Grand challenges in nanomedicine.
Nanotherapeutics and nanopharmaceuticals could achieve and facilitate earlier and more precise individual diagnosis, improve targeted therapies, reduce side effects, and enhance therapeutic monitoring. These advantages will improve quality of life, support a healthier and more independent aging population, and be instrumental in maximizing the cost-effectiveness of health care. However, the field of nanomedicine is at its early stage, most of the research still stays in the laboratory phase, and few success stories are translated into clinical trials and medical practice. This review will demonstrate the numerous challenges that are encountered during the development of commercial nanoparticle-based therapeutics and the possible solutions.


Normotensive patients with obstructive sleep apnoea: changes in 24-h ambulatory blood pressure monitoring with continuous positive airway pressure treatment.
Continuous positive airway pressure (CPAP) treatment reduces blood pressure (BP) in obstructive sleep apnoea (OSA) and hypertensive patients, but there is a lack of data about the effects of CPAP on the BP in normotensive patients. The aim of the study was to evaluate BP changes in normotensive OSA individuals receiving CPAP treatment. We selected 131 normotensive outpatients with an apnoea/hypopnoea index (AHI) greater than 15 events/hour who required CPAP treatment. All patients underwent a sleep study and 24-h ambulatory BP monitoring (ABPM) at baseline and after 6 months. In addition, the patients were assessed for the presence of baseline masked hypertension, defined as office BP less than 140/90 mmHg and increased BP on 24-h ABPM (mean 24-h BP ≥130/80 mmHg). After 6 months of CPAP treatment, a mild reduction in all 24-h ABPM variables was observed, but only the mean 24-h DBP [-1.39 mmHg, 95% confidence interval (95% CI), -2.50 to -0.27], mean daytime DBP (-1.39 mmHg, 95% CI -2.56 to -0.22) and the mean 24-h ambulatory BP (-1.80 mmHg, 95% CI, -3.16 to -0.44) reached statistical significance. The reduction was primarily due to BP changes in individuals with masked hypertension who displayed a mean BP reduction of -4.78 mmHg (-7.25 to -2.30 mmHg). Consistent with a circadian BP pattern, a reduction in mean nocturnal BP of -4.73 mmHg (-7.39 to -2.06 mmHg) was observed at 6 months in nondippers; in contrast, the mean nocturnal BP in dippers increased by 2.61 mmHg (0.60-4.62 mmHg). Our findings suggest that the CPAP effects may be different in normotensive outpatients depending on the presence of undiagnosed masked hypertension and the dipping pattern. Therefore, it is important to consider measuring ABPM in this type of patient.


A survey in uncharted territory: A collaborative study to explore the approach to atopic dermatitis patient management in allopathy and naturopathy.
Atopic dermatitis (AD) patients frequently use both conventional and complementary medicines for treatment. Allopathic and naturopathic providers may be unaware of each other's approach to AD diagnosis, skin care, and treatment, affecting patient and provider communication, patient safety, and potential for collaborative studies. To identify core commonalities and differences in allopathic and naturopathic approach to AD. Thirty allopathic and 21 naturopathic providers completed an 11-question free-text comment survey, covering patient education and evaluation, skin care, and treatment of AD. Qualitative content analysis detected key ideas and concepts, and word cloud analysis provided a quantitative visual representation of recurrent words in each group's responses. All respondents indicated using similar physical features to diagnose AD. In both allopathic and naturopathic fields, the majority of providers did not perform routine testing for AD diagnosis. Skin care with moisturization and "soak-and-seal" bathing practices were routine in both fields. Naturopathic providers heavily emphasized the role of food and diet in AD pathogenesis, education, and management, while allopathic providers indicated little to no role for food and diet in AD. For treatment, allopathic providers favored topical steroids, phototherapy, and immunomodulators, whereas naturopathic providers recommended botanicals, supplements, and other complementary and alternative methods. Providers should be aware of the differences between allopathic and naturopathic providers and their approach to AD management, particularly concerning the role of food and diet. There may be opportunities to harmonize skin care regimens for patients given similar approach in both fields, and to collaborate further on studies of diet in AD and treatments not yet effectively tested.


Development of bioactive peptides from fish proteins and their health promoting ability.
Great amount of marine fish species have been identified with potential nutraceutical and medicinal values. Consequently, a number of bioactive compounds have been identified including fish muscle proteins, peptides, collagen and gelatin, fish oil, fish bone. Bioactive peptides derived from various fish muscle proteins have shown various biological activities including antihypertensive, antibacterial, anticoagulant, anti-inflammatory, and antioxidant activities, and hence they may be a potential material for biomedical and food industries. Further, they are commonly used in medical and pharmaceutical industries as carrier molecules for drugs, proteins, and genes. Hence, fish muscle protein-derived peptides are valuable natural resources that can be potential material for biomedical, nutraceutical, and food industries.


Differentiation in vivo and in vitro of pyruvate kinase isozymes in rat muscle.
The M type isozymes of Pyruvate-kinase have been studied by isoelectrofocusing in thin layer acrylamide ampholine gel, during the ontogeny of rat muscle in vivo and during the differentiation in vitro of myoblasts of a line established by Yaffe. In both cases, multiple subbands have been seen; the most acid (pHi 5.2) was the predominant band in myoblasts and in fetal muscle at the 15th day. Several more cathodic bands appear sequentially in vitro as in vivo, one of them corresponding to the "M2" or "K" band (predominant in kidney). The most cathodic band M1 (pHi 7.3), characteristic of the adult muscle, appears at the 9th day of culture in vitro in multinucleated myotubes and at the 20th day of fetal life in vivo. Kinetic results confirm these electrofocusing results, showing in fetal muscle and in myoblasts a sigmoid saturation curve of pyruvate kinase activity with phosphoenolpyruvate as substrate. This allosteric kinetic is progressively replaced by a Michaëlian kinetics in vitro as in vivo. Consequently, the studies in vitro may serve as a model for myogenesis in vivo, and may contribute to the understanding of the significance of the multiple forms of pyruvate-kinase during this myogenesis.


Five novel and four recurrent point mutations in the antithrombin gene causing venous thrombosis.
We analyzed the antithrombin (AT) gene in 9 unrelated Japanese patients with thrombotic disease. All 7 exons, the splice junctions, and the 5'-flanking region of the AT gene were amplified by polymerase chain reaction and sequenced directly. Nine different point mutations, all in the heterozygous state, were identified. Five novel (M-32T, M89K, L146H, Q159X, and L409P) and 2 previously reported (R132X and R359X) point mutations were identified in patients with type 1 deficiency. Two different missense mutations, R393C and R393H, located in the protease reactive site were detected in patients with type 2 deficiency. No other sequence abnormalities in the AT gene were detected by direct sequencing. None of the mutations was present in 100 alleles from 50 unrelated Japanese control subjects Although type 1 deficiency was diagnosed in patient 7 on the basis of approximately 50% AT antigen and activity levels, the data indicated that the novel L409P mutation is a type 2 pleiotropic effects (PE) deficiency because its location in the C-terminal portion of the reactive site is similar to the locations of reported PE type mutations, and it is highly conserved among other serpins.


Immunosuppression in uterine transplantation.
Uterine transplantation (UTx) is the only effective treatment for uterine infertility patients to become genetic mothers. After decades of research, the surgical methods of UTx are very developed. There are numerous factors that affect the results of UTx, such as selection of the donor uterus before transplantation, immunosuppressive therapy post-transplantation, rejection monitoring, and immune tolerance. Studies have shown that immune rejection is a crucial factor affecting the survival rate after organ transplantation. Unlike liver or kidney transplantation, the aim of UTx is to obtain a functional uterus that is able to support successful pregnancy and birth of a healthy fetus. Because of the unique purpose of UTx, its immunosuppressive program is relatively specialized. Some immunosuppressive agents can cause perinatal complications, and inducing immune tolerance is necessary to resolve these side effects. Further understanding of the immune mechanism of UTx and the continuous development of new immunosuppressive agents, combined with the application of assisted reproductive technology, will be more conducive to the realization of UTx to breed offspring.


