Paediatric-onset hereditary spastic paraplegias: a retrospective cohort study.
To describe the clinical and neurogenetic spectrum of paediatric-onset hereditary spastic paraplegias (HSPs) diagnosed in our unit. We report on 47 patients (30 males, 17 females; mean [SD] age 12y 7mo [6y 2mo], range 4-34y) clinically diagnosed with an HSP at the Child Neurology Unit, IRCCS-ASMN (Reggio Emilia, Italy) between 1990 and 2018, who were genetically investigated by means of single-gene direct sequencing and/or next-generation sequencing technologies (targeted panels, whole-exome sequencing [WES]). Complex forms prevailed slightly (n=26), autosomal dominant being the main inheritance pattern (n=11), followed by recessive (n=5) and X-linked (n=1). A definite genetic diagnosis was achieved in 17 patients. Spastic paraplegia 3A (n=4) was the most frequent cause of autosomal dominant HSP in our cohort, while no genetic variant prevailed in autosomal recessive forms and pathogenic/likely pathogenic variants were disclosed in a wide range of different genes. We found wide phenotypic and genetic heterogeneity. With increasing accessibility to WES, a higher number of patients receive a diagnosis, allowing detection of variants in ultra-rare disease-causing genes and refining genotype-phenotype correlations. A genetic diagnosis of paediatric-onset hereditary spastic paraplegia was achieved in one-third of patients. Pathogenic/likely pathogenic variants in rare genes were found. Genotypic and phenotypic heterogeneity favours targeted panel/whole-exome sequencing for diagnosis.


SNX-25a, a novel Hsp90 inhibitor, inhibited human cancer growth more potently than 17-AAG.
17-Allylamino-17-demethoxygeldanamycin (17-AAG), a typical Hsp90 inhibitor derived from geldanamycin (GA), has entered Phase III clinical trials for cancer therapy. However, it has several significant limitations such as poor solubility, limited bioavailability and unacceptable hepatotoxicity. In this study, the anticancer activity and mechanism of SNX-25a, a novel Hsp90 inhibitor, was investigated comparing with that of 17-AAG. We showed that SNX-25a triggered growth inhibition more sensitively than 17-AAG against many human cancer cells, including K562, SW-620, A375, Hep-2, MCF-7, HepG2, HeLa, and A549 cell lines, especially at low concentrations (<1 μM). It showed low cytotoxicity in L-02, HDF and MRC5 normal human cells. Compared with 17-AAG, SNX-25a was more potent in arresting the cell cycle at G2 phase, and displayed more potent effects on human cancer cell apoptosis and Hsp90 client proteins. It also exhibited a stronger binding affinity to Hsp90 than 17-AAG using molecular docking. Considering the superiority effects on Hsp90 affinity, cell growth, cell cycle, apoptosis, and Hsp90 client proteins, SNX-25a is supposed as a potential anticancer agent that needs to be explored in detail.


Fertility counseling of young breast cancer patients.
Approximately 6% of women with breast cancer are diagnosed before the age of 40. Young age is an independent predictor of adverse outcome and most young breast cancer patients receive systemic treatment with chemotherapy, hormonal therapy or both. The loss or impairment of fertility is a potential side effect of antineoplastic treatments. Due to the rising trend to delaying pregnancy in life, an increasing proportion of young cancer patients who are yet to have a pregnancy will face the problem of iatrogenic menopause in the future. The incidence of anticancer-treatment-related ovarian failure depends on the type of chemotherapy regimen administered, the use of tamoxifen and the age of patients. It rises with increasing age, in the range of 22-61% and 61-97% in women aged <40 years and >40 years respectively. Although there is a clear trend to increasing incidence of ovarian failure with the rise in aging, there may be a small proportion of patients who became amenorrhoeic despite the very young age, thus indicating that also individual factors still unknown may affect the probability of treatment-related ovarian failure. A prompt referral of patients to reproductive counseling and a multidisciplinary team including Oncology and Reproductive Units are essential to face the management of fertility issues in cancer patients. Fertility counseling should include a detailed description of all the available techniques to preserve fertility. The main available fertility preservation techniques, standard and experimental, for young breast cancer patients include: temporary ovarian suppression during chemotherapy with gonadotropin-releasing hormone analogues, embryo cryopreservation, cryopreservation of oocytes and cryopreservation of ovarian tissue. Research efforts are still necessary to improve the efficacy and safety of the available fertility preservation strategies as well as an efficient collaboration between oncologists and gynecologists is necessary to improve patients' access to the strategies themselves.


MMP2-9 cleavage of dystroglycan alters the size and molecular composition of Schwann cell domains.
Myelinating glial cells exhibit a spectacular cytoarchitecture, because they polarize on multiple axes and domains. How this occurs is essentially unknown. The dystroglycan-dystrophin complex is required for the function of myelin-forming Schwann cells. Similar to other tissues, the dystroglycan complex in Schwann cells localizes with different dystrophin family members in specific domains, thus promoting polarization. We show here that cleavage of dystroglycan by matrix metalloproteinases 2 and 9, an event that is considered pathological in most tissues, is finely and dynamically regulated in normal nerves and modulates dystroglycan complex composition and the size of Schwann cell compartments. In contrast, in nerves of Dy(2j/2j) mice, a model of laminin 211 deficiency, metalloproteinases 2 and 9 are increased, causing excessive dystroglycan cleavage and abnormal compartments. Pharmacological inhibition of cleavage rescues the cytoplasmic defects of Dy(2j/2j) Schwann cells. Thus, regulated cleavage may be a general mechanism to regulate protein complex composition in physiological conditions, whereas unregulated processing is pathogenic and a target for treatment in disease.


[Changes in the myeloperoxidase and acid phosphatase activities in human peripheral blood neutrophils with the cells stimulated in vitro].
In four series of experiments human peripheral blood neutrophils were found capable of synthetizing the active forms of such enzymes as myeloperoxidase and acid phosphatase after stimulation with opsonized zymosan, and the optimum conditions for testing the synthetizing activity of neutrophils were established. The examination of 39 practically healthy donors revealed an approximate equilibrium between the synthesis of the active forms of the enzyme and its excretion from the cell after this cell was activated. Considerable changes in the enzymatic activity of peripheral blood neutrophils were found in patients with yersiniosis, chronic herpes, chronic bronchitis and AIDS-associated complex. The possibility of a deficient enzymatic activity in some patients was suggested.


Tungsten-based polyoxometalate nanoclusters with remarkable reactive oxygen species-scavenging activity efficiently quenched luminol-based electrochemiluminescence for sensitive detection of Her-2.
This study aimed to develop a quenching-type electrochemiluminescence (ECL) immunosensor for human epidermal growth factor receptor (Her-2) detection. Firstly, Pd/NiFeOx nanoflowers decorated by in situ formation of gold nanoparticles (Au NPs) and 2D Ti3C2 MXene nanosheets were synthesized (AuPd/NiFeOx/Ti3C2) as carriers to load luminol and primary antibodies. Impressively, AuPd/NiFeOx/Ti3C2 with excellent peroxidase-like activity could accelerate the decomposition of the coreactant H2O2 generating more reactive oxygen species (ROSs) under the working potential from 0 to 0.8 V, resulting in highly efficient ECL emission at 435-nm wavelengths. The introduction of tungsten-based polyoxometalate nanoclusters (W-POM NCs) which exhibit remarkable ROSs-scavenging activity as secondary antibody labels could improve the sensitivity of immunosensors. The ZnO nanoflowers were employed to encapsulate minute-sized W-POM NCs, and polydopamine was self-polymerized on the surface of Zn(W-POM)O to anchor secondary antibodies. The mechanism of the quenching strategy was explored and it was found that W-POM NCs could consume ROSs by the redox reaction of W5+ resulting in W6+. The proposed ECL immunosensor displayed a wide linear response range of 0.1 pg·mL-1 to 50 ng·mL-1, and a low detection limit of 0.036 pg mL-1 (S/N = 3). The recoveries ranged from 93.9 to 99.4%, and the relative standard deviation (RSD) was lower than 10%. This finding is promising for the design of detecting new protein biomarkers.


Poly(N-isopropylacrylamide)-based dual-crosslinking biohybrid injectable hydrogels for vascularization.
Injectable hydrogels provide a powerful and non-invasive approach for numerous applications in cell transplantation, growth factor delivery, tissue regeneration and so forth. The properties of injectable hydrogels should be well-tuned for specific applications, where their overall design should ensure biocompatibility, non-toxicity, robust mechanical properties, and most importantly the ability to promote vascularization and integration with the host tissue/organ. Among these criteria, vascularization remains a key design element in the development of functional therapeutic hydrogels for successful translation into clinical settings. To that end, there is still a critical need for the development of the next generation of injectable hydrogels with precisely tuned biophysical and biochemical properties which could simultaneously promote tissue vascularization. In this work, we developed a temperature responsive, dual-crosslinking, biohybrid hydrogels, modified with a vasculogenic peptide for applications in regenerative medicine, specifically tissue vascularization. The synthesized hydrogels consisted of poly(N-isopropylacrylamide)-based copolymer, functionalized gelation and angiogenic VEGF-mimetic QK peptide with enhanced shear-thinning and injectability properties. QK peptide is a VEGF-mimetic vasculogenic peptide which binds to VEGF receptors and activates intercellular pathway for vascularization. Apart from the presence of QK peptide, the mechanical properties of the hydrogels were precisely tuned by altering the polymer concentration, enabling successful assembly and endothelial cell network formation. Extended in vitro studies demonstrated successful encapsulation and homogeneous distribution of endothelial cells within the three-dimensional (3D) environment of the hydrogel matrix with significantly enhanced vascularization in presence of the QK peptide as early as 3 days of culture. A small, preliminary in vivo study in mice showed a trend of increased blood vessel formation in hydrogels that incorporated the QK peptide. Overall, our study presents the design and characterization of injectable, dual-crosslinking and vasculogenic hydrogels with controlled properties which could be utilized for numerous applications in regenerative medicine, minimally invasive cell and drug delivery as well as fundamental studies on tissue vascularization and angiogenesis. STATEMENT OF SIGNIFICANCE: In this work, we synthesized a new class of temperature responsive, dual-crosslinking, biohybrid injectable hydrogels with enhanced vascularization properties for broad applications in regenerative medicine and minimally invasive cell/drug delivery. The developed hydrogels properly accommodated 3D culture, assembly and network formation of endothelial cells, as evidenced by in vitro and in vivo studies.


