromatase inhibitors appears to gather the widest consensus on the basis of the results published to date. This article aims to review this new category of drugs, illustrating their rationale of use, the results obtained in the treatment of breast neoplasm and the main studies in which they are currently being investigated.


Guidelines and Experience Using Imaging Biomarker Explorer (IBEX) for Radiomics.
Imaging Biomarker Explorer (IBEX) is an open-source tool for medical imaging radiomics work. The purpose of this paper is to describe how to use IBEX's graphical user interface (GUI) and to demonstrate how IBEX calculated features have been used in clinical studies. IBEX allows for the import of DICOM images with DICOM radiation therapy structure files or Pinnacle files. Once the images are imported, IBEX has tools within the Data Selection GUI to manipulate the viewing of the images, measure voxel values and distances, and create and edit contours. IBEX comes with 27 preprocessing and 132 feature choices to design feature sets. Each preprocessing and feature category has parameters that can be altered. The output from IBEX is a spreadsheet that contains: 1) each feature from the feature set calculated for each contour in a data set, 2) image information about each contour in a data set, and 3) a summary of the preprocessing and features used with their selected parameters. Features calculated from IBEX have been used in studies to test the variability of features under different imaging conditions and in survival models to improve current clinical models.


The significance of poor renal transplant concentrating ability as assessed by I-131 Hippuran imaging.
A pattern of very poor renal allograft concentration of I-131 Hippuran and good bladder activity has been observed by the authors. The kidneys are typically barely visualized and the renogram curve is flat. The significance of this particular finding has not been described in the literature. Accordingly, a retrospective review of all patients exhibiting this scan pattern was performed and the authors attempted to correlate it with clinical, laboratory, and pathological findings at the time of study. Of 11 patients exhibiting this scan pattern, three had very high urine outputs at the time of study. Of the remaining eight patients, five had chronic rejection. In the remaining three patients, the diagnosis was: one each, acute rejection, mixed acute and chronic rejection, and cyclosporine toxicity. The authors conclude that although this pattern is non-specific, if the patient is not in a high output state, it is usually related to chronic rejection.


Serine 16 of oncoprotein 18 is a major cytosolic target for the Ca2+/calmodulin-dependent kinase-Gr.
Oncoprotein 18 (Op18) is a cytosolic protein that was initially identified due to its up-regulated expression in acute leukemia and its complex pattern of phosphorylation in response to diverse extracellular signals. We have previously identified in vivo phosphorylation sites and some of the protein kinase systems involved. Two distinct proline-directed kinase families phosphorylate Ser25 and Ser38 of Op18 with overlapping but distinct site preference. These two kinase families, mitogen-activated protein (MAP) kinases and cyclin-dependent cdc2 kinases, are involved in receptor-regulated and cell-cycle-regulated phosphorylation events, respectively. During analysis of Op18 phosphorylation in the Jurkat T-cell line, we also found that Ser16 of Op18 is phosphorylated in response to a Ca2+ signal generated by T-cell receptor stimulation or the Ca2+ ionophore ionomycin. As suggested by a previous study, T-cell-receptor-induced phosphorylation events may be mediated by the Ca2+/CaM-dependent protein kinase type Gr (CaM kinase-Gr). The present study shows that activation of this protein kinase correlates with phosphorylation of Ser16 of Op18, and in vitro experiments reveal efficient and selective phosphorylation of this residue. The CaM kinase-Gr is only expressed in certain lymphoid cell lines, and the present study shows that ionomycin-induced phosphorylation of Op18 Ser16 is restricted to cells expressing this protein kinase. Finally, CaM kinase-Gr-dependent in vitro phosphorylation of a crude cellular extract reveals a striking preference of this protein kinase for Op18 compared to other cellular substrates. In conclusion, the results suggest that Ser16 of Op18 is a major cytosolic target for activated CaM kinase-Gr.