Transcranial Near-Infrared Laser Therapy for Stroke: How to Recover from Futility in the NEST-3 Clinical Trial.
Development of drugs and devices for the treatment of stroke is not exempt from current translational research standards, which include Stroke Treatment Academic Industry Roundtable (STAIR) criteria and RIGOR guidelines. Near-infrared laser therapy (NILT) was developed to treat stroke in an era when STAIR criteria were not adhered to, thus NILT was not optimized in multiple species, nor was it optimized for efficacy across barriers in translational animal models before proceeding to expensive and extensive clinical trials. Moreover, the majority of rodent studies did not adhere to RIGOR guidelines. This ultimately led to failure in the NeuroThera Effectiveness and Safety Trial-3. Because NILT remains a promising therapeutic approach to treat stroke, we designed a systematic study to determine laser light penetration profiles across the skull of four different species with increasing skull thickness: mouse, rat, rabbit, and human.Our study demonstrates that NILT differentially penetrates the skulls. There is especially extensive attenuation of light energy penetration across the human calvaria, compared with animal skulls, which suggests that the power density setting used in stroke clinical trials may not have optimally stimulated neuroprotection and repair pathways. The results of our study suggest that NILT cannot be sufficiently optimized in "small" animals and directly translated to humans because of significant variances of skull thickness and penetration characteristics across species. NILT neuroprotection should be further studied using a research design that endeavors to incorporate human skull characteristics (thickness) into the development plan to increase the probability of success in stroke victims.


Infantile spasms.
Infantile spasms are a unique disorder of infancy and early childhood. The average age at onset of infantile spasms is 6 months and the average incidence of the disorder is approximately 0.31 per 1000 live births. Approximately one-quarter of patients will spontaneously stop having spasms within 1 year of onset. There are three main types of epileptic spasms: flexor, extensor, and mixed flexor-extensor. Spasms frequently occur in clusters and commonly occur upon arousal from sleep. The motor spasms are frequently confused with other normal and abnormal infant behaviors. Typically, the interictal EEG reveals hypsarrhythmia or one of its variants. A variety of ictal EEG patterns may be seen, the most common of which is a generalized slow-wave transient followed by an attenuation of the background activity in all regions. The primary treatment objective is to improve the EEG and stop the spasms as soon as possible and to avoid prolonged treatment durations with any form of therapy. Currently, there is no conclusive evidence that medical or surgical treatment of infantile spasms significantly alters long-term outcome. Although the pathophysiological mechanism underlying infantile spasms is unknown, several animal models of infantile spasms have been developed in recent years.


Effects of adrenalectomy upon proceptivity, receptivity and sexual attractiveness in ovariectomized marmosets (Callithrix jacchus).
The sexual behaviour of seven pairs of marmosets was observed during blocks of 30 minute tests before and after the ovariectomized partners were bilaterally adrenalectomized. Adrenalectomized females were maintained by intramuscular injections of deoxycorticosterone pivalate (DC) and hydrocortisone hemisuccinate (HC). Twice daily injections of HC were required to maintain the high levels of plasma cortisol typical of marmosets and some other New World primates. Adrenalectomy had no significant effects upon proceptivity, receptivity or female sexual attractiveness. Increasing the replacement dose of DC had no effects upon sexual behaviour. Oestradiol treatment caused a marked increase in proceptivity (tongue-flicking, staring and immobile displays) and in receptive tongue-flicking behaviour. Males ejaculated more frequently during tests with oestradiol-treated partners. These results indicate that during "pair tests" adrenocortical sex steroids are not essential for maintenance of sexual behaviour in female marmosets and that activation of proceptivity by oestradiol 17 beta can occur in the absence of the adrenal glands.


Growth-promoting effect of oestriol in a lymphoma lacking oestrogen receptors.
Various doses (1 microgram to 10 mg) of oestriol (E3) were intraperitoneally injected into mice immediately after subcutaneous inoculation of an oestrogen receptor-negative lymphoma cell line (KE-5) established from a spontaneously developed AKR thymic lymphoma. The growth of KE-5 cells was markedly promoted by E3 at the early stage of tumour growth. At this stage, 1 microgram E3 enhanced tumour growth significantly and the maximum effect was obtained with 1 mg E3. Normal female mice showed a higher incidence and shorter latency than males. However, once tumours became palpable, the tumour growth rate appeared to be unaffected. Histological observations using Alcian blue and colloidal iron revealed a marked increase of hyaluronic acid in the subcutaneous connective tissue of the tumour-injection site within 3-5 days after intraperitoneal administration of 1 mg E3. Biochemical analyses showed a rapid and marked increase in skin hyaluronic acid content to over 3 times the control levels (0.25 +/- 0.10 mg g-1 skin) within 3 days of E3 administration. Subcutaneous inoculation of KE-5 cells together with hyaluronic acid (0.2 mg) resulted in markedly enhanced tumour growth, particularly at the early stage. These results suggest that an increase in stromal hyaluronic acid content is the most likely mechanism responsible for the promoting effect of E3 on KE-5 cells.


Biomimetic cellulose-based superabsorbent hydrogels for treating obesity.
In the treatment of obesity, nutritional and behavioral modifications are difficult to implement and maintain. Since vegetable consumption is a fundamental part of many dietary interventions and daily nutrient requirements, we developed a novel cellulose-based superabsorbent hydrogel (CB-SAH) platform, inspired by the composition and mechanical properties of raw vegetables, as a mechanobiological therapy. The CB-SAHs properties were studied in a simulated gastrointestinal environment, while their impact on gut tissue was investigated by an ex vivo organ culture (EVOC) model. Functional fibers and raw vegetables were used as reference. CB-SAHs demonstrated orders of magnitude higher elasticity in comparison to the tested functional fibers, however performed similar to the tested raw vegetables. Notably, the biomimetic CB-SAHs with elasticity levels similar to raw vegetables showed benefits in preserving and regulating the gut tissue in the EVOC model. Non-systemic oral mechanotherapeutics based on this technology were advanced through clinical studies, with a first product cleared as an aid for weight management in the US and Europe.


A case of non-pulmonary tuberculosis due to Mycobacterium africanum.
A case is reported of tuberculous osteitis of the ileum in an Asian woman who arrived in the United Kingdom from Uganda in 1970. The causative organism was M. africanum.


B lymphocyte activation in systemic lupus erythematosus: spontaneous production of IgG antibodies to DNA and environmental antigens in cultures of blood mononuclear cells.
IgG antibodies to DNA, influenza virus haemagglutinin (HA), adenovirus hexon (HX) and mannan from Candida albicans (MN) have been determined in supernatants from 2-day unstimulated cultures of peripheral blood mononuclear cells from SLE patients and controls. Mean values were much higher in the SLE group, with from 20% (MN) to 85% (DNA) of patients giving values above the normal range. Although a significant correlation was observed between anti-DNA and anti-HA production, anti-HX and anti-MN showed no such correlations. The specificity of the ELISA assays was demonstrated by inhibition tests. It is concluded that a selective form of polyclonal activation in SLE results in the production of antibodies to foreign as well as to self antigens.