Outcomes of four patients with homocysteine remethylation disorders detected by newborn screening.
We evaluated the clinical outcome in homocysteine remethylation disorders following newborn screening (NBS) and initiation of early specific treatment. Five patients with remethylation disorders were included in this study. Two asymptomatic patients (one with cblG and one with cblE) were identified by NBS using an approach that combines a postanalytical interpretive tool (available on the Region 4 Stork (R4S) collaborative project website, http://www.clir-r4s.org) and a second-tier test for total homocysteine determination. Both the initial screening and the second-tier test are performed on the same blood spot, with no additional patient contact, resulting in no false-positive outcomes. Two additional patients with methylenetetrahydrofolate reductase deficiency were detected by NBS using low methionine as a marker. Although already symptomatic despite the early diagnosis, the latter two patients greatly improved with treatment and their outcomes are compared with that of another patient with methylenetetrahydrofolate reductase deficiency and significant morbidity who was diagnosed clinically at 3 months of age. Early detection by NBS and timely and specific treatment considerably improve at least short-term outcomes of homocysteine remethylation disorders. When a remethylation disorder is suspected, group-specific treatment could be started prior to the completion of in vitro confirmatory testing because all disorders from this group require similar intervention.


Almond By-Products: Valorization for Sustainability and Competitiveness of the Industry.
The search for waste minimization and the valorization of by-products are key practices for good management and improved sustainability in the food industry. The production of almonds generates a large amount of waste, most of which is not used. Until now, almonds have been used for their high nutritional value as food, especially almond meat. The other remaining parts (skin, shell, hulls, etc.) are still little explored, even though they have been used as fuel by burning or as livestock feed. However, interest in these by-products has been increasing as they possess beneficial properties (caused mainly by polyphenols and unsaturated fatty acids) and can be used as new ingredients for the food, cosmetic, and pharmaceutical industries. Therefore, it is important to explore almond's valorization of by-products for the development of new added-value products that would contribute to the reduction of environmental impact and an improvement in the sustainability and competitiveness of the almond industry.


A novel soy-based meal replacement formula for weight loss among obese individuals: a randomized controlled clinical trial.
To assess the efficacy and safety of a low calorie soy-based meal replacement program for the treatment of obesity. A 12-week prospective randomized controlled clinical trial. Outpatient weight control research unit. One hundred obese (28<BMI<or=41 kg/m(2)) volunteers between the ages of 35 and 65 y. Seventy-four participants completed the trial. Participants were randomized to either the meal replacement treatment group (n=50; 240 g/day, 1200 kcal/day) or control group (n=50). Both groups at baseline received a single dietary counseling session and a pamphlet describing weight loss practices. Weight, body fat, serum lipid concentrations. : By intent-to-treat analysis, the treatment group lost significantly more weight than the control group (7.00 vs 2.90 kg; P<0.001) and had a greater change in total (22.5 vs 6.8 mg/dl; P=0.013) and LDL cholesterol (21.2 vs 7.1 mg/dl; P<0.009). Among completers only, the treatment group again lost more weight (7.1 kg; n=37 vs 2.9 kg; n=37; P=0.0001) and had a greater reduction in total cholesterol (26.1 mg/dl; n=37 vs 6.7 mg/dl; P=0.0012) and a greater change in LDL cholesterol (21.6 vs 5.5 mg/dl; P=0.0025). (For any given degree of weight loss, the reduction in LDL cholesterol was significantly greater in the treatment group.) Treatment was well tolerated and no serious side effects were detected. Use of this soy-based meal replacement formula was effective in lowering body weight, fat mass and in reducing LDL cholesterol beyond what could be expected given the weight lost.


The Design of Stretch: A Compact, Lightweight Mobile Manipulator for Indoor Human Environments.
Mobile manipulators for indoor human environments can serve as versatile devices that perform a variety of tasks, yet adoption of this technology has been limited. Reducing size, weight, and cost could facilitate adoption, but risks restricting capabilities. We present a novel design that reduces size, weight, and cost, while supporting a variety of tasks. The core design consists of a two-wheeled differential-drive mobile base, a lift, and a telescoping arm configured to achieve Cartesian motion at the end of the arm. Design extensions include a 1 degree-of-freedom (DOF) wrist to stow a tool, a 2-DOF dexterous wrist to pitch and roll a tool, and a compliant gripper. We justify our design with anthropometry and mathematical models of static stability. We also provide empirical support from teleoperating and autonomously controlling a commercial robot based on our design (the Stretch RE1 from Hello Robot Inc.) to perform tasks in real homes.


A computational model of altered gait patterns in parkinson's disease patients negotiating narrow doorways.
We present a computational model of altered gait velocity patterns in Parkinson's Disease (PD) patients. PD gait is characterized by short shuffling steps, reduced walking speed, increased double support time and sometimes increased cadence. The most debilitating symptom of PD gait is the context dependent cessation in gait known as freezing of gait (FOG). Cowie et al. (2010) and Almeida and Lebold (2010) investigated FOG as the changes in velocity profiles of PD gait, as patients walked through a doorway with variable width. The former reported a sharp dip in velocity, a short distance from the doorway that was greater for narrower doorways. They compared the gait performance in PD freezers at ON and OFF dopaminergic medication. In keeping with this finding, the latter also reported the same for ON medicated PD freezers and non-freezers. In the current study, we sought to simulate these gait changes using a computational model of Basal Ganglia based on Reinforcement Learning, coupled with a spinal rhythm mimicking central pattern generator (CPG) model. In the model, a simulated agent was trained to learn a value profile over a corridor leading to the doorway by repeatedly attempting to pass through the doorway. Temporal difference error in value, associated with dopamine signal, was appropriately constrained in order to reflect the dopamine-deficient conditions of PD. Simulated gait under PD conditions exhibited a sharp dip in velocity close to the doorway, with PD OFF freezers showing the largest decrease in velocity compared to PD ON freezers and controls. PD ON and PD OFF freezers both showed sensitivity to the doorway width, with narrow door producing the least velocity/ stride length. Step length variations were also captured with PD freezers producing smaller steps and larger step-variability than PD non-freezers and controls. In addition this model is the first to explain the non-dopamine dependence for FOG giving rise to several other possibilities for its etiology.


Construction of a PLGA based, targeted siRNA delivery system for treatment of osteoporosis.
Osteoporosis, a systemic skeletal disorder, occurs when bone turnover balance is disrupted. With the identification of the genes involved in the pathogenesis of the disease, studies on development of new treatments has intensified. Short interfering RNA (siRNA) is used to knockdown disease related gene expressions. Targeting siRNA in vivo is challenging. The maintenance of therapeutic plasma level is hampered by clearance of siRNA from the body. Targeted systems are useful in increasing the drug concentration at the target site and decreasing side effects. Aim of the present study was to develop an injectable siRNA delivery system to protect siRNA during systemic distribution and target the siRNA to bone tissue using a thermoresponsive, genetically engineered, elastin-like recombinamer (ELR), designed to interact with the mineral component of bone. The delivery system consisted of DNAoligo as a siRNA substitute complexed with the cationic polymer, polyethyleneimine (PEI), at N/P ratio of 20. The complex was encapsulated in poly(lactic acid-co-glycolic acid) (PLGA) nanocapsules. PLGA capsules were characterized by SEM, TEM and XPS. FTIR was used to show the preferential attachment of ELR to HAp. Encapsulation efficiency of the complex in PLGA nanocapsules was 48%. The release kinetics of the complex fits the Higuchi release kinetics.


On-Ice Return-to-Hockey Progression After Anterior Cruciate Ligament Reconstruction.
Synopsis The literature pertaining to the rehabilitation of ice hockey players seeking to return to sport after anterior cruciate ligament reconstruction (ACLR) is currently limited. The purpose of this clinical commentary was to present a criterion-based progression for return to ice hockey for athletes after ACLR. First, we review pertinent literature and provide previously published guidelines on general rehabilitation after ACLR. Then, we present a 4-phase, on-ice skating progression with objective criteria to initiate each phase. During the early on-ice phase, the athlete is reintroduced to specific demands, including graded exposure to forward, backward, and crossover skating. In the intermediate on-ice phase, the emphasis shifts to developing power and introducing anticipated changes of direction within a controlled environment. During the late on-ice phase, the focus progresses to developing anaerobic endurance and introducing unanticipated changes of direction, but still without other players or contact. Finally, once objective return-to-sport criteria are met, noncontact team drills, outnumbered and even-numbered drills, practices, scrimmages, and games are progressively reintroduced during the return-to-sport phase. Recommendations for off-ice strength and conditioning exercises complement the on-ice progression. Additionally, we apply the return-to-hockey progression framework to a case report of a female collegiate defensive ice hockey player who returned to sport successfully after ACLR. This criterion-based return-to-hockey progression may guide rehabilitation specialists managing athletes returning to ice hockey after ACLR. J Orthop Sports Phys Ther 2017;47(5):324-333. Epub 29 Mar 2017. doi:10.2519/jospt.2017.7245.


Bringing back the fruit into fruit fly-bacteria interactions.
Female Mediterranean fruit flies (Ceratitis capitata) oviposit in fruits, within which the larvae develop. This development is associated with rapid deterioration of the fruit, and frequently with invasion by secondary pests. Most research on the associations between medflies and microorganisms has focused on the bacteria inhabiting the digestive system of the adult fly, while the role of the fruit in mediating, amplifying or regulating the fruit fly microflora has been largely neglected. In this study, we examine the hypothesis that the host fruit plays a role in perpetuating the fly-associated bacterial community. Using direct and cultured-based approaches, we show that this community is composed in its very large majority of diazotrophic and pectinolytic Enterobacteriaceae. Our data suggest that this fly-associated enterobacterial community is vertically transmitted from the female parent to its offspring. During oviposition, bacteria are transferred to the fruit, establish and proliferate within it, causing its decay. These results show that the host fruit is indeed a central partner in the fruit fly-bacterial interaction as these transmitted bacteria are amplified by the fruit, and subsequently maintained throughout the fly's life. This enterobacterial community may contribute to the fly's nitrogen and carbon metabolism, affecting its development and ultimately, fitness.