Quality Assessment of Modern Total Ankle Arthroplasty Clinical Outcomes Research.
Research demonstrating improved outcomes with third-generation ankle replacement implants has resulted in increasing utilization of total ankle arthroplasty over the past 3 decades. The purpose of this study was to examine the quality and trends of clinical outcomes research being published on third-generation total ankle arthroplasty implants. Two fellowship-trained foot and ankle surgeons reviewed all peer-reviewed, Medline-indexed English-language clinical outcomes studies evaluating total ankle arthroplasty published between 2006 and 2019. Articles were assessed for study design and indicators of study quality. A total of 694 published articles were reviewed and 231 met all inclusion criteria. The majority (78%) of studies were retrospective, most of which were case series (54%) or cohorts (32%). Ten percent (10%) of studies were funded by industry and 28% did not disclose funding sources. Thirty-eight percent (38%) of studies reported a conflict of interest and 6% did not disclose whether or not there were conflicts. The average patient follow-up time across studies was 72 months. We found that although the study of outcomes with third-generation total ankle arthroplasty prostheses is steadily increasing, most studies are Level IV, retrospective case series. Some studies have disclosed industry funding and/or a conflict of interest, and a considerable number did not disclose potential funding and/or financial conflicts. Future investigators should strive to design studies with the highest quality methodology possible.


Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome.
Chronic Fatigue Syndrome (CFS) is a prevalent debilitating condition that affects approximately 250,000 people in the UK. There is growing interest in the role of mitochondrial function and mitochondrial DNA (mtDNA) variation in CFS. It is now known that fatigue is common and often severe in patients with mitochondrial disease irrespective of their age, gender or mtDNA genotype. More recently, it has been suggested that some CFS patients harbour clinically proven mtDNA mutations. MtDNA sequencing of 93 CFS patients from the United Kingdom (UK) and South Africa (RSA) was performed using an Ion Torrent Personal Genome Machine. The sequence data was examined for any evidence of clinically proven mutations, currently; more than 200 clinically proven mtDNA mutations point mutations have been identified. We report the complete mtDNA sequence of 93 CFS patients from the UK and RSA, without finding evidence of clinically proven mtDNA mutations. This finding demonstrates that clinically proven mtDNA mutations are not a common element in the aetiology of disease in CFS patients. That is patients having a clinically proven mtDNA mutation and subsequently being misdiagnosed with CFS are likely to be rare. The work supports the assertion that CFS should not be considered to fall within the spectrum of mtDNA disease. However, the current study cannot exclude a role for nuclear genes with a mitochondrial function, nor a role of mtDNA population variants in susceptibility to disease. This study highlights the need for more to be done to understand the pathophysiology of CFS.


Endothelin antiserum decreases volume-stimulated and basal plasma concentration of atrial natriuretic peptide.
Endothelin-1 (ET-1) is the most powerful factor known to release atrial natriuretic peptide (ANP) in vivo and in cultured cardiac myocytes or preparations of atrium. We tested the role of endogenous ET-1 in the regulation of ANP release by passive immunization in anesthetized rats. Intravenous injection of antiserum against ET-1 was shown to decrease basal and volume-stimulated plasma concentrations of ANP, whereas control serum was without effect. Antiserum generated in rabbits cross-reacted 100% with endothelin-2 and -3. In pentobarbital-anesthetized Wistar rats treated with ET-1 antiserum, plasma ANP concentration measured by radioimmunoassay was reduced by 37% from starting level after 10 minutes and by 30% after 60 minutes. Control rat serum had no effect on plasma ANP. Rapid intravenous infusion of 8 mL of 0.9% NaCl caused a sixfold increase of plasma ANP concentration in control rats but only twofold in rats pretreated with ET-1 antiserum (P < .01). This effect of ET-1 antiserum was dose dependent. ET-1 antiserum changed neither blood pressure nor heart rate significantly in anesthetized rats. Pretreatment with ET-1 antiserum did not affect the initial hypotensive response to intravenous ET-1 0.5 nmol/kg but significantly attenuated the subsequent hypertensive response to endothelin. Endothelin may be a physiological modulator of both basal and stimulated ANP release.