Is it possible to achieve an acceptable disease control by dietary therapy alone in Berardinelli Seip type 1? Experience from a case report.
Severe metabolic complications generally manifest at an early age in Berardinelli - Seip congenital lipodystrophy (BSCL) and their management is especially challenging. Nutritional intervention with low lipid diets is considered by experts to be fundamental in treating the disease when associated with medical therapy, however little is known about the beneficial effects of dietary interventions alone. To underline the importance of a well-structured low-fat diet in BSCL patients. A BSCL male patient strictly followed a hypocaloric hypolipemic diet (60% carbohydrates, 22% fats and 18% proteins) since clinical diagnosis at the age of one year. Interestingly, pharmacological interventions were not required at any point during the follow-up. Aged 16 years the patient was referred to our center. Biochemistry, hormonal evaluation, 75 mg oral glucose tolerance test, cardiac evaluation and abdominal ultrasound were performed, revealing no abnormalities. Genetic analysis and leptin dosage were carried out, confirming the diagnosis of BSCL type 1 (homozygosity for c.493-1G>C pathogenic variant in AGPAT2 gene) and showing undetectable circulating levels of leptin (< 0.2 mcg/L). Diet therapy alone was therefore maintained, scheduling follow-up visits every six months, with acceptable disease control ever since. This report proves how a low-fat diet is of great help in the management of BSCL and its complications. In addition, a specific hypolipemic diet could be used alone as an effective treatment in selected cases with high compliance and, probably, a milder phenotype.


Neuroethical implications of focused ultrasound for neuropsychiatric illness.
MR-guided focused ultrasound is a promising intervention for treatment-resistant mental illness, and merits contextualized ethical exploration in relation to more extensive ethical literature regarding other psychosurgical and neuromodulation treatment options for this patient population. To our knowledge, this topic has not yet been explored in the published literature. The purpose of this paper is to review and discuss in detail the neuroethical implications of MR-guided focused ultrasound for neuropsychiatric illness as an emerging treatment modality. Due to the lack of published literature on the topic, the approach involved a detailed survey and review of technical and medical literature relevant to focused ultrasound and established ethical issues related to alternative treatment options for patients with treatment-resistant, severe and persistent mental illness. The manuscript is structured according to thematic and topical findings. This technology has potential benefits for patients suffering with severe mental illness, compared with established alternatives. The balance of technical, neuroscientific and clinical considerations should inform ethical deliberations. The nascent literature base, nuances in legal classification and permissibility depending upon jurisdiction, influences of past ethical issues associated with alternative treatments, tone and framing in media articles, and complexity of clinical trials all influence ethical assessment and evaluations of multiple stakeholders. Recommendations for future research are provided based on these factors. Salient ethical inquiry should be further explored by researchers, clinicians, and ethicists in a nuanced manner methodologically, one which is informed by past and present ethical issues related to alternative treatment options, broader psychiatric treatment frameworks, pragmatic implementation challenges, intercultural considerations, and patients' ethical concerns.


Mapping of bowel occult microscopic endometriosis implants surrounding deep endometriosis nodules infiltrating the bowel.
To provide a mapping of bowel occult microscopic endometriosis implants from colorectal specimens removed from patients who had undergone colorectal resection for deep endometriosis infiltrating the rectum. A series of consecutive patients with deep endometriosis infiltrating the rectum or/and sigmoid colon, between January 2013 and December 2013. University tertiary referral center. Twenty-six patients with deep endometriosis infiltrating the rectum or/and sigmoid colon. Surgical management by colorectal resection. Twenty-six patients with prospective recording of data (age, clinical history, symptoms, preoperative assessment, and intraoperative findings) underwent colorectal resection for bowel endometriosis. Mapping of occult microscopic endometriosis implants from specimens was established by histologic examination of 1,051 microsection slides taken from transversal macrosections of 3-mm thickness (40 microsections per patient on average). The mean (SD) length of colorectal specimens was 110 (42) mm. Microimplants were found at varying distances up to 54 mm from macronodule limits. Multiple macroscopic nodules were identified in five patients (19.2%). In 18 specimens (69%) diffusion of endometriosis microimplants was longitudinal, whereas in 8 specimens (31%) diffusion was concentrated around the macroscopic nodule. Respectively, 31%, 19%, 8%, and 4% of patients presented with endometriosis microimplants at 2, 3, 4, and 5 cm from macroscopic nodules. The present data suggest that in patients presenting with deep colorectal endometriosis, microscopically complete excision of rectal endometriosis may be unachievable because of bowel occult microscopic endometriosis implants located far from macroscopic nodules.


Anger in PTSD: is there a need for a concept of PTSD-related posttraumatic anger?
Despite extensive research on posttraumatic stress disorder (PTSD), anger in PTSD has received little attention. This is surprising, given anger is a key predictor of treatment outcome in PTSD. This paper seeks to build an argument for investigating anger in PTSD as a discrete entity. A key argument is that the capacity to image visual mental phenomena is crucial to the aetiology and maintenance of anger in PTSD. Evidence is reviewed for the influence of visual imagery in anger in PTSD from the perspectives of neuropsychology, psychopathology, anger and PTSD. An argument is advanced for including visual imagery in an integrated (visual-linguistic) cognitive model of anger in PTSD. Directions for research on visual imagery in anger in PTSD and its treatment implications are discussed.


Initial insights from a quality improvement initiative to develop an evidence-informed young adult substance use program.
High rates of substance misuse during emerging adulthood (~17-25 years of age, also referred to as young adulthood) require developmentally appropriate clinical programs. This article outlines: 1) the development of an evidence-informed young adult outpatient substance use program that takes a biopsychosocial patient-centred approach to care; 2) a quality improvement process and protocol; and 3) the patient characteristics of an initial cohort. Literature reviews, program reviews, environmental scans, and consultations with interested parties (including individuals with lived expertise) were used to develop the program. A 12-week measurement-based care program was developed comprising: 1) individual measurement-based care and motivational enhancement therapy sessions; 2) group programming focused on cognitive behavioural therapy, mindfulness, distress tolerance, and emotional regulation; 3) clinical consultations for diagnostic clarification and/or medication review; and 4) an independent Community Reinforcement Approach Family Training (CRAFT) group for loved ones. A measurement system was concurrently created to collect clinical and program evaluation data at six time points. In the first 21 months of the program, 152 young adults enrolled in the program (mean age = 21 years old, 47% female gender) primarily reporting treatment targets of cannabis (68%) and alcohol (63%) and almost all presenting with co-occurring mental health concerns (95%). The initial cohort who completed the program showed symptom improvements. Collectively, the program demonstrates the feasibility of developing an evidence-informed young adult substance use program using measurement-based care, but also the need for flexibility and ongoing monitoring to meet local needs.


Chronic treatment with vascular endothelial growth factor preserves agonist-evoked vascular responses in the streptozotocin-induced diabetic rat.
Vascular dysfunction is a hallmark of diabetes mellitus and endothelial dysfunction is considered to be a key early component of vascular dysfunction. Attenuated agonist-evoked responses are considered to be a barometer of endothelial/vascular dysfunction. We sought to determine whether vascular endothelial growth factor (VEGF) could prevent dysfunction from developing in the streptozotocin (STZ)-induced rat model of type 1 diabetes. One week after induction of diabetes, STZ rats began a 4-week treatment protocol of twice-weekly i.v. injections of 2 microg VEGF or inactivated VEGF. Corresponding non-diabetic rats served as controls. Agonist-evoked vascular responses were recorded 1 day after the last treatment in anaesthetised rats. Acetylcholine (0.1-12.5 microg/kg) evoked increases in superior mesenteric arterial conductance and decreases in mean blood pressure, while methoxamine (12.5-100 microg/kg) and endothelin-1 (100-1,200 pmol/kg) evoked decreases in superior mesenteric arterial conductance and increases in mean blood pressure. These responses to all three agonists were attenuated in STZ rats, and chronic treatment with VEGF improved these responses dramatically. Both the reduction in plasma nitrate and nitrite and the elevation in aortic superoxide associated with STZ diabetes were normalised with VEGF treatment. VEGF also prevented the apparent paradoxical increased endothelial nitric oxide synthase expression seen in untreated STZ rats. Chronic treatment with VEGF early in diabetes is able to prevent the attenuated agonist-evoked vascular responses in STZ rats and normalise the oxidative environment associated with the disease.