Molecular cloning of protein phosphatase inhibitor-1 and its expression in rat and rabbit tissues.
A cDNA encoding the complete amino acid sequence of rat protein phosphatase inhibitor-1 was obtained by screening a skeletal muscle library. The coding region represents a 171-residue polypeptide which demonstrated 80% overall identity with the primary sequence of rabbit inhibitor-1. Sequence homology between the rat and rabbit proteins was particularly striking (98% identity) in the NH2-terminal 61 amino acids, which encompass the threonine phosphorylated by cyclic AMP-dependent protein kinase. This domain possesses full inhibitor activity against type-1 protein phosphatases. In contrast, a domain of similar size at the COOH terminus showed only 57% conservation of primary structure between the two proteins. This reflects a remarkable difference in evolutionary pressures experienced by these domains and may emphasize a lesser role for the COOH-terminal region in inhibitor-1 function. Northern hybridization analysis of RNA from rat and rabbit tissues indicated the presence of two mRNAs, a major 0.7-kilobase and a minor 1.8-kilobase mRNA. The highest expression of inhibitor-1 mRNA was noted in skeletal muscle from both species. Analysis of mRNA levels illustrates potential post-transcriptional mechanisms controlling inhibitor-1 expression in some mammalian tissues.


Effect of exercise training on the density of endothelial cells in the white adipose tissue of rats.
We examined the effects of a 9-week exercise training (TR) in Wistar male rats, beginning at 4 weeks of age, on the density of endothelial cells (ECs) in epididymal white adipose tissue (WAT) and the mRNA expression of angiogenic factors in adipose tissue stromal vascular fraction (SVF) cells. The number of ECs and mRNA expressions were assessed by lectin staining and real-time reverse transcriptase-polymerase chain reaction, respectively. Compared with control (CR) rats, TR rats gained weight more slowly and had significantly lower final weight of WAT due to the reduction in the size and the number of adipocytes. TR significantly increased the number of ECs per square millimeter and per adipocyte (1.37- and 1.23-fold, respectively) in WAT. This is probably because the number of adipocytes is fewer while the number of ECs is constant in the WAT of TR rats, because the regression line of TR rats for adipocyte number-dependent EC number was shifted toward the left without significant differences in the slopes between groups. TR also induced the upregulation of mRNA expression of vascular endothelial growth factor (Vegf)-A and Vegf-receptor-2 in SVF cells, thereby retaining a constant number of ECs in the WAT.


Ubiquitinated deiodinase: not dead yet.
Originating in the thyroid, the prohormone thyroxine is converted to triiodothyronine, which is essential in brain development, growth, and metabolism. A study in this issue reveals a novel mechanism for controlling triiodothyronine production that provides the first example of enzyme activity being restored by deubiquitination.


Noble Gases in Sea Water.
Concentrations of noble gases in samples of sea water obtained at depths to 3437 meters from a Pacific Ocean station were measured by mass spectrometry. An excess of helium, in relation to concentrations of the other noble gases, is attributed to influx of atoms of this gas from the sediments where it is produced by the natural radioactive decay of members of the uranium and thorium series. On the basis of a steady-state model, the escape of helium from the earth is calculated at 6.4 x 10(13) atoms per square centimeter per year.


Highly malignant tumor variants retain tumor-specific antigens recognized by T helper cells.
We have studied the components of a complex of tumor-specific antigens to determine if all of the components of the complex were lost during progression from a rather benign regressor tumor to a highly malignant (HM) cancer. We find that the HM tumor cells have lost antigens recognized by CTL but retained antigens recognized by Th cells. Immunization with variants expressing Th-defined antigens induced tumor-specific immunity to challenge with a parental variant that expressed a CTL-recognized target antigen, but did not induce immunity to challenge with the variant that expressed the Th-defined antigen alone. Together, these findings suggested that Th cells fail to exert direct selective pressure upon the tumor, resulting in retention of "lineage-specific," Th-recognized antigens by highly immunoselected variants. Possible advantage could be taken of this fact for the development of specific immunotherapy.


Mathematical modelling of nitric oxide activity in wound healing can explain keloid and hypertrophic scarring.
Keloid and hypertrophic lesions are both types of scarring pathologies which arise as a consequence of excess collagen deposition during the wound healing process. The exact mechanism by which this occurs is not understood and currently no effective treatment exists. In this paper, we study the possible role of nitric oxide in excess scar formation. In recent years, the physiological role of this free radical in mammalian tissue has been extensively studied; in particular numerous groups have studied its role in wound healing. We describe a mathematical model which offers a possible explanation for keloid scarring in terms of the presence of higher than normal nitric oxide concentrations related to the fact that nitric oxide stimulates synthesis of collagen by fibroblasts. As a consequence of this, we put forward a suggestion for a treatment strategy involving the surgical excision of the keloid lesion combined with the application of a low-dose nitric oxide inhibitor. In addition, we show that a quasi-steady-state analysis of our model reveals a possible approach to distinguishing between hypertrophic and keloid lesions, a task which has to date proven to be clinically difficult. We also present an extended model which confirms these results in the context of a more complicated and biologically more realistic system. The fuller model demonstrates additional features of keloid and hypertrophic scarring which we were not able to consider in the basic model, and as a consequence further supports our hypothesis that nitric oxide activity could play a key role in keloid scarring.


Standardized nursing and therapeutic effect of oxycontin on oral mucosal pain in nasopharyngeal carcinoma patients.
This study aims to explore the standardized nursing and therapeutic effect of OxyContin on oral mucosal pain in nasopharyngeal carcinoma (NPC) patients with concurrent chemoradiotherapy. From March 2016 to December 2017, 60 patients with NPC were selected from the Sun Yat-Sen University Cancer Center. Patients consuming OxyContin for moderate and severe pain were divided into the experimental group and control group, respectively. All the patients were given OxyContin 10 mg orally, and the dose was adjusted according to the degree of pain relief until it was significantly relieved. At the same time, the combination of analgesic drugs with standardized nursing intervention for pain was granted, and the analgesic effect, adverse effects, and quality of life of both groups were analyzed. There was no significant difference between the total dose of radiotherapy and OxyContin. OxyContin could significantly improve the quality of life in patients with moderate pain (P < 0.05), while the effect was not significant in patients with severe pain. Patients with NPC having oral mucosal pain after radiotherapy and chemotherapy need intervention at the earliest. The application of OxyContin and cancer pain standardized nursing care can improve the analgesic efficacy, reduce drug adverse effects, and improve the patient's quality of life.


Assessing the binding properties of the anti-PD-1 antibody landscape using label-free biosensors.
Here we describe an industry-wide collaboration aimed at assessing the binding properties of a comprehensive panel of monoclonal antibodies (mAbs) against programmed cell death protein 1 (PD-1), an important checkpoint protein in cancer immunotherapy and validated therapeutic target, with well over thirty unique mAbs either in clinical development or market-approved in the United States, the European Union or China. The binding kinetics of the PD-1/mAb interactions were measured by surface plasmon resonance (SPR) using a Carterra LSA instrument and the results were compared to data collected on a Biacore 8K. The effect of chip type on the SPR-derived binding rate constants and affinities were explored and the results compared with solution affinities from Meso Scale Discovery (MSD) and Kinetic Exclusion Assay (KinExA) experiments. When using flat chip types, the LSA and 8K platforms yielded near-identical kinetic rate and affinity constants that matched solution phase values more closely than those produced on 3D-hydrogels. Of the anti-PD-1 mAbs tested, which included a portion of those known to be in clinical development or approved, the affinities spanned from single digit picomolar to nearly 425 nM, challenging the dynamic range of our methods. The LSA instrument was also used to perform epitope binning and ligand competition studies which revealed over ten unique competitive binding profiles within this group of mAbs.


Risk factors for mortality before age 18 years in cystic fibrosis.
Understanding early-life risk factors for childhood death in cystic fibrosis (CF) is important for clinical care, including the identification of effective interventions. Data from the Epidemiologic Study of Cystic Fibrosis (ESCF) collected 1994-2005 were linked with the Cystic Fibrosis Foundation Patient Registry (CFFPR) demographic and mortality data from 2013. Inclusion criteria were ≥1 visit annually at age 3-5 years and ≥1 FEV1 measurement at age 6-8 years. Demographic data, nutritional parameters, pulmonary signs and symptoms, microbiology, and FEV1 were evaluated as risk factors for death before age 18 years. Multivariable Cox proportional hazards regression was used to model the simultaneous effects of risk factors associated with death before age 18 years. Among 5365 patients enrolled in ESCF who met inclusion criteria, 3880 (72%) were linked to the CFFPR. Among these, 191 (5.7%) died before age 18 years; median age at death was 13.4 ± 3.1 years. Multivariable regression showed clubbing, crackles, female sex, unknown CFTR genotype, minority race or ethnicity, Medicaid insurance (a proxy of low socioeconomic status), Pseudomonas aeruginosa on 2 or more cultures, and weight-for-age <50th percentile were significant risk factors for death regardless of inclusion of FEV1 at age 6-8 years in the model. We identified multiple risk factors for childhood death of patients with CF, all of which remained important after incorporating FEV1 at age 6-8 years. Among the factors identified were the presence of clubbing or crackles at age 3-5 years, signs which are not routinely collected in registries.


Precision Nephrology Is a Non-Negligible State of Mind in Clinical Research: Remember the Past to Face the Future.
CKD is a major public health problem. It is characterized by a multitude of risk factors that, when aggregated, can strongly modify outcome. While major risk factors, namely, albuminuria and low estimated glomerular filtration rate (eGFR) have been well analyzed, a large variability in disease progression still remains. This happens because (1) the weight of each risk factor varies between populations (general population or CKD cohort), countries, and single individuals and (2) response to nephroprotective drugs is so heterogeneous that a non-negligible part of patients maintains a high cardiorenal risk despite optimal treatment. Precision nephrology aims at individualizing cardiorenal prognosis and therapy. The purpose of this review is to focus on the risk stratification in different areas, such as clinical practice, population research, and interventional trials, and to describe the strategies used in observational or experimental studies to afford individual-level evidence. The future of precision nephrology is also addressed. Observational studies can in fact provide more adequate findings by collecting more information on risk factors and building risk prediction models that can be applied to each individual in a reliable fashion. Similarly, new clinical trial designs can reduce the individual variability in response to treatment and improve individual outcomes.