Supramolecular Tropism Driven Aggregation of Nanoparticles In Situ for Tumor-Specific Bioimaging and Photothermal Therapy.
Inorganic nanomedicine has attracted increasing attentions in biomedical sciences due to their excellent biocompatibility and tunable, versatile functionality. However, the relatively poor accumulation and retention of these nanomedicines in targeted tissues have often hindered their clinical translation. Herein, highly efficient, targeted delivery, and in situ aggregation of ferrocene (Fc)-capped Au nanoparticles (NPs) are reported to cucurbit[7]uril (CB[7])-capped Fe3 O4 NPs (as an artificial target) that are magnetically deposited into the tumor, driven by strong, multipoint CB[7]-Fc host-guest interactions (here defined as "supramolecular tropism" for the first time), leading to high tumor accumulation and retention of these NPs. The in vitro and in vivo studies demonstrate the precisely controlled, specific accumulation, and retention of Au NPs in the tumor cells and tissue via supramolecular tropism and in situ aggregation, which afford locally enhanced CT imaging of cancer and enable tumor-specific photothermal therapy attributed to the plasmonic coupling effects between adjacent Au NPs within the supramolecular aggregations. This work provides a novel concept of supramolecular tropism, which may drive targeted delivery and enable specific accumulation, retention, and activation of nanomedicine for improved bioimaging and therapy of cancer.


Anomalous exciton condensation in graphene bilayers.
In ordinary semiconductor bilayers, exciton condensates appear at total Landau-level filling factor nu{T}=1. We predict that similar states will occur in Bernal stacked graphene bilayers at many nonzero integer filling factors. For nu{T}=-3, 1 we find that the superfluid density of the exciton condensate vanishes and that a finite-temperature fluctuation-induced first order isotropic-smectic phase transition occurs when the layer densities are not balanced. These anomalous properties of bilayer graphene exciton condensates are due to the degeneracy of Landau levels with n=0 and n=1 orbital character.


Evaluation of Two 3D Printers for Guided Implant Surgery.
To compare the suitability of a fused filament fabrication (FFF) consumer 3D printer with a professional digital light processing (DLP) printer for the production of surgical templates for guided oral implant surgery. Eight virtual templates were printed with two different 3D printers. These were optically scanned and the incongruences between virtual and printed templates were determined after alignment of the surface scans and the virtual data. Minimum, maximum, and mean incongruences were determined, and a t test between both groups was performed to determine statistically significant differences in accuracy. Templates printed with the professional DLP printer showed statistically significantly less incongruence (P = .001) than those fabricated by the consumer FFF 3D printer. The accuracy of manufactured templates is strongly dependent on the printing device and method. At this time, the tested consumer 3D FFF printer is not suitable for the fabrication of templates for implant guided surgery. Minimum requirements regarding printers' features and 3D-printed templates need to be assessed in future studies.


Relationship between HLA antigens and infectious agents in contributing towards the development of Graves' disease.
Graves' disease (GD) is an autoimmune thyroid disorder which is associated with the human leucocyte antigens HLA-DR3 and DQA1* O501 in Caucasians. We have explored the possibility that some patients with certain HLA specificities develop anti-HLA antibodies which are correlated with environmental factors that may contribute to the development of GD. We studied 40 GD patients and 157 healthy individuals (controls). Serology was used to type HLA-A, -B, -Cw, and -DR antigens. The frequencies of these antigens in relation to lymphocytotoxic anti-HLA-A-B-Cw-DR antibodies and two environmental factors (Yersinia enterocolitica and Coxsackie B virus) were determined. The frequencies of HLA-B15, -B21 and DR3 antigens were increased, whereas HLA-DR5 antigen was decreased in GD patients. A significant association between HLA-DR3 antigen and lymphocytotoxic antibodies was observed, i.e., IgGs from GD patients were cytotoxic to HLA-DR3+ normal B cells. Following absorption with Yersinia enterocolitica or Coxsackie-B-virus, only Coxsackie-B virus completely inhibited the lymphocytotoxic reactions against HLA-DR3+ B cells. Besides confirming the association of HLA-DR3 with GD, this study also suggests the role of Coxsackie-reactive HLA-DR3 antibodies as contributing factors to the pathogenesis of the disease.