The neuropilin-1 receptor mediates enhanced tumor delivery of H2K polyplexes.
Promising plasmid-based treatments have limited value without an effective delivery system. Recently, the linear H2K with a repeating -KHHK- pattern was determined to be an effective plasmid carrier to tumor xenografts in vivo. Although unpacking of the H2K polyplex within the tumor may have a role, the mechanism for the enhanced efficacy remains unclear. After solid-phase synthesis of linear and branched histidine-lysine (HK) peptide carriers of plasmids, the peptides were compared for their ability to lyse endosomes with a red blood cell model and to transfect MDA-MB-435 xenografts in the presence or absence of neuropilin-1 receptor (NRP-1) antibodies. To examine stability, polyplexes were incubated with trypsin or NaCl and then analyzed by electrophoresis. After screening peptides with a model for endosomal lysis at two pHs, the 33-mer H3K peptide lysed red blood cells effectively at the lower pH. Combining H3K and H2K peptides as carriers of plasmids expressing luciferase were more effective than H2K alone. Based on the repeating -KHHK- sequences of H2K, we studied whether the widespread gene expression in the tumor may be mediated by NRP-1. By blocking NRP-1 in tumor-bearing mice, luciferase activity in tumors delivered by HK polyplexes was reduced by 96%, whereas activity in normal tissues was minimally reduced. Combining an endosomolytic peptide, H3K, with H2K polyplexes as a carrier further enhanced transfection in vivo. Moreover, the widespread distribution of H2K polyplexes is mediated by NRP-1, suggesting that transcytosis of these polyplexes through the tumor endothelium may lead to efficient transfection. Copyright © 2016 John Wiley & Sons, Ltd.


[Can the thick drop/smear examination for malaria be replaced by a rapid diagnostic test in first intention? The Mayotte experience].
Malaria is a public health problem in the French island of Mayotte (160,000 inhabitants) in the Indian Ocean. In the late 1990, resistance to chloroquine greatly increased, and so did the number of malaria cases, so that a new health policy had to be adopted. Since 2001, the initial smear/thick drop examination, the results of which took too long to obtain, has systematically been replaced by a rapid diagnosis test (Optimal IT Diamed) in all hospitals and public health centers. Epidemiological data of malaria on the island was collected and a prospective study was made from March 2005 to February 2006, on two sites (the emergency department of the main hospital and a rural health centre) on all patients presenting with malaria (104 and 139 cases respectively). The first Optimal IT test diagnosed the condition accurately in 88 and 96% of the cases, respectively. Every time symptoms would persist after negative test results and an Optimal IT test was repeated within three days, the parasitemia level was low (0.08 to 0.66%). Very low parasitemia level was very likely to account for a false negative (test result). These results concerning malaria (and its epidemiological data) in Mayotte show that the initial use of an Optimal IT test instead of the thin/thick blood smear results in a faster management of patients with malaria, although the Optimal IT test is slightly less sensitive and requires training/practice.


Heightened Anxiety and Depression Among Autistic Adolescents with ADHD: Findings From the National Survey of Children's Health 2016-2019.
Data from the National Survey of Children's Health 2016-2019 was used to examine the co-occurrence of autism and ADHD and the impact on anxiety and depression among adolescents age 12-17. Rates of anxiety and depression were up to ten-fold the prevalence of adolescents not diagnosed with autism or ADHD. Over half of autistic females (57%) and nearly half of autistic males (49%) are also diagnosed with ADHD. Autistic females with ADHD had the highest co-occurrence of anxiety at 72% followed by autistic males with ADHD at 69%. The prevalence of depression was highest among autistic adolescents with ADHD yet was consistent across genders (male/female) at 38-39%. Adolescents diagnosed with autism and/or ADHD are at heightened risk for anxiety and depression.


Resveratrol modulates autophagy and NF-κB activity in a murine model for treating non-alcoholic fatty liver disease.
In this study, we aimed to investigate the therapeutic effects and involved mechanisms of resveratrol on an established non-alcoholic fatty liver disease (NAFLD) murine model. Wild-type and autophagic mediator ULK1 heterozygous knockout mice were induced to have NAFLD by high-fat diet for 8weeks. After that, resveratrol treatment was applied with the high-fat diet feeding for another 4weeks. Typical features of NAFLD, including histological changes, fibrosis, insulin resistance, oxidative status, and inflammation were characterized. After-treatment with resveratrol showed ameliorative effects on all measured features of NAFLD, from histology, insulin resistance, glucose tolerance to oxidative stress and inflammation. resveratrol treatment also reduced the activity of nuclear factor-κB (NF-κB) through the restoration of its inhibitor IκBα. Partial inhibition of ULK1 expression impaired the ameliorative effects of resveratrol on hepatic histology, fibrosis, oxidative status, inflammation, and NF-κB activity. In conclusion, resveratrol improved NAFLD-caused hepatic injury partially through regulating autophagic and IκBα-NF-κB pathways.


Blood transfusions and Jehovah's Witnesses. The impact of the patient's unusual beliefs in critical care.
This article explains the belief of Jehovah's Witnesses regarding blood transfusions, and argues that a physician must ethically respect that belief.


Revalidation of Yphthimoides inornata (Hayward, 1962 (Lepidoptera: Nymphalidae: Satyrinae: Satyrini: Euptychiina) based on morphological and molecular data with description of the immature stages.
Yphthimoides inornata (Hayward, 1962) stat. rev., currently regarded as a nomen dubium and synonym of Yphthimoides yphthima (C. Felder R. Felder, 1867) has its status revalidated based on morphological characters and the DNA barcode. Images of the male and female, including their genitalia, information on the distribution, habitat, and immature stages are provided.


Facilitating family needs and support at the end of life in hospital: A descriptive study.
Caring for family members of dying patients is a vital component of end-of-life care, yet family members' needs at the end of life may be unmet. To explore hospital clinician assessment and facilitation of family needs and practices to support families at the end of life. Descriptive study utilising a retrospective medical record audit. Undertaken in a large public hospital, the sample included 200 deceased patients from four specialities; general medicine (n = 50), intensive care (n = 50), inpatient palliative care (n = 50) and aged rehabilitation (n = 50). Data were analysed according to age; under 65-years and 65-years or over. Deceased patients' mean age was 75-years, 60% were Christian and Next-of-Kin were documented in 96% of cases. 79% spoke English, yet interpreters were used in only 6% of cases. Formal family meetings were held in 64% of cases. An assessment of family needs was undertaken in 52% of cases, and more likely for those under 65-years (p = 0.027). Cultural/religious practices were supported/facilitated in only 6% of all cases. Specialist palliative care involvement was more likely for those aged 65-years or over (p = 0.040) and social work involvement more likely for those under 65-years (p = 0.002). Pastoral care and bereavement support was low across the whole sample. Prioritising family needs should be core to end-of-life care. Anticipation of death should trigger routine referral to support personnel/services to ensure practice is guided by family needs. More research is needed to evaluate how family needs assessment can inform end-of-life care, supported by policy.