Long-term follow-up of indolent lymphoma patients treated with high-dose sequential chemotherapy and autografting: evidence that durable molecular and clinical remission frequently can be attained only in follicular subtypes.
To evaluate the prognostic relevance of molecular monitoring of minimal residual disease in indolent lymphomas receiving high-dose sequential chemotherapy and autografting. A polymerase chain reaction- (PCR-)based strategy was used to evaluate the presence of residual tumor cells in a panel of 70 indolent lymphoma patients: 40 with follicular (FCL), 14 with small lymphocytic (SLL), and 16 with mantle-cell (MCL) lymphomas. They were treated either with first-line (n = 61) or second-line (n = 9) therapy with an intensified high-dose chemotherapy program followed by peripheral-blood progenitor cells autografting. The Bcl-1, Bcl-2, and immunoglobulin gene rearrangements were used as lymphoma-specific markers. Overall, a molecular marker was obtained from the diagnostic tissue in 60 of 70 patients (86%). Results The collection of PCR-negative cells and the achievement of posttransplantation molecular remission (MR) were common in patients with FCL subtype (54% and 70%, respectively), whereas they were not frequent among SLL and MCL (25% and 12.5%, respectively) patients. With a median molecular follow-up of 75 months, an 88% incidence of relapse was observed among patients never attaining MR. In contrast, relapse incidence was only 8% among patients attaining a durable MR (P <.005). At present, 26 patients (20 with FCL and six with non-FCL) are long-term survivors in absence of clinical and molecular disease. Our results indicate that among indolent lymphomas, FCL and non-FCL subtypes show a significantly different behavior in terms of MR achievement, and MR after intensive chemotherapy and autografting is predictive for a prolonged disease-free survival, whereas persistent PCR positivity is associated with a high risk of relapse.


Policy for material efficiency--sustainable taxation as a departure from the throwaway society.
The present economy is not sustainable with regard to its per capita material consumption. A dematerialization of the economy of industrialized countries can be achieved by a change in course, from an industrial economy built on throughput to a circular economy built on stock optimization, decoupling wealth and welfare from resource consumption while creating more work. The business models of a circular economy have been known since the mid-1970s and are now applied in a number of industrial sectors. This paper argues that a simple and convincing lever could accelerate the shift to a circular economy, and that this lever is the shift to a tax system based on the principles of sustainability: not taxing renewable resources including human labour--work--but taxing non-renewable resources instead is a powerful lever. Taxing materials and energies will promote low-carbon and low-resource solutions and a move towards a 'circular' regional economy as opposed to the 'linear' global economy requiring fuel-based transport for goods throughput. In addition to substantial improvements in material and energy efficiency, regional job creation and national greenhouse gas emission reductions, such a change will foster all activities based on 'caring', such as maintaining cultural heritage and natural wealth, health services, knowledge and know-how.


Generation of high-level stable transgene expressing human embryonic stem cell lines using Chinese hamster elongation factor-1 alpha promoter system.
The utilization of human embryonic stem cells (hESC) in regenerative medicine largely depends on the development of technologies that will allow efficient genetic manipulation of the cells in vitro. Although a few studies have described the transfection of hESC for generation of reporter lines stably expressing specific transgenes driven by different promoters, the optimal choice of promoter system for driving transgene in hESC has yet to be elucidated. We show for the first time that Chinese hamster elongation factor-1 alpha (CHEF1) promoter robustly drove reporter gene expression higher than the human elongation factor 1 alpha (hEF1 alpha), other constitutive Chinese hamster promoters, human cytomegalovirus (CMV) immediate early enhancer/promoter and SV40 promoters in hESC by quantitative analysis. We also successfully generated stably transfected hESC lines using this CHEF1 promoter system and demonstrated that they continued to express enhanced green fluorescent protein (EGFP) during prolonged undifferentiated proliferation, in differentiated embryoid bodies (EBs), and in teratomas without transgene silencing. By immunofluorescence staining and D ow cytometry analysis, the pluripotent markers, OCT-4, SSEA-4, and TRA-1-60, continued to be expressed in undifferentiated CHEF1-EGFP expressing hESC lines. When the stably transfected hESC were directed to differentiate into neural precursors in vitro, high-level EGFP expression was maintained and co-expression of neural markers, Nestin, and beta-tubulin III was observed. The morphology, karyotype, and telomerase activity of CHEF1-EGFP expressing hESC were normal after >50 continuous passages, and the cells retained the ability to differentiate into derivatives of the three germ layers in vitro as confirmed by RT-PCR analysis and immunocytochemical staining and in vivo teratoma formation. Therefore, stable CHEF1-EGFP hESC lines retained the capability for self-renewal and pluripotency. The novel CHEF1 promoter system described here enables high-level transgene expression in the stably transfected hESC. It may have signi, cant implication for uses in bioprocess development and future development of gene-modified hESC in tissue regeneration and transplantation applications.


Adherence to the Mediterranean diet in metabolically healthy and unhealthy overweight and obese European adolescents: the HELENA study.
To examine the adherence to the Mediterranean dietary pattern (MDP) in metabolically healthy overweight or obese (MHO) and metabolically unhealthy obese (MUO) European adolescents. In this cross-sectional study, 137 overweight/obese adolescents aged 12-17 years old from the HELENA study were included. Height, weight, waist circumference and skinfold thickness were measured and body mass index and body fat percent were calculated. Systolic and diastolic blood pressure, glucose, HDL cholesterol, triglycerides and cardiorespiratory fitness (20 m shuttle run test) were measured. MHO and MUO phenotypes were categorized following the Jolliffe and Janssen criteria. Two non-consecutive 24 h recalls were used for dietary intake assessment and the adherence to the MDP was calculated using the Mediterranean dietary pattern score (MDP score) (range 0-9). A total of 45 (22 girls) adolescents (32.8%) were categorized as MHO. The adherence to the MDP was significantly higher in MHO than in MUO adolescents regardless of age, sex, body fat percentage, energy intake and center (MDP score: 4.6 ± 1.6 vs. 3.9 ± 1.5, p = 0.036), but this difference became non-significant after further adjustment for cardiorespiratory fitness. Participants who had a low adherence to the MDP (MDP score ≤ 4) had a higher likelihood of having MUO phenotype regardless of sex, age, energy intake, center and body fat percentage (OR 2.2; 95% CI 1.01-4.81, p = 0.048). Adherence to the MDP might be beneficial to maintain metabolic health in overweight/obese adolescents, yet cardiorespiratory fitness seems to play a key role on the metabolic phenotype.


Cyclodextrin-based Schiff base pro-fragrances: Synthesis and release studies.
A simple method for the preparation of β-cyclodextrin derivatives containing covalently bonded aldehydes via an imine bond was developed and used to prepare a series of derivatives from 6I-amino-6I-deoxy-β-cyclodextrin and the following volatile aldehydes - cinnamaldehyde, cyclamen aldehyde, lilial, benzaldehyde, anisaldehyde, vanillin, hexanal, heptanal, citral, and 5-methylfurfural. Subsequently, the rate of release of the volatile compound from selected pro-fragrances, as a function of the environment (solvent, pH), was studied by 1H NMR spectroscopy (for benzaldehyde) and static headspace-gas chromatography (for benzaldehyde, heptanal, and 5-methylfurfural). The aldehyde release rate from the imine was shown to depend substantially on the pH from the solution and the air humidity from the solid state.


[Molecular and morphological characterisation of two closely related species belonging to the subgenus Phlebotomus chabaudi Croset, Abonnenc & Rioux, 1970 et P. riouxi Depaquit, Killick-Kendrick & Léger, 1998 (Diptera: Psychodidae)].
In 1998, the description of Phlebotomus riouxi emphasised the difficulty to differentiate the female from the closely related P. chabaudi, a suspected vector of Leishmania killicki in several foci in Tunisia. In order to be able to distinguish the females of these two species, we started a molecular study based on 37 Algerian and Tunisian specimens. The alignment of the sequences of the cytochrome b of the mitochondrial DNA and their analysis using Neighbor-Joining, maximum likelihood and maximum parsimony shows the individualisation of two species including an intraspecific variability. Following a morphological approach, it is not possible to distinguish the females on the basis of their spermathecae. A new character is proposed: the presence of anterolateral teeth of the pharyngeal armature for P. chabaudi, never observed in P. riouxi. However, a molecular typing is necessary at the present time for a sure identification of the females.


Comprehensive screening for antigens overexpressed on carcinomas via isolation of human mAbs that may be therapeutic.
Although several murine mAbs that have been humanized became useful therapeutic agents against a few malignancies, therapeutic Abs are not yet available for the majority of the human cancers because of our lack of knowledge of which antigens (Ags) can become useful targets. In the present study we established a procedure for comprehensive identification of such Ags through the extensive isolation of human mAbs that may become therapeutic. Using the phage-display Ab library we isolated a large number of human mAbs that bind to the surface of tumor cells. They were individually screened by immunostaining, and clones that preferentially and strongly stained the malignant cells were chosen. The Ags recognized by those clones were isolated by immunoprecipitation and identified by MS. We isolated 2,114 mAbs with unique sequences and identified 21 distinct Ags highly expressed on several carcinomas. Of those 2,114 mAbs 356 bound specifically to one of the 21 Ags. After preparing complete IgG(1) Abs the in vitro assay for Ab-dependent cell-mediated cytotoxicity (ADCC) and the in vivo assay in cancer-bearing athymic mice were performed to examine antitumor activity. The mAbs converted to IgG(1) revealed effective ADCC as well as antitumor activity in vivo. Because half of the 21 Ags showed distinct tumor-specific expression pattern and the mAbs isolated showed various characteristics with strong affinity to the Ag, it is likely that some of the Ags detected will become useful targets for the corresponding carcinoma therapy and that several mAbs will become therapeutic agents.


[Fast DNA amplification in small ultrathin-wall microplates].
A new method was developed for fast DNA amplification by polymerase chain reaction in tiny ultrathin microplates formed directly on the thermocycler's thermoblock. The microplates are made from thin (40-60 microns) polypropylene film by the thermal vacuum-formation method. Due to the effective heat transfer to 10-15 microliters samples and a high velocity of heating and cooling of the thermoblock (up to 7 degrees C/s), the total duration of the DNA amplification (30 cycles) is only 15-30 min.