Contrast-enhanced magnetic resonance angiography with biodegradable (Gd-DTPA)-cystamine copolymers: comparison with MS-325 in a swine model.
The purpose of this study is to evaluate the use of (Gd-DTPA)-cystamine copolymers (GDCC), a novel biodegradable intravascular polydisulfide-based macromolecular gadolinium(III) contrast agent, for first-pass and steady-state contrast-enhanced magnetic resonance angiography (MRA) in a swine model. A breath-hold background-suppressed 3D MRA of the thorax was performed for first-pass imaging and repeated every 10 min after GDCC injection to monitor the tissue enhancement time course. A navigator-gated 3D MRA of the coronary arteries was performed during steady state following the first-pass imaging. Imaging with intravascular agent MS-325 approximately 1 h after GDCC injection was also included for comparison. Experimental results indicated that GDCC provided significant blood signal-to-noise ratio (SNR) improvement, approximately 1633% for first-pass and 33% for steady-state contrast-enhanced MRA. Compared to MS-325, GDCC provided similar blood enhancement for first-pass and steady-state imaging but with a different tissue enhancement time course. The blood SNR enhancement half-time was 10 +/- 6 min for GDCC and 46 +/- 33 min for MS-325. GDCC provided less enhancement in the liver, bone growth plates, and muscle than MS-325.


Anabolic Adaptations Occur in Conscripts During Basic Military Training Despite High Prevalence of Vitamin D Deficiency and Decrease in Iron Status.
In Estonian Defense Forces that are drawn up on the basis of the conscription model considerable numbers of young men are prematurely discharged from military service for medical reasons, but causes leading to premature dropout of conscripts have not been systematically studied. However, one of the factors involved could be relatively demanding physical training that starts at the beginning of military service in the form of basic military training (BMT). Cumulative training and nontraining stresses experienced by conscripts during BMT may exceed their physiological adaptability and increase the probability of becoming prematurely discharged. Therefore, the primary purpose of this study was to assess physiological responses to 10-week BMT in Estonian conscripts. The protocol of the study confirmed to the standards set by the Declaration of Helsinki and it was approved by the Research Ethics Committee of the University of Tartu. Mean ± SD age and body mass index of 94 conscripts studied was 20.9 ± 1.7 years and 24.2 ± 3.0 kg · m-2, respectively. Fasting venous blood analysis was performed four times during BMT (October to December) and once 15 weeks after the end of BMT (in March). One-factor (time) repeated measures analysis of variance was used to evaluate the differences within the variables. Statistical significance was set at p < 0.05. Where a significant main effect was observed, Tukey's honesty significant difference post-hoc analysis was used to locate differences between the means. A Pearson product moment coefficient of correlation (r) with α level set at 0.05 was applied to determine the relationship between variables. Significant increases in serum testosterone concentration (60.6%), testosterone to cortisol ratio (61.1%), blood erythrocyte count (4.3%), hemoglobin concentration (3.8%) and hematocrit (2.2%), and decrease in serum ferritin concentration (39.3%) occurred between weeks 1 and 10 during BMT (in all cases p < 0.0001). Fifteen weeks later, these parameters were still at increased or decreased levels, respectively, compared to week 1. The prevalence of vitamin D deficiency (serum 25(OH) D concentration <50 nmol · L-1) increased from 42.6% in week 1 to 80.8% in week 10 and to 91.5% 15 weeks later. Serum 25(OH)D levels did not correlate with testosterone concentrations (r = 0.062, p = 0.552 in Wk-1 and r = -0.079, p = 0.448 in Wk-25). These findings suggest that BMT induces anabolic physiological adaptations in conscripts despite vitamin D deficiency and decrease in iron status. However, high prevalence of vitamin D deficiency and decline in iron status may limit physiological adaptations and improvement in physical work capacity to a suboptimal level. Furthermore, as vitamin D influences a variety of functions important for health, deficiency in conscripts should be considered a major concern that needs treatment. An acknowledged limitation of the study is the lack of a control group of conscripts possessing normal vitamin D status and stable serum ferritin levels throughout the study period. Nevertheless, the research design employed enabled to determine two factors that potentially limit physiological adaptability of conscripts to military training loads in ecologically authentic environment.