QM/MM and SCRF studies of the ionization state of 8-methylpterin substrate bound to dihydrofolate reductase: existence of a low-barrier hydrogen bond.
Using combined semiempirical quantum mechanics and molecular mechanics (QM/MM) and ab initio self-consistent reaction field (SCRF) calculations, we determined that a low-barrier hydrogen bond (LBHB) is formed when the mechanism-based substrate 8-methylpterin binds to dihydrofolate reductase (DHFR). The substrate initially was assumed bound either in the ion-pair form corresponding to N3-protonated substrate hydrogen (H) bonded to the unprotonated (carboxylate) of the conserved Glu30 residue in the active site, or in the neutral-pair form corresponding to unprotonated substrate H bonded to the neutral (carboxylic acid) from of Glu30. The free energy of interaction of these H-bonded systems with the protein/solvent surroundings was computed using a coordinate-coupled free energy perturbation (FEP) method implemented within the molecular dynamics (MD) simulation scheme and using a semiempirical (PM3) QM/MM force field. The free energy obtained from the QM/MM force-field simulations corresponds most closely with the corresponding free energy component obtained from HF/6-31G* SCRF calculations using a value of 2 for the dielectric constant (epsilon) for the solvated protein. Calculations were performed at levels ranging from HF/6-31G to MP2/6-31G* to B3LYP/6-31 + G**, with varying dielectric constants. The energy-minimized path for motion of the proton in the H bond along a one-dimensional reaction coordinate was calculated at HF/6-31G, HF/6-31G* (epsilon = 1) and B3LYP/6-31G* (epsilon = 2) levels. These calculations identified a second neutral-pair complex, involving the 2-amino group of substrate, which also interacts with Glu30, which is lower in energy than the ion-pair form. A harmonic vibrational analysis shows that the first vibrational state appears to lie near or above the TS connecting potential energy minima corresponding to the two neutral-pair configurations, thus indicating an LBHB. Consequently, the H-bonded system will have a significant probability of being found in the ion-pair form, in agreement with experimental spectral studies indicating an enzyme-bound cation and suggesting that the LBHB would activate substrate towards hydride-ion transfer from NADPH.


Comparison of thin-layer chromatographic detection methods for histamine from food extracts.
The specificity and sensitivity of four visualization reagents, ninhydrin, o-phthalaldehyde (OPT), fluorescamine and o-diacetylbenzene (DAB), for the detection of histamine on thin-layer chromatograms developed in several optimal solvent systems were compared. While the ninhydrin reagent is the most sensitive with a detection limit of 0.4 nmoles of histamine, the DAB and fluorescamine reagents offer the most potential as histamine-specific visualization reagents. The OPT reagent was unsatisfactory because the fluorescent sports developed with this reagent were unstable. Of 19 amines tested in addition to histamine, ninhydrine reacted with 17, fluorescamine with 8 and DAB with 15. Since only histidyl-leucine, octopamine, serotonin and tryptophan interfere in the resolution of histamine in any of the solvent systems used, DAB provides some advantages by not reacting with histidyl-leucine. In addition, with the acetone-ammonia (95:5) solvent system, which adequately separates histamine from all other tested amines, no background interference problems were noted when using DAB as the visualization reagent. Background interference problems with the acetone-ammonia system were evident with the other visualization reagents. The sensitivity of the DAB and fluorescamine methods (4 nmoles of histamine) allows both reagents to act as semi-quantitative screening agents for potentially toxic levels of histamine in food extracts. With a variety of food samples, DAB visualization following development in acetone-ammonia (95:5) was the optimal thin-layer chromatographic method.


Effect of pulse laser frequency on PLD growth of LuFeO3 explained by kinetic simulations of in-situ diffracted intensities.
Atomistic processes during pulsed-laser deposition (PLD) growth influence the physical properties of the resulting films. We investigated the PLD of epitaxial layers of hexagonal LuFeO[Formula: see text] by measuring the X-ray diffraction intensity in the quasiforbidden reflection 0003 in situ during deposition. From measured X-ray diffraction intensities we determined coverages of each layer and studied their time evolution which is described by scaling exponent [Formula: see text] directly connected to the surface roughness. Subsequently we modelled the growth using kinetic Monte Carlo simulations. While the experimentally obtained scaling exponent [Formula: see text] decreases with the laser frequency, the simulations provided the opposite behaviour. We demonstrate that the increase of the surface temperature caused by impinging ablated particles satisfactorily explains the recorded decrease in the scaling exponent with the laser frequency. This phenomena is often overlooked during the PLD growth.


[Not Available].
In addition to roasted pistachios other products, e.g. pastes for the production of ice-cream, were analyzed at CVUA Sigmaringen. A relative high contamination was found in some cases.


AZT side effect on mitochondria does not depend on either inhibition of electron flow or mitochondrial uncoupling.
The mitochondrial myopathy associated with long-term AZT therapy limits the clinical efficacy of this drug in AIDS therapy. Thus, in order to determine how AZT can affect mitochondria bioenergetics, the capability of AZT to both uncouple oxidative phosphorylation and inhibit electron flow in isolated rat liver mitochondria was investigated. The failure of AZT to oxidize intramitochondrial pyridine nucleotides, to stimulate mitochondrial swelling in K+-acetate plus valinomycin or to cause ATP hydrolysis shows that AZT is not an uncoupler.


Evaluation of CBCT based dose calculation in the thorax and pelvis using two generic algorithms.
This work examines the dosimetric performance of two algorithms creating a corrected CBCT (corrCBCT) and a virtual CT (vCT) implemented in a commercial treatment planning system. 60 patients distributed across all patient groups treated with curative intent at Vejle Hospital (breast, lung, prostate and anal/rectal cancer) were selected for the present study. Clinical treatment plans were recalculated on corrCBCT and vCT, as well as a reference CT (refCT) acquired as close in time to the CBCT image as possible. Recalculated doses were compared using gamma analysis, as well as by comparing D98%, D50%, and D2% for all delineated targets and organs at risk. High dosimetric accuracy is demonstrated on both the corrCBCT and vCT. Gamma 2%/2mm pass rates >98% were found for all patients except two outliers still having >93% pass rates. Equivalence of all evaluated dose metrics within ±1Gy was observed for all patient groups, while the pelvic patients additionally showed equivalence for all metrics within ±1% of the refCT dose. For the thoracic patients, equivalence within ±2.5% was established for all metrics except median dose to the ipsilateral lung, calculated on corrCBCT for the breast patient group. The corrCBCT and vCT images are shown in excellent dosimetric agreement with refCT images, and show high potential for future use for streamlined adaptive radiotherapy workflows.


Effects of pulsatile assistance and nonpulsatile flow on subendocardial perfusion during cardiopulmonary bypass.
We compared the effects of pulsatile and nonpulsatile perfusion in 12 dogs on extracorporeal circulation. In beating empty and fibrillating hearts at 37 degrees and 28 degrees C, coronary blood flow was measured by flowmeter and microspheres at diastolic pressures ranging between 50 and 130 mm Hg. At fixed systemic flow rates (range, 600 to 2,400 ml/min), pulsatile perfusion produced a transient (3 to 4 second) augmentation of diastolic pressure and then resulted in the following: (1) decreased peripheral vascular resistance (p less than 0.05); (2) unchanged peak diastolic pressure (compared with nonpulsatile perfusion); (3) decreased mean aortic pressure (6 to 37%) (p less than 0.05); (4) decreased coronary blood flow (10 to 45%) (p less than 0.05); and (5) decreased subendocardial blood flow (from 512 to 438 ml/100 gm/min) (p less than 0.05). Pulsatile perfusion in beating hearts (37 degrees or 28 degrees C) did not reduce subendocardial vascular resistance, but did improve subendocardial perfusion by 27% and 36% in fibrillating hearts at 37 degrees and 28 degrees C, respectively. We conclude that with the exception of ventricular fibrillation, pulsatile assistance offers no advantage over nonpulsatile perfusion and has the potential disadvantage of requiring higher pump flow rates to achieve any desired level of coronary and subendocardial flow.