Epidemiology of hypertension in the elderly with chronic kidney disease.
As the population of the United States ages, the prevalence of age-related chronic conditions such as hypertension and chronic kidney disease (CKD) will also increase. Available studies in nationally representative samples and select outpatient populations indicate that hypertension is very common in older adults with CKD, and despite the use of medication it is often poorly controlled. Generally, less than one-third of the elderly patients with CKD achieve a level of blood pressure control consistent with that of the current guideline recommendations. However, limited evidence is available from observational studies and clinical trials to inform management of hypertension in the elderly population with CKD. The available published data suggest that the relationship between clinical outcomes and the treatment of hypertension among older adults with CKD is complex and distinct from that of their younger counterparts. Larger and more robust analyses are needed for a better understanding of the association between hypertension, its treatment, and clinical events in elderly patients with CKD.


Self-Assembled Amphiphilic Chitosan Nanomicelles: Synthesis, Characterization and Antibacterial Activity.
Although amphiphilic chitosan has been widely studied as a drug carrier for drug delivery, fewer studies have been conducted on the antimicrobial activity of amphiphilic chitosan. In this study, we successfully synthesized deoxycholic acid-modified chitosan (CS-DA) by grafting deoxycholic acid (DA) onto chitosan C2-NH2, followed by grafting succinic anhydride, to prepare a novel amphiphilic chitosan (CS-DA-SA). The substitution degree was 23.93% for deoxycholic acid and 29.25% for succinic anhydride. Both CS-DA and CS-DA-SA showed good blood compatibility. Notably, the synthesized CS-DA-SA can self-assemble to form nanomicelles at low concentrations in an aqueous environment. The results of CS, CS-DA, and CS-DA-SA against Escherichia coli and Staphylococcus aureus showed that CS-DA and CS-DA-SA exhibited stronger antimicrobial effects than CS. CS-DA-SA may exert its antimicrobial effect by disrupting cell membranes or forming a membrane on the cell surface. Overall, the novel CS-DA-SA biomaterials have a promising future in antibacterial therapy.


Vaccinia virus infections in martial arts gym, Maryland, USA, 2008.
Vaccinia virus is an orthopoxvirus used in the live vaccine against smallpox. Vaccinia virus infections can be transmissible and can cause severe complications in those with weakened immune systems. We report on a cluster of 4 cases of vaccinia virus infection in Maryland, USA, likely acquired at a martial arts gym.


[Some ideas regarding establishment of Chinese medicine clinical assessment indices system for studying irritable bowel syndrome].
Irritable bowel syndrome (IBS) is a commonly seen disease in clinical practice, and Chinese medicine shows certain preponderance in treating the disease contrasted with modern medicine. However, the clinical effect of Chinese medicine was hardly approved by the world, and the lack of widely accepted clinical assessment indices (CAI) is an important cause. The establishment of Chinese medicine CAI system for studying IBS was discussed in this paper based upon the characteristics of clinical effect and clinical assessment of Chinese medicine.


Selective Catalytic Reduction of NOx over Perovskite-Based Catalysts Using CxHy(Oz), H2 and CO as Reducing Agents-A Review of the Latest Developments.
Selective catalytic reduction (SCR) is probably the most widespread process for limiting NOx emissions under lean conditions (O2 excess) and, in addition to the currently used NH3 or urea as a reducing agent, many other alternative reductants could be more promising, such as CxHy/CxHyOz, H2 and CO. Different catalysts have been used thus far for NOx abatement from mobile (automotive) and stationary (fossil fuel combustion plants) sources, however, perovskites demand considerable attention, partly due to their versatility to combine and incorporate various chemical elements in their lattice that favor deNOx catalysis. In this work, the CxHy/CxHyOz-, H2-, and CO-SCR of NOx on perovskite-based catalysts is reviewed, with particular emphasis on the role of the reducing agent nature and perovskite composition. An effort has also been made to further discuss the correlation between the physicochemical properties of the perovskite-based catalysts and their deNOx activity. Proposed kinetic models are presented as well, that delve deeper into deNOx mechanisms over perovskite-based catalysts and potentially pave the way for further improving their deNOx efficiency.


Multidisciplinary treatment for macrometastatic osteogenic sarcoma.
Using a co-ordinated multidisciplinary approach with surgery, radiation therapy, and chemotherapy, 14 out of 21 patients with metastases from osteogenic sarcoma were rendered free of disease for over two to over 18 months. Most patients had pulmonary metastases, two had bony metastases, and one had metastases in the iliac nodes. As part of this multidisciplinary approach weekly high-dose methotrexate was given and caused tumour regression in seven out of 15 patients. After all clinical evidence of disease had been removed high-dose methotrexate was administered every two to three weeks as maintenance treatment. To assess the efficacy of treatment the results were compared with those in a historical control group of 82 consecutive patients who developed pulmonary or other metastases. The results in the study group were significantly better. This experience may be similar to that in Wilms's tumour, where actinomycin D has increased the cure rate when administered as adjuvant therapy after treatment of localised or overt metastatic disease.


CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease.
Cognitive dysfunction and memory loss are common features of Alzheimer's disease (AD). Abnormalities in the expression profile of immediate early genes that play a critical role in memory formation, such as the cAMP-response element binding protein (CREB), have been reported in the brains of AD patients. Here we show that amyloid-β (Aβ) accumulation, which plays a primary role in the cognitive deficits of AD, interferes with CREB activity. We further show that restoring CREB function via brain viral delivery of the CREB-binding protein (CBP) improves learning and memory deficits in an animal model of AD. Notably, such improvements occur without changes in Aβ and tau pathology, and instead are linked to an increased level of brain-derived neurotrophic factor. The resulting data suggest that Aβ-induced learning and memory deficits are mediated by alterations in CREB function, based on the finding that restoring CREB activity by directly modulating CBP levels in the brains of adult mice is sufficient to ameliorate learning and memory. Therefore, increasing CBP expression in adult brains may be a valid therapeutic approach not only for AD, but also for various brain disorders characterized by alterations in immediate early genes, further supporting the concept that viral vector delivery may be a viable therapeutic approach in neurodegenerative diseases.


Hypothermic storage with University of Wisconsin solution preserves endothelial and vascular smooth-muscle function.
The effect of University of Wisconsin (UW) solution on coronary endothelial function is debated. Although earlier studies demonstrated preservation of stimulated release of endothelial vasoactive factors, the effect of UW solution on basal nitric oxide release has not been investigated, and this was the purpose of the present study. Isolated canine coronary arteries were evaluated immediately after being harvested (group 1) and after 24-hour hypothermic (4 degrees C) storage in either buffered physiological saline solution (group 2) or UW solution (group 3). Smooth-muscle vascular response to sodium nitroprusside (10(-9) to 10(-6) mol/L), KCl (5 to 50 mmol/L), and prostaglandin F2alpha (10(-9) to 10(-6) mol/L) was comparable among the groups, as was the endothelial response to acetylcholine (10(-9) to 10(-6) mol/L) and calcium ionophore A23187 (10(-9) to 10(-6) mol/L). Vessels in group 3 exhibited better preservation of basal release of nitric oxide, as measured by contraction to either N(G)-monomethyl L-arginine (10(-4) mol/L) or methylene blue (10(-5) mol/L), in comparison with control arteries exposed to saline solution (group 2). There was no difference in the basal production of nitric oxide between group 1 and group 3 vessels. The present study demonstrated preservation of vascular smooth muscle and endothelium-dependent relaxations after prolonged hypothermic storage in UW solution. Furthermore, storage in this solution preserved basal release of nitric oxide.


Prostaglandin F2alpha and oxytocin compared with hypertonic saline and oxytocin for the induction of second trimester abortion.
Second trimester abortion was induced in a randomized investigation using a single dose of prostaglandin F2alpha (PGF2alpha) in combination with oxytocin in one group of patients, and hypertonic saline (20%) in combination with oxytocin in another group of patients. Oxytocin was administered in order to induce a rapid abortion, and was given intravenously in a glucose drip (100 I.U. oxytocin added to 1 litre of 5% glucose). Administration rate was 10 I.U./hour. The PG-group consisted of 16 patients. The mean induction-abortion interval for this group was 14.2 hours, and all patients aborted within 24 hours. In three cases the bleeding exceeded 200 ml. In one of these cases infection occurred. Only mild side effects occurred. The saline group also consisted of 16 patients. The mean induction-abortion interval in this group was 21.5 hours. Eleven patients aborted within 24 hours. In two cases the bleeding exceeded 200 ml. No side effects occurred. Intraamniotic instillation of PGF2alpha seems to be a good alternative to hypertonic saline for termination of second trimester pregnancies.


[Biogeographic zonation of the Eurasian fresh waters based on the macrobenthic faunas].
Spatial differentiation of the Eurasian freshwater faunas is analyzed based on the original and published data on the aquatic insects, crustaceans, and mollusks (about 8800 species in total). The Hacker-Dice similarity index is employed as a principal criterion of differentiation. The schemes of biogeographic zonation are constructed for the nine large macrobenthic taxa, namely, Odonata, Ephemeroptera, Plecoptera, Hemiptera, Coleoptera, Trichoptera, Malacostraca, Gastropoda, and Bivalvia. Discussed are principal discordances in distribution of three different ecological-systematic groups of the macrobenthos, namely, limnophylic insects, rheophylic insects, and crustaceans with mollusks. A generalized zonation system of the Eurasian fresh waters is elaborated, which is fundamentally divided into Palaearctic and Oriental Regions. The former is further divided into five subregions: Euro-Ob, Near East, Central Asia, Eastern Siberia, and Japan. The latter is divided into three subregions: Indo-Himalaya, China, and Malay. Preliminary classification of the provinces is also provided. Disagreements between the biogeographic systems of different authors are discussed.