Comparison of maxillary anterior tooth width and facial dimensions of 3 ethnicities.
As the cosmetic demands of patients increase, determining the appropriate dimensions of the maxillary anterior teeth has become increasingly relevant. The relationship between facial measurements and tooth size provide guidance for maxillary anterior tooth size selection. However, most publications on this topic have focused on the white population, and more data for tooth sizes and their proportions in other ethnicities are needed. The purpose of this observational study was to investigate the relationship between the mesiodistal dimensions of the 6 maxillary anterior teeth and the bizygomatic width, interpupillary distance, intercanthal distance, interalar width, and intercommissural width of individuals of Asian, African-American, and white ethnicities. Standardized digital images of 360 participants (120 Asian, 120 African-American, and 120 white) were used to measure facial segments. Individual dimensions of the 6 maxillary anterior teeth were measured using stone casts with digital sliding caliper. The combined width of the 6 maxillary anterior teeth on a straight line corresponded to the sum of the anterior tooth width. The means and standard deviations from descriptive measurements were calculated and analyzed for face and maxillary anterior tooth ratios and correlations. Statistical analysis was done using the Kruskal-Wallis procedure to compare facial and tooth parameters among the 3 ethnicities. Appropriate post hoc comparisons that adjusted for multiple testing were conducted when warranted (α=.05). The Spearman rho correlation, a nonparametric correlate of the Pearson correlation, was used to associate the facial and tooth parameters within the strata of sex and ethnicity. No consistent ratios were found among the examined facial dimensions and the mesiodistal dimensions of the 6 maxillary anterior teeth among the 3 ethnicities, except for the central incisor width-to-bizygomatic width ratio. No correlations were found between the facial dimensions and mesiodistal dimensions of the 6 maxillary anterior teeth among the 3 ethnicities except in Asian women. For Asian women, the intercommissural width correlated with the width of the central incisor (P=.001), the width of 2 central incisors (P=.001), the width of 4 incisors (P=.003), and the width of 6 maxillary anterior teeth (P=.005). No facial proportions by which the exact width of maxillary anterior teeth could be predicted were found in Asian, African-American, or white populations.


Structural insights into the architecture of the Shigella flexneri virulence factor IcsA/VirG and motifs involved in polar distribution and secretion.
IcsA/VirG is a key virulence factor of the human pathogen Shigella flexneri, acting as both an adhesin and actin-polymerizing factor during infection. We identified a soluble expression construct of the IcsA/VirG α-domain using the ESPRIT library screening system and determined its structure to 1.9Å resolution. In addition to the previously characterized autochaperone domain, our structure reveals a new domain, which shares a common fold with the autochaperone domains of various autotransporters. We further provide insight into the previously structurally uncharacterized β-helix domain that harbors the polar targeting motif and passenger-associated transport repeat. This structure is the first of any member of the recently identified passenger-associated transport repeat-containing autotransporters. Thus, it provides new insights into the overall architecture of this class of autotransporters, the function of the identified additional autochaperone domain and the structural properties of motifs involved in polar targeting and secretion of the Shigella flexneri virulence factor IcsA/VirG.