Impaired Neurocognitive Performance in Children after Liver Transplantation.
To assess longitudinal neurocognitive development after liver transplantation and evaluate factors associated with neurocognitive performance. Data from neurocognitive testing of 65 children (aged <18 years) who underwent liver transplantation at Oslo University Hospital between 1995 and 2018 were collected from the testing program after transplantation. The parent-reported version of the Behavior Rating Inventory of Executive Function was used to assess executive function. A total of 104 neurocognitive tests were conducted on 65 patients. At the first test, conducted at a median of 4.1 years (IQR, 1.5-5.3 years) after transplantation and at a median age of 6.7 years (IQR, 5.4-10.5 years), the mean full-scale IQ (FSIQ) was 91.7 ± 14, and the mean verbal comprehension index was 92.0 ± 14.5. In the 30 patients tested more than once, there was no significant difference in FSIQ between the first test at a median age of 5.8 years (IQR, 5.2-8.5 years) and the last test at a median age of 10.8 years (IQR, 9.8-12.9 years) (87.4 ± 12.9 vs 88.5 ± 13.2; P = .58). Compared with the patients who underwent transplantation a age >1 year (n = 35), those who did so at age <1 year (n = 30) had a lower FSIQ (87.1 ± 12.6 vs 96.6 ± 13.8; P = .005) and lower verbal comprehension index (87.3 ± 13.8 vs 95.4 ± 13.0; P = .020). Age at transplantation (P = .005; adjusted for cholestasis: P = .038) and transfusion of >80 mL/kg (P = .004; adjusted for age at transplantation: P = .046) were associated with FSIQ. Young age at transplantation and large blood transfusions during transplantation are risk factors for poor neurocognitive performance later in life. Children who undergo transplantation before 1 year of age have significantly lower neurocognitive performance compared with those who do so later in childhood. Cognitive performance did not improve over time after transplantation.


Combined cone-beam CT imaging and microsurgical dissection of cadaver specimens to study cerebral venous anatomy: a technical note.
Cadaver dissections and X-ray based 3D angiography are considered gold standards for studying neurovascular anatomy. We sought to develop a model that utilize the combination of both these techniques to improve current tools for anatomical research, teaching and preoperative surgical planning, particularly addressing the venous system of the brain. Seven ethanol-fixed human cadaveric heads and one arm were injected with a latex-barium mixture into the internal jugular veins and the brachial artery. After the ethanol-based fixation, specimens were scanned by high-resolution cone-beam CT and images were post-processed on a 3D-workstation. Subsequent, microsurgical dissections were performed by an experienced neurosurgeon and venous anatomy was compared with relevant 3D venograms. Latex-barium mixtures resulted in a homogenous cast with filling of the cerebral venous structures down to 150 μm in diameter. The ethanol-based preparation of the cadaveric brains allowed for near-realistic microsurgical maneuverability during dissection. The model improves assessment of the venous system for anatomical education and hands-on surgical training. To our knowledge we describe the first preparation method which combines near-realistic microsurgical dissection of human heads with high-resolution 3D imaging of the cerebral venous system in the same specimens.


Snapshot summary of diagnosis and management of hepatocellular adenoma subtypes.
Hepatocellular adenomas (HCA) are rare benign hepatocellular tumors occurring mainly in women taking oral contraceptives with 2 major complications: severe bleeding and malignant transformation that can be avoided if nodules exceeding 5 cm are resected. This simple attitude has been challenged in the recent years with HCA in men, in young adolescent, in aged persons, and complications in hepatocellular adenomas below 5 cm. The discovery of specific mutations leading to specific phenotypes has modified the clinical spectrum of the disease. The phenotypic immune classification of HCA based on the molecular classification is being widely used in liver referral centers. The aim of this snapshot is to briefly present for each subtype the clinical, pathological, immuno-pathological criteria as well as the risk of complications and guidelines for treatment and management.


Immunotherapy of DC-CIK cells enhances the efficacy of chemotherapy for solid cancer: a meta-analysis of randomized controlled trials in Chinese patients.
Professional antigen-presenting dendritic cells (DCs) and cytokine-induced killer (CIK) cells, components of anti-cancer therapy, have shown clinical benefits and potential to overcome chemotherapeutic resistance. To evaluate whether DC-CIK cell-based therapy improves the clinical efficacy of chemotherapy, we reviewed the literature on DC-CIK cells and meta-analyzed randomized controlled trials (RCTs). We searched several databases and selected studies using predefined criteria. RCTs that applied chemotherapy with and without DC-CIK cells separately in two groups were included. Odds ratio (OR) and mean difference (MD) were reported to measure the pooled effect. Twelve reported RCTs (826 patients), which were all performed on Chinese patients, were included. Combination therapy exhibited better data than chemotherapy: 1-year overall survival (OS) (OR=0.22, P<0.01), 2-year OS (OR=0.28, P<0.01), 3-year OS (OR=0.41, P<0.01), 1-year disease-free survival (DFS) (OR=0.16, P<0.05), 3-year DFS (OR=0.32, P<0.01), objective response rate (ORR) (OR=0.54, P<0.01), and disease control rate (DCR) (OR=0.46, P<0.01). Moreover, the levels of CD3(+) T-lymphocytes (MD=-11.65, P<0.05) and CD4(+) T-lymphocytes (MD=-8.18, P<0.01) of the combination group were higher. Immunotherapy of DC-CIK cells may enhance the efficacy of chemotherapy on solid cancer and induces no specific side effect. Further RCTs with no publishing bias should be designed to confirm the immunotherapeutic effects of DC-CIK cells.


Neuropsychological follow-up of patients operated for aneurysms of the middle cerebral artery and posterior communicating artery.
This study assessed with a neuropsychological battery the outcome of 27 patients operated on for an aneurysm of the Middle Cerebral Artery a mean of 35 months before, and of 27 patients operated for aneurysms of the Posterior Communicating Artery, a mean of 47 months before. Both groups showed a defective pattern of performance that was related to the hemispheric side of the aneurysm with left-sided patients impaired on naming, verbal fluency and verbal short-term memory and right sided patients on both short-term and long-term spatial memory and discrimination of line orientation. In single cases, the scope of neuropsychological impairment was sometimes wider than that expected only on the basis of the competence of the affected hemisphere.


A lifeworld phenomenological study of the experience of falling ill with diabetes.
The aim of the study was to develop knowledge from a patient perspective about falling ill with diabetes. The focus on the process of falling ill process is useful to increase the understanding of this patient group and thus these patients could be met in a way that better lessens their suffering and better facilitates their adaptation to the illness and the new life situation. The study has been carried out within caring science and a lifeworld phenomenological approach. The data were composed by written narratives, which were analyzed for meaning. Seven persons with newly discovered diabetes at two hospitals in the south of Sweden have participated in the study. The result shows that the essential meaning of falling ill with diabetes is a fight not to become one's illness, that everything is to remain as usual and that the new situation will become the natural one. To fall ill with diabetes means to be involved in a course of events charged with emotional diversity. An initial feeling of bodily imbalance can be denied or given a natural explanation, but gives rise to a suspicion that something is wrong. When the bodily imbalance is verified as diabetes, it can be acknowledged and eventually accepted, but the acceptance is possibly an illusory or false reconciliation to be able to go on. There is anyway no choice, if they want to feel well they have to be "adaptable" to their illness, which makes demands that have to be reconciled; demands that must not be allowed to "govern" their lives. Despite being diagnosed with diabetes they still want to continue the same life and be the same persons as before-although they now carry a disease. The result of the study indicates that more caring focus needs to be directed to the process of falling ill. More efforts are needed to prevent the ill persons from becoming their illness.