DNA cytofluorometric analysis using HP/DAPI double staining of parathyroid carcinoma arising in a patient with chronic renal failure and secondary hyperparathyroidism.
A 55-year old female patient on long-term hemodialysis began to suffer from pain in her knees and ankles. An ultrasonographic study showed enlargement of all four parathyroid glands. Serum parathyroid hormone and calcium levels were increased. Parathyroidectomy was performed. The right superior gland was enlarged and adherent to surrounding tissues. The other three glands were slightly enlarged. Histologically, the largest gland was a parathyroid carcinoma because capsular and vascular invasion were observed. To our knowledge, there have been only 13 cases of parathyroid carcinomas arising in patients with chronic renal failure reported in the English literature. To evaluate the characteristics of this tumor, we measured nuclear DNA and protein content using stains for HP (hematoporphyrin)/DAPI (4,6-diamidino-2-phenylindole dihydroporphyrin chloride). The nuclear DNA pattern was typically diploid or tetraploid. The cellular protein content was similar to that seen in the controls. The discrepancy between the histology, indicative of malignancy and the cytofluorometrical findings show that it is difficult to determine the prognosis for patients with secondary hyperparathyroidism and parathyroid carcinomas solely from the results of tumor DNA cytometry.


[Are there sport-specific craniocerebral traumas?].
The incidence of sports accidents is on the increase. The authors examined the question whether this is also true of craniocerebral injuries during sports activities. For this purpose they studied and assessed all grade I and II craniocerebral injuries treated during 1982 at the departments of Surgery and Neurosurgery at the University of Göttingen. The craniocerebral injuries had a share of 13.5% in the total incidence of Sports accidents. This figure is markedly above the comparative figures quoted so far. The incidence of craniocerebral trauma varies from one sports discipline to another, depending on the popularity of the particular sport. However, a comparison with data published in the literature shows that craniocerebral trauma is the most frequent sports injury in all disciplines in which the head is particularly exposed.


Transformation of human fibroblasts and keratinocytes with human papillomavirus type 16 DNA.
Human keratinocytes and fibroblasts isolated from foreskin were transformed by transfection with recombinant human papillomavirus type 16 (HPV16) DNA. The transformed cells exhibited an extended (fibroblasts) or indefinite (keratinocytes) life-span compared with that of normal controls. In addition, HS27, a human fibroblast cell line previously transfected with origin-defective simian virus 40, was successfully transfected. HPV16 sequences were stably maintained in the cells, and extensive amplification and rearrangements occurred with continuous culturing. Moreover, both fibroblasts and keratinocytes expressed several specific HPV16 mRNAs. Because HPV16-transfected cells had viral transcripts and because transfection with the vector alone did not extend the life-span of the cells, it is likely that the virus was responsible for the indefinite life-span. Transfected fibroblast and keratinocyte lines will be useful for investigating the molecular biology of HPV16 and the interactions between the viral DNA and the human genome. Moreover, transfected keratinocytes provide a model for analyzing the effects of HPV16 on the differentiation properties of human epithelial cells.


Nerve root cut-off on metrizamide-enhanced computerized tomography.
The "wink" sign of nerve root cut-off seen on metrizamide-enhanced computerized tomography correlates well with compression of a lumbar nerve by a herniated disk. Seven of 46 patients had normal or equivocal myelograms, but had definite nerve root cut-off on metrizamide-enhanced CT scan. All seven patients were found to have a herniated lumbar disk at operation or a diskogram positive for herniation at the time of chymopapain injection. The wink sign is an additional objective finding that can be used in assessing the patient with sciatica.


Elevated cortisol in older adults with generalized anxiety disorder is reduced by treatment: a placebo-controlled evaluation of escitalopram.
Generalized anxiety disorder (GAD) is a common disorder in older adults, which has been linked to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in this age group. The authors examined whether treatment of GAD in older adults with a selective serotonin reuptake inhibitor (SSRI) corrects this HPA axis hyperactivity. The authors examined adults aged 60 years and older with GAD in a 12-week randomized controlled trial comparing the SSRI escitalopram with placebo. The authors collected salivary cortisol at six daily time points for 2 consecutive days to assess peak and total (area under the curve) cortisol, both at baseline and posttreatment. Compared with placebo-treated patients, SSRI-treated patients had a significantly greater reduction in both peak and total cortisol. This reduction in cortisol was limited to patients with elevated (above the median) baseline cortisol, in whom SSRI-treated patients showed substantially greater reduction in cortisol than did placebo-treated patients. Reductions in cortisol were associated with improvements in anxiety. Additionally, genetic variability at the serotonin transporter promoter predicted cortisol changes. SSRI treatment of GAD in older adults reduces HPA axis hyperactivity. Further research should determine whether these treatment-attributable changes are sustained and beneficial.


Using ecological momentary assessment to investigate short-term variations in sexual functioning in a sample of peri-menopausal women from Iran.
The investigation of short-term changes in female sexual functioning has received little attention so far. The aims of the study were to gain empirical knowledge on within-subject and within- and across-variable fluctuations in women's sexual functioning over time. More specifically, to investigate the stability of women´s self-reported sexual functioning and the moderating effects of contextual and interpersonal factors. A convenience sample of 206 women, recruited across eight Health care Clinics in Rasht, Iran. Ecological momentary assessment was used to examine fluctuations of sexual functioning over a six week period. A shortened version of the Female Sexual Function Index (FSFI) was applied to assess sexual functioning. Self-constructed questions were included to assess relationship satisfaction, partner's sexual performance and stress levels. Mixed linear two-level model analyses revealed a link between orgasm and relationship satisfaction (Beta = 0.125, P = 0.074) with this link varying significantly between women. Analyses further revealed a significant negative association between stress and all six domains of women's sexual functioning. Women not only reported differing levels of stress over the course of the assessment period, but further differed from each other in how much stress they experienced and how much this influenced their sexual response. Orgasm and sexual satisfaction were both significantly associated with all other domains of sexual function (P<0.001). And finally, a link between partner performance and all domains of women`s sexual functioning (P<0.001) could be detected. Except for lubrication (P = 0.717), relationship satisfaction had a significant effect on all domains of the sexual response (P<0.001). Overall, our findings support the new group of criteria introduced in the DSM-5, called "associated features" such as partner factors and relationship factors. Consideration of these criteria is important and necessary for clinicians when diagnosing FSD.


Biosynthesis of cardiac glycosides: Nucleotide-bound 2,6-dideoxy-3-O-methylhexoses in leaf extracts of Nerium oleander.
From the leaves of NERIUM OLEANDER L. (Apocynaceae) nucleotide bound D-sarmentose and D-diginose were isolated and purified by use of PVP- and charcoal treatment and further separated by paper chromatography and electrophoresis. D-sarmentose and D-diginose werde identified by repeated thinlayer co-chromatography in two different solvent systems. Complete separation of L-oleandrose, D-cymarose, D-sarmentose, D-diginose and D-digitoxose was achieved for the first time with one single TLC-system.


Nurses' lived experience of being a preceptor.
Registered nurses' lived experience of preceptorship was studied in this phenomenological study. To illuminate the meaning of registered nurses' experience of being a preceptor for student nurses, individual tape-recorded interviews were conducted with 17 registered nurses. They narrated their experience of being a personal preceptor for student nurses during practical training on a hospital unit, and the interviews transcribed verbatim were analyzed phenomenological-hermeneutically. The analysis revealed two main themes (1) including the student in their daily work and (2) increasing awareness of the process of learning, as well as six other themes, which contributed to a new comprehension of the meaning of being a preceptor. All the themes were related to the ongoing preceptor-preceptee relationship. The preceptors' thinking on past experiences and their ideas of nursing care in the future were present simultaneously. Nurses acting as preceptors were perceived as conscious individuals, demanding a balance of their daily work responsibility with increased awareness of the professional demands of nursing care. Preceptors gained increased awareness of and a desire to fulfill the student nurses' varied learning needs and increased awareness of their own learning process.


Diversity of Viruses Infecting Eukaryotic Algae.
Algae are photosynthetic organisms that drive aquatic ecosystems, e.g. fuelling food webs or forming harmful blooms. The discovery of viruses that infect eukaryotic algae has raised many questions about their influence on aquatic primary production and their role in algal ecology and evolution. Although the full extent of algal virus diversity is still being discovered, this review summarizes current knowledge of this topic. Where possible, formal taxonomic classifications are referenced from the International Committee on Taxonomy of Viruses (ICTV); since the pace of virus discovery has far surpassed the rate of formal classification, however, numerous unclassified viruses are discussed along with their classified relatives. In total, we recognized 61 distinct algal virus taxa with highly variable morphologies that include dsDNA, ssDNA, dsRNA, and ssRNA genomes ranging from approximately 4.4 to 560 kb, with virion sizes from approximately 20 to 210nm in diameter. These viruses infect a broad range of algae and, although there are a few exceptions, they are generally lytic and highly species or strain specific. Dedicated research efforts have led to the appreciation of algal viruses as diverse, dynamic, and ecologically important members of the biosphere, and future investigations will continue to reveal the full extent of their diversity and impact.


Inulin alleviates perfluorooctanoic acid-induced intestinal injury in mice by modulating the PI3K/AKT/mTOR signaling pathway.
Perfluorooctanoic acid (PFOA) is a widely used industrial compound that has been found to induce intestinal toxicity. However, the underlying mechanisms have not been fully clarified and effective interventions are rarely developed. Inulin, a prebiotic, has been used as a supplement in human daily life as well as in gastrointestinal diseases and metabolic disorders. In this study, male mice were exposed to PFOA with or without inulin supplementation to investigate the enterotoxicity and potential intervention effects of inulin. Mice were administered PFOA at 1 mg/kg/day, PFOA with inulin at 5 g/kg/day, or Milli-Q water for 12 weeks. Histopathological analysis showed that PFOA caused colon shortening, goblet cell reduction, and inflammatory cell infiltration. The expression of the tight junction proteins ZO-1, occludin and claudin5 significantly decreased, indicating impaired barrier function. According to the RNA-sequencing analysis, PFOA exposure resulted in 917 differentially expressed genes, involving 39 significant pathways, such as TNF signaling and cell cycle pathways. In addition, the protein expression of TNF-α, IRG-47, cyclinB1, and cyclinB2 increased, while Gadd45γ, Lzip, and Jam2 decreased, suggesting the involvement of the TNF signaling pathway, cell cycle, and cell adhesion molecules in PFOA-associated intestinal injury. Inulin intervention alleviated PFOA-induced enterotoxicity by activating the PI3K/AKT/mTOR signaling pathway and increasing the protein expression of Wnt1, β-catenin, PI3K, Akt3, and p62, while suppressing MAP LC3β, TNF-α, and CyclinE expression. These findings suggested that PFOA-induced intestinal injury, including inflammation and tight junction disruption, was mitigated by inulin through modifying the PI3K/AKT/mTOR signaling pathways. Our study provides valuable insights into the enterotoxic effects of PFOA and highlights the potential therapeutic role of inulin.


Parkinson's disease is associated with greater regularity of repetitive voluntary movements.
Bradykinesia is a cardinal symptom of Parkinson's disease (PD). Both aging and disease are shown to be associated with decreased adaptability to environmental stresses characterized by reduced complexity (or increased regularity) of biorhythms. The purpose of this study was to investigate the regularity of movement in individuals with PD, and the effect of dopaminergic medication. Nine subjects with PD and eight controls performed wrist flexion/extension movements at maximal velocity and range of motion. Subjects with PD were tested under two medication conditions. Approximate entropy (ApEn) was calculated to assess the regularity of the movement, with the smaller value associated with the greater regularity. Data revealed that subjects with PD had lower ApEn values than controls. Medication did not alter the ApEn values. These findings demonstrate that impaired voluntary movement in individuals with PD is associated with increased regularity of movement and this exaggerated regularity appears less sensitive to anti-PD medication.


Reducing legal fees in medical group practices. The role of health care alternative dispute resolution.
Conflict is a growth industry, particularly in an increasingly complex health care system. Litigation is the most common, and most costly, method of settling health care disputes. Highly adversarial, the process of litigation often generates as much, if not more, hostility than the original dispute. In addition, satisfaction with the outcome is very low. The challenge that has arisen is to manage the conflicts so that the underlying needs and interests of all the parties can best be met. Often the techniques and processes of alternative dispute resolution (ADR) can be successfully used in resolving these sorts of conflicts quickly, cheaply and with greater satisfaction for all parties. Various applications of ADR are currently being used or tested in a variety of health care disputes in the United States and Canada. Tremendous success has been achieved in mediating medical malpractice claims, medical staff disputes, economic credentialing conflicts, insurer relations issues and denial of coverage disputes. Professional relations and departmental staff disputes, partnership and employee conflicts, and organizational disputes within clinics, HMOs and large group practices have all been found particularly amenable to ADR. These are all situations in which everyone benefits from quick, non-hostile resolutions and on-going relationships can continue.


Corrections and clarifications.
D. G. Rainnie et al., in their report "Adenosine inhibition of mesopontine cholinergic neurons: Implications for EEG arousal" (4 Feb., p. 689), suggested that adenosine may mediate sleep-debt related potentiation of EEG slow-wave activity in non-REM sleep. This is similar to a hypothesis proposed by J. H. Benington et al. [Sleep Res. 22, 4 (1993)]. Rainnie et al. suggested that adenosine exerts this effect by means of inhibition of mesopontine cholinergic neurons rather than by direct inhibition of neurons in the cerebral cortex.


Transplanted small bowel and expression of the insulin-like growth factor binding proteins.
The insulin-like growth factor binding proteins (IGFBPs) act to modulate the growth and differentiation of the gastrointestinal mucosa by regulating cellular responses to the important mitogens, the insulin-like growth factors (IGFs). The transplanted small bowel must maintain the normal growth factor interrelationships and signaling pathways despite the potential of host rejection. Ostomy effluent of patients after small bowel or combined liver/small bowel transplantation was assayed for IGFBPs to investigate the effect of rejection on the IGF-IGFBP axis. Seventeen patients were studied over an 18-month period. The transplanted small bowel produced no measurable IGFBPs in the ostomy effluent under normal circumstances. However, when rejection was taking place the ostomy effluent was found to have measurable IGFBP levels in 6 of 12 episodes, the 6 episodes occurring in 6 different patients. Mostly, the IGFBPs present did not exhibit a serum-like pattern indicating the secretion of IGFBPs into the effluent was not the result of loss of mucosal barrier integrity. There were no statistically significant differences in protein content of the ostomy fluids in the presence or absence of rejection. Our results suggest that the gastrointestinal IGF axis is altered during some instances of transplanted small bowel rejection, with increased secretion of IGFBPs.


Prehipertension: influence of psychological stress in adolescents.
The article examines the association between psychological stress (PS) and prehypertension (PH) in 690 adolescents, 260 males and 430 females, whose average age was 15.2 years (SD = 1.5). Their blood pressure (BP) was measured on separate days at school, by the oscillometric method (Dinamap) in a seating position. All of them completed a survey assessing life events and social readjustment (both scales associated with life stressors in adolescence). Participants were classified according to BP levels in prehypertensive (PH) and normotensive (N). The presence of PS was evaluated as severe stressful life events. The Chi-square test was used to study the association between PS and the presence of PH. The results showed the presence of PH in 9.2% (n = 24) in males and 3.5% (n = 15) in females, while the presence of PS ocurred in 70 males (26.9%) and 155 females (36.0%).When applied to the whole data, the Chi-square statistical test showed no association between PS and the condition of prehypertension [PH with PS = 15 vs. N with PS = 24, (P= 0.42)]. However, when subjects were classified by gender, there was a significant association between PS and PH in female adolescents [PH with PS = 9 vs N with PS = 6 (P = 0.04)]. This result suggests that, at early ages, female adolescents may be more vulnerable than males to PS as a determining factor to the condition of PH.


Behavioral science research in diabetes: lifestyle changes related to obesity, eating behavior, and physical activity.
Lifestyle factors related to obesity, eating behavior, and physical activity play a major role in the prevention and treatment of type 2 diabetes. In recent years, there has been progress in the development of behavioral strategies to modify these lifestyle behaviors. Further research, however, is clearly needed, because the rates of obesity in our country are escalating, and changing behavior for the long term has proven to be very difficult. This review article, which grew out of a National Institute of Diabetes and Digestive and Kidney Diseases conference on behavioral science research in diabetes, identifies four key topics related to obesity and physical activity that should be given high priority in future research efforts: 1) environmental factors related to obesity, eating, and physical activity; 2) adoption and maintenance of healthful eating, physical activity, and weight; 3) etiology of eating and physical activity; and 4) multiple behavior changes. This review article discusses the significance of each of these four topics, briefly reviews prior research in each area, identifies barriers to progress, and makes specific research recommendations.


Reproducibility and accuracy of measurements with a hand held autorefractor in children.
To determine reproducibility and accuracy of the Nikon Retinomax autorefractor when used with children who were made cycloplegic. Autorefraction and retinoscopy or subjectively refined retinoscopy (where, under the patient's direction, the refraction was varied until the best visual acuity was achieved) were performed on the right eye of 47 children, age 11-93 months. Autorefraction was performed using the Nikon Retinomax, which provides up to eight measured values of refractive error and one representative measurement of refractive error. Autorefractor measurements were successfully obtained from 7/9 children age 3 years or younger, and from all older children. Vector methods were used to calculate differences. Retinomax reproducibility averaged 0.43 D. Unbiased Retinomax and retinoscopy measurements differed by an average of 0.82 D. Unbiased Retinomax and subjectively refined retinoscopy differed by an average of 1.03 D. Reproducibility of Retinomax measured values in children is comparable with reproducibility of retinoscopy, subjective refraction, and autorefraction measurements in adults. Agreement between Retinomax and retinoscopy and agreement between Retinomax and subjective refinement in children is comparable with agreement between autorefraction and subjective refraction in adults. The study indicates that the Retinomax is a useful instrument for measuring refractive errors in young children.


Histopathological Characteristics of Distal Middle Cerebral Artery in Adult and Pediatric Patients with Moyamoya Disease.
Moyamoya disease (MMD) is a unique progressive steno-occlusive disease of the distal ends of bilateral internal arteries and their proximal branches. The difference in clinical symptoms between adult and children MMD patients has been well recognized. In this study, we sought to investigate the phenomenon through histopathological study. Fifty-one patients underwent surgical procedures for treatment of standard indications of MMD at Kyoto University Hospital. Fifty-nine specimens of MCA were obtained from MMD patients during the surgical procedures. Five MCA samples were also obtained in the same way from control patients. The samples were analyzed by histopathological methods. In this study, MCA specimens from MMD patients had significantly thinner media and thicker intima than control specimens. In subsequent analysis, adult (≥ 20 years) patients had thicker intima of MCA compared to pediatric (< 20 years) patients. There is no difference in internal elastic lamina pathology between adult and pediatric patients. Our results indicated that the pathological feature of MMD in tunica media occurs in both adult and pediatric patients. However, the MMD feature in tunica intima of MCA is more prominent in adult patients. Further analysis from MCA specimens and other researches are necessary to elucidate the pathophysiology of MMD.


UV-B-Induced Inflammasome Activation Can Be Prevented by Cis-Urocanic Acid in Human Corneal Epithelial Cells.
The cornea is continually exposed to highly energetic solar UV-B (280-320 nm). Our aim was to investigate whether UV-B triggers the activation of NLRP3 inflammasomes and the production of IL-1β and/or IL-18 in human corneal epithelial (HCE) cells. Additionally, we studied the capability of cis-urocanic acid (cis-UCA) to prevent inflammasome activation or alleviate inflammation through other signaling pathways. HCE-2 cell line and primary HCE cells were primed using lipopolysaccharide or TNF-α. Thereafter, cells were exposed to UV-B before or after the addition of cis-UCA or caspase-1 inhibitor. Caspase-1 activity was measured from cell lysates by an enzymatic assay. IL-1β, IL-18, IL-6, IL-8, and NLRP3 levels were detected using the ELISA method from cell culture media. Additionally, intracellular NLRP3 levels were determined by the Western blot technique, and cytotoxicity was measured by the LDH assay. UV-B exposure significantly increased caspase-1 activity in TNF-α-primed HCE cells. This result was consistent with the concurrently induced IL-1β secretion. Both caspase-1 activity and release of IL-1β were reduced by cis-UCA. Additionally, UV-B stimulated the caspase-1-independent production of IL-18, an effect also reduced by cis-UCA. Cis-UCA decreased the release of IL-6, IL-8, and LDH in a time-dependent manner when administered to HCE-2 cells after UV-B exposure. Our findings demonstrate that UV-B activates inflammasomes in HCE cells. Cis-UCA can prevent the secretion of IL-1β and IL-18 and therapeutically reduces the levels of IL-6, IL-8, and LDH in UV-B-stressed HCE cells.