Prophylaxis of venous thromboembolism.
The objective of prophylaxis in venous thromboembolism is, first, to prevent fatal pulmonary embolism and, second, to reduce the morbidity associated with deep vein thrombosis (DVT) and the postphlebitic limb. This should now be standard practice for most patients over 40 years of age undergoing major surgery and for younger patients with a history of venous thromboembolism. Particularly high-risk groups include patients over 60 years of age undergoing major surgery, those with malignancy, and those requiring hip operations. Low-dose subcutaneous heparin 5,000 IU commencing 2 hours preoperatively and continuing 12 hourly until the patient is fully mobile is unequivocally effective in preventing DVT in medical and surgical patients and, most importantly, significantly reduces the incidence of fatal postoperative pulmonary embolism and total mortality. Such prophylaxis, in the presence of established DVT, also limits proximal clot propagation, which is the precursor of major pulmonary embolism. Low-dose heparin prophylaxis is associated with a small risk of bleeding complications, evidenced mostly by an increased frequency of wound hematoma rather than major clinical hemorrhage. Low molecular weight heparin fragments (e.g., Fragmin, Choay, Enoxaparine) are emerging as useful alternative agents, having the advantage of once daily administration and yet providing similar efficacy in the prevention of DVT. Mechanical methods of prevention which counteract venous stasis, such as graduated elastic compression stockings, are also useful in protecting against DVT but have not been shown to prevent fatal postoperative pulmonary embolism. They are recommended particularly for patients in whom heparin prophylaxis is best avoided (e.g., neurosurgery) and possibly in combination with heparin in very high-risk patients.


Differential Effects of Pharmacologic and Genetic Modulation of NMDA Receptor Activity on HIV/gp120-Induced Neuronal Damage in an In Vivo Mouse Model.
HIV-associated neurocognitive disorder (HAND) consists of motor and cognitive dysfunction in a relatively large percentage of patients with AIDS. Prior work has suggested that at least part of the neuronal and synaptic damage observed in HAND may occur due to excessive stimulation of NMDA-type glutamate receptors (NMDARs). Here, we compared pharmacological and genetic manipulation of NMDAR activity using an improved derivative of the NMDAR antagonist memantine, termed NitroMemantine, and the modulatory NMDAR subunit GluN3A in the HIV/gp120 transgenic (tg) mouse model of HAND. Interestingly, we found that while both NitroMemantine and GluN3A have been shown to inhibit NMDAR activity, NitroMemantine protected synapses in gp120-tg mice, but overexpression of GluN3A augmented the damage. Given recent findings in the field, one explanation for this apparently paradoxical result is the location of the NMDARs primarily affected, with NitroMemantine inhibiting predominantly extrasynaptic pathologically activated NMDARs, but GluN3A disrupting normal NMDAR-mediated neuroprotective activity via inhibition of synaptic NMDARs.


On a non-Markov neuronal model and its approximations.
Single neuron's activity modeling is considered with reference to some earlier contributions in which a non-Markov Gaussian process is assumed to describe the time course of the neuron's membrane potential. After re-formulating the problem in a rigorous framework and pinpointing the limits of validity of such a model, the available results on the firing probability density are compared with those obtained by us by means of an ad hoc numerical algorithm implemented for the leaky integrator diffusion firing model and with some data constructed by a simulation procedure of non-Markov Gaussian processes with pre-assigned covariances. Throughout this paper, the notion of 'correlation time' plays a fundamental role for the neuronal coding process modeling.


[Acute disseminated encephalomyelitis: epidemiological, clinical, and outcome analysis in 16 patients].
Acute disseminated encephalomyelitis (ADEM) is a rare paediatric disease of autoimmune origin. The aim of this study is to estimate its impact in our area over the past 10 years and to analyse the clinical, laboratory and radiological presentation, as well as study the response to treatment and outcome. A retrospective analysis of cases diagnosed with current ADEM criteria. The age and month of the year at onset, sex, family history of demyelination, initial symptoms, disease or previous vaccination, CSF features, serology, PCR for herpes virus group in blood and CSF, oligoclonal bands in CSF, EEG and neuroimaging features of the skull by MRI, the type of treatment received and the response were recorded on each of the patients diagnosed. There were 16 patients, with a mean age of 5.6 years. Male/female: 11/5, with a dominant debut in the colder months of the year, predominantly gait disorder, changes in consciousness and seizures. The radiology by MRI showed a predominance of multiple lesions in the same T2 stage, in deep white matter and lesions in deep grey matter. There were no in blood parameters and the CSF was normal in half of the cases. The origin was determined in 7 cases. The annual incidence in children under 14 years was estimated at 0.64/100,000. The clinical and radiological findings were the basis of diagnosis. The human herpes virus 6 was involved in 4 cases. Most patients recovered completely.


The effect of the water soluble fraction of crude oil on survival, physiology and behaviour of Caspian roach, Rutilus caspicus (Yakovlev, 1870).
The water soluble fraction (WSF) of crude oil is a complex and toxic mixture of hydrocarbons that aquatic organisms directly encounter in oil spills. WSF plays an important role in the toxicity of crude oil to aquatic organisms. In the present study, the effects of WSF on juvenile Caspian roach, Rutilus caspicus, at lethal and sub-lethal level was investigated. The lethality of WSF on R. caspicus was studied by conducting 96h LC50 tests with semi-static exposure methods with 6 and 24h solution renewals. The 96h LC50 of WSF was estimated at 62.5% and 35.9% WSF concentrations for 24h and 6h renewal methods, respectively. To investigate the sub-lethal effect of WSF on R. caspicus, fish were exposed to 62.5, 31.3, and 6.3% concentrations of WSF for 24h and changes in their respiration rate and swimming activity was monitored during the exposure. At the end of the exposure period, four hematologic parameters [O2 and CO2 pressures (pO2 and pCO2), hematocrit, and hemoglobin content] of the fish were measured. The result of the behavioural experiment revealed that all three studied concentrations of WSF elevated the respiration rate and reduced the swimming activity of R. caspicus. No significant changes were detected in the hematocrit and hemoglobin content of the fish blood, but the blood pO2 of the fish exposed to 62.5% WSF decreased while the blood pCO2 increased. The results of this study suggest that the egression of the volatile components in hydrocarbon mixtures during conventional semi-static toxicity tests may lead to underestimating the toxicity of the hydrocarbons. The results of the sub-lethal experiments propose that failure of the respiratory system that leads to asphyxia may be a major mechanism that results in lethal effect of WSF in high concentrations.