Increasing confidence in vergence as a cue to distance.
Multiple cues contribute to the visual perception of an object's distance from the observer. The manner in which the nervous system combines these various cues is of considerable interest. Although it is accepted that image cues play a significant role in distance perception, controversy exists regarding the use of kinaesthetic information about the eyes' state of convergence. We used a perturbation technique to explore the contribution of vergence to visually based distance estimates as a function of both fixation distance and the availability of retinal information. Our results show that the nervous system increases the weighting given to vergence as (i) fixation distance becomes closer; and (ii) the available retinal image cues decrease. We also identified the presence of a strong contraction bias when distance cues were studied in isolation, but we argue that such biases do not suggest that vergence provides an ineffectual signal for near-space perception.


Intensified inundation shifts a freshwater wetland from a CO2 sink to a source.
Climate change has altered global precipitation patterns and has led to greater variation in hydrological conditions. Wetlands are important globally for their soil carbon storage. Given that wetland carbon processes are primarily driven by hydrology, a comprehensive understanding of the effect of inundation is needed. In this study, we evaluated the effect of water level (WL) and inundation duration (ID) on carbon dioxide (CO2 ) fluxes by analysing a 10-year (2008-2017) eddy covariance dataset from a seasonally inundated freshwater marl prairie in the Everglades National Park. Both gross primary production (GPP) and ecosystem respiration (ER) rates showed declines under inundation. While GPP rates decreased almost linearly as WL and ID increased, ER rates were less responsive to WL increase beyond 30 cm and extended inundation periods. The unequal responses between GPP and ER caused a weaker net ecosystem CO2 sink strength as inundation intensity increased. Eventually, the ecosystem tended to become a net CO2 source on a daily basis when either WL exceeded 46 cm or inundation lasted longer than 7 months. Particularly, with an extended period of high-WLs in 2016 (i.e., WL remained >40 cm for >9 months), the ecosystem became a CO2 source, as opposed to being a sink or neutral for CO2 in other years. Furthermore, the extreme inundation in 2016 was followed by a 4-month postinundation period with lower net ecosystem CO2 uptake compared to other years. Given that inundation plays a key role in controlling ecosystem CO2 balance, we suggest that a future with more intensive inundation caused by climate change or water management activities can weaken the CO2 sink strength of the Everglades freshwater marl prairies and similar wetlands globally, creating a positive feedback to climate change.


Adherence and ingestion of Escherichia coli serotype 055 by trophozoites of Entamoeba histolytica.
Carbohydrate-binding activity present on the Entamoeba histolytica cell surfaces was found to mediate the adherence of two types of bacteria, Escherichia coli serotype 055 and Salmonella greenside 050. Adherence was inhibited by low-molecular-weight carbohydrates (10 mg/ml) such as galactose, lactose, and N-acetylgalactosamine, as well as by asialofetuin and the lipopolysaccharide extracted from E. coli 055. Mild periodate oxidation of the bacteria inhibited their adherence, whereas heat inactivation, glutaraldehyde fixation, or gamma-irradiation had no effect. On the other hand, pretreatment of trophozoites with glutaraldehyde, cytochalasin B, or cold (5 degrees C) abolished adherence. None of these treatments, however, affected the attachment of bacteria that contain on their cell surface type I pili with mannose-binding capacity. These findings lend further support to our earlier observations on how amoebae interact with bacteria.


Exposure biomarkers in chemoprevention studies of liver cancer.
Hepatocellular carcinoma (HCC) is the most common type of liver cancer, the major risk factors being hepatitis B and C viruses and aflatoxins; other factors such as alcohol are also of importance in some populations. Aflatoxin exposure biomarkers include urinary aflatoxin metabolites and aflatoxin-albumin adducts in peripheral blood. These biomarkers are well validated and have been applied in studies of many populations worldwide. They are proving to be valuable end-points in intervention studies, including chemoprevention studies. The biomarkers permit assessment of primary prevention measures to reduce aflatoxin intake. In addition, the determination of individual urinary aflatoxin metabolite profiles means that the effectiveness of chemopreventive agents designed to modulate aflatoxin metabolism can also be evaluated. Both aflatoxin-albumin adducts and urinary aflatoxin metabolites have been associated with increased HCC risk in prospective studies, indicating the predictive value of these biomarkers at the group level. However, given the multifactorial and multistep nature of HCC, it is unlikely that these exposure biomarkers will be predictive at the individual level or be of value as surrogate end-points in longer-term intervention trials aimed at reducing disease incidence. Aflatoxin-related mutations at codon 249 of the p53 gene in plasma may be more relevant in this regard but their application requires further understanding of the temporal appearance of this biomarker in relation to the natural history of the disease.


Changes in polyamine catabolism in HL-60 human promyelogenous leukaemic cells in response to etoposide-induced apoptosis.
The topoisomerase II inhibitor etoposide induced apoptosis in HL-60 cells within 4 h of exposure to the drug, as measured by changes in morphology, DNA fragmentation and cytotoxicity assays. Etoposide-induced apoptosis was accompanied by an increase in polyamine efflux from the cells and a decrease in total polyamine content during the first 24 h of exposure to the drug. Although both enzyme activities increased slightly, there were no significant changes in spermidine/spermine N1-acetyltransferase activity or polyamine oxidase activity. After longer exposures (48-72 h), significant induction of spermidine/spermine N1-acetyltransferase activity and loss of polyamine content occurred. These results suggest that polyamine oxidation and the resultant hydrogen peroxide produced may be associated with the initiation of apoptosis, while induction of the acetyltransferase and overall loss of intracellular polyamines may be involved in the final, possibly necrotic, stages of cell death.


Pulmonary function impairment predicted poor prognosis of patients with hepatocellular carcinoma after hepatectomy.
Tumor hypoxia can influence the progression and metastasis of various cancers, including hepatocellular carcinoma (HCC). Clinical studies have indicated that hyperbaric oxygen may improve the prognosis and reduce complications in HCC patients; however, whether pulmonary function can influence the prognosis of HCC remains unknown. In this study, we found that pulmonary function was associated with clinicopathological features, including smoking, liver cirrhosis, tumor size Edmondson-Steiner grade, total operative blood loss and perioperative blood transfusion. Through Cox proportional hazard regression analysis, smoking, tumor number, tumor size, liver cirrhosis, total operative blood loss and pulmonary function were independent risk factors for overall survival (OS) and disease-free survival (DFS). In addition, poor pulmonary function was independently associated with shorter survival and increased HCC recurrence in patients. Notably, we also found that HCC with liver cirrhosis predicted worse prognosis. In summary, our study found pulmonary function could influence HCC progression. Improve pulmonary function may enhance the OS and DFS of patients with HCC.


Feasibility of eight physical fitness tests in 1,050 older adults with intellectual disability: results of the healthy ageing with intellectual disabilities study.
Although physical fitness is relevant for well-being and health, knowledge on the feasibility of instruments to measure physical fitness in older adults with intellectual disability (ID) is lacking. As part of the study Healthy Ageing with Intellectual Disabilities with 1,050 older clients with ID in three Dutch care services, the feasibility of 8 physical fitness tests was expressed in completion rates: box and block test, response time test, Berg balance scale, walking speed, grip strength, 30-s chair stand, 10-m incremental shuttle walking test, and the extended modified back saver sit and reach test. All tests had moderate to good feasibility in all subgroups, except for the participants with profound ID (all tests), severe ID (response time test and Berg balance scale), and wheelchair users (all tests that involve the legs). We conclude that the 8 tests are feasible to measure physical fitness in most older adults with ID.


Antibacterial Amino Acid-Based Poly(ionic liquid) Membranes: Effects of Chirality, Chemical Bonding Type, and Application for MRSA Skin Infections.
Bacteria induced infection remains a serious medical hazard to humans. Antibacterial polymeric materials, which can kill or inhibit bacteria by disrupting cell membranes, inhibiting certain enzymes, or interfering with the transcription or synthesis of DNA or RNA, have been applied to reduce or inhibit microbial drug resistance. Herein, amino acid-based ionic liquids (ILs) and poly(ionic liquid) (PIL) membranes were synthesized and used as antibacterial materials to treat skin wounds infected by methicillin-resistant Staphylococcus aureus (MRSA). The effects of chirality (D- or L-enantiomers) and chemical bonding (ionic or covalent) of the amino acid groups attached to the IL (or PIL) on antibacterial properties were investigated. Both the ILs and PIL membranes containing D-enantiomeric amino acid groups exhibited higher antibacterial activities compared with those containing L-enantiomeric amino acids. In addition, the ionically-bonded PIL membranes showed higher antibacterial activities than the corresponding covalently-bonded polymeric membranes. These results indicate that both the chirality and chemical bonding type of amino acid groups affect the antimicrobial activity of the PIL membranes. Additionally, the amino acid-based PIL membranes accelerated the wound-healing process, alleviated local tissue inflammation, and reduced the influence of bacteria on vital organs (liver and spleen) in MRSA-infected mouse models, demonstrating the potential applications for antimicrobial wound dressing.


[Constructing a new pedagogical proposal in the nursing program of the State University of Londrina].
The objective of this article is to outline the history of the Nursing Curriculum of the State University of Londrina. The first curriculum was created in the beginning of the nursing course in 1972 and the last one in January 2000. The results of the bibliographic research show that the curriculum of the nursing course in this university has changed along the years mainly due to professors' academic questions and demands of the labor market. The present study explains and justifies the changes in the curriculum and contributes for a better understanding of the new pedagogical proposal in the current Integrated Curriculum of the Nursing Course of the State University of Londrina.


Guidelines for routine measurement of blood hemoglobin oxygen affinity. International Federation of Clinical Chemistry, Scientific Division, Committee on pH, Blood Gases and Electrolytes.
Two methods for the routine determination of blood hemoglobin oxygen affinity are described. Both methods use whole blood and do not require special equipment, tonometry or special gas mixtures. The first method consists of a one-point determination of p50, and requires only 200 microL to 400 microL of whole blood, therefore making it suitable for the pediatric population. The second method uses multiple points, thereby establishing both the shape and position of the hemoglobin oxygen equilibrium curve between 10 and 99% oxygen saturation. Interpretation of p50 is discussed in relation to evaluation of patients with hemoglobinopathies and as a parameter in estimating availability of oxygen to the tissues.