Femtomolar detection of staphylococcal enterotoxin 'B' using a fluorescent quantum dot based hybrid Apta-immunosensor.
Food poisoning is a gastrointestinal illness caused by food-borne enterotoxin produced by the bacterium Staphylococcus aureus. The effective dose of Staphylococcal enterotoxin 'B' (SEB) is estimated to be 0.4 ng/kg of body weight, whereas the 50 % lethal dose is found to be 20 ng/kg of body weight for humans exposed by the inhalation route. The present report highlights the development of a fluorescence resonance energy transfer (FRET) based assay for the detection of Staphylococcal enterotoxin. Highly fluorescent, aqueous quantum dots were synthesized and conjugated with Staphylococcal enterotoxin 'B' specific bioreceptors. SEB specific aptamer and SEB antibody were labeled with fluorescent quantum dots for recognizing and binding two separate epitopes in the SEB. A combination of two probes against different epitopic regions in a homogeneous sandwich assay format enhanced the sensitivity and specificity of SEB detection. In the presence of the enterotoxin, both the aptamer and antibody came in close proximity with each other and FRET was observed. A linear decrease in the fluorescence at 562 nm and a corresponding increase in the signal at 644 nm was observed with increasing concentrations of SEB, when excited at the absorption maximum of quantum dots. The limit of detection for the developed assay obtained was less than 1 ng/ml. The method was employed in apple juice and quantitated using Enzyme-linked Immunosorbent Assay (ELISA). The designed assay was rapid and robust and can be extrapolated as a platform for the detection of various disease-causing agents of biomedical significance.


The association between the interaction of migration background and physical activity with loneliness in middle-aged and older adults living in Germany.
Reduced physical activity and having a migration background are both associated with higher loneliness; however, the moderating role of migration background in the association between loneliness and physical activity remains largely unknown. We used cross-sectional data from the sixth wave (year 2017) of the German Ageing Survey (DEAS). Loneliness was measured using the De Jong Gierveld tool and physical activity was dichotomised into either of the following (i.e., at least 150 min of moderate physical activity per week) or not following physical activity recommendations of the World Health Organization (WHO). For evaluation of the associations we applied adjusted linear regression models with robust standard errors. We included 6257 (average age = 67 years, 50% female) and 285 (average age = 63 years, 51% female) participants without and with migration background, respectively. In multiple linear regressions both migration background (ß = 0.13, P = 0.001), as well as not following the WHO physical activity recommendations (ß = 0.06, P < 0.001) were associated with increased loneliness. Moreover, the respective interaction term reached statistical significance (ß = -0.27, P = 0.013). Participants with migration background have a more pronounced association between following the WHO physical activity recommendations and reduced loneliness compared to participants without migration background. Among middle-aged and older individuals, those with migration background benefit to a larger extent from following physical activity recommendations than the population without migration background regarding loneliness. Thus, motivating individuals with migration background to follow the WHO physical activity guidelines could particularly assist in reducing loneliness.


Depositional history and inventories of polychlorinated biphenyls (PCBs) in sediment cores from an Antarctic Specially Managed Area (Admiralty Bay, King George Island).
Temporal patterns, fluxes and inventories of polychlorinated biphenyls (PCBs) were assessed in nine sediment cores collected from selected areas of Admiralty Bay off the Antarctic Peninsula. Concentrations of total PCBs were low, but slightly higher in comparison to low-impacted, remote environments in the world, ranging from below the detection limit to 11.9ngg-1 in dry weight. PCB concentrations and inventories suggest a possible minor influence related to the nearby logistic activities, especially in the sediment core collected close to the Ferraz Station. Despite being the most remote and protected area on the planet, the Antarctic continent is no longer a pristine environment.


Gender differences in active musculoskeletal stiffness. Part II. Quantification of leg stiffness during functional hopping tasks.
Leg stiffness was compared between age-matched males and females during hopping at preferred and controlled frequencies. Stiffness was defined as the linear regression slope between the vertical center of mass (COM) displacement and ground-reaction forces recorded from a force plate during the stance phase of the hopping task. Results demonstrate that subjects modulated the vertical displacement of the COM during ground contact in relation to the square of hopping frequency. This supports the accuracy of the spring-mass oscillator as a representative model of hopping. It also maintained peak vertical ground-reaction load at approximately three times body weight. Leg stiffness values in males (33.9+/-8.7 kN/m) were significantly (p<0.01) greater than in females (26.3+/-6.5 kN/m) at each of three hopping frequencies, 3.0, 2.5 Hz, and a preferred hopping rate. In the spring-mass oscillator model leg stiffness and body mass are related to the frequency of motion. Thus male subjects necessarily recruited greater leg stiffness to drive their heavier body mass at the same frequency as the lighter female subjects during the controlled frequency trials. However, in the preferred hopping condition the stiffness was not constrained by the task because frequency was self-selected. Nonetheless, both male and female subjects hopped at statistically similar preferred frequencies (2.34+/-0.22 Hz), therefore, the females continued to demonstrate less leg stiffness. Recognizing the active muscle stiffness contributes to biomechanical stability as well as leg stiffness, these results may provide insight into the gender bias in risk of musculoskeletal knee injury.


A highly concentrated diet increases biogas production and the agronomic value of young bull's manure.
The increasing demand for animal protein has driven significant changes in cattle breeding systems, mainly in feedlots, with the use of young bulls fed on diets richer in concentrate (C) than in forage (F). These changes are likely to affect animal manure, demanding re-evaluation of the biogas production per kg of TS and VS added, as well as of its agronomic value as a biofertilizer, after anaerobic digestion. Here, we determined the biogas production and agronomic value (i.e., the macronutrient concentration in the final biofertilizer) of the manure of young bulls fed on diets with more (80% C+20% F; 'HighC' diet) or less (65% C+35% F; 'LowC' diet) concentrate, evaluating the effects of temperature (25, 35, and 40°C) and the use of an inoculum, during anaerobic digestion. A total of 24 benchtop reactors were used, operating in a semi-continuous system, with a 40-day hydraulic retention time (HRT). The manure from animals given the HighC diet had the greatest potential for biogas production, when digested with the use of an inoculum and at 35 or 40°C (0.6326 and 0.6207m(3)biogas/kg volatile solids, or VS, respectively). We observed the highest levels of the macronutrients N, P, and K in the biofertilizer from the manure of animals given HighC. Our results show that the manure of young bulls achieves its highest potential for biogas production and agronomic value when animals are fed diets richer in concentrate, and that biogas production increases if digestion is performed at higher temperatures, and with the use of an inoculum.


Impact of renal function on eligibility for chemotherapy and survival in patients who have undergone radical nephro-ureterectomy.
What's known on the subject? and what does the study add?: Radical nephroureterectomy (RNU), the standard of care treatment for high-risk urothelial carcinoma of the upper tract (UTUC), results in loss of a renal unit. Loss of renal function decreases eligibility for systemic chemotherapies and results in decreased overall survival in various malignancies. The study shows that only a small proportion of patients had a preoperative renal function that would allow cisplatin-based chemotherapy. Moreover, eGFR significantly decreased after RNU, thereby lowering the rate of cisplatin eligibility to only 16 and 52% of patients based on the thresholds of 60 and 45 mL/min/1.73 m(2) , respectively. Taken together with the rest of the literature, the findings of the study support the use of cisplatin-based chemotherapy, when indicated, in the neoadjuvant rather than adjuvant setting. To report (i) the estimated glomerular filtration rate (eGFR) changes in patients undergoing radical nephro-ureterectomy (RNU) for upper tract urothelial carcinoma (UTUC); (ii) the rate of change in eGFR in patients eligible for cisplatin-based chemotherapy; and (iii) the association of preoperative, postoperative and rate of change of renal function variables with survival outcomes. We performed a retrospective analysis of 666 patients treated with RNU for UTUC at seven international institutions from 1994 to 2007. The eGFR was calculated at baseline and at 3-6 months (Modification of Diet in Renal Disease formula (MDRD) and Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EP) equations). The median (interquartile range) eGFR decreased by 18.2 (8-12)% after RNU. A total of 37% of patients had a preoperative eGFR ≥ 60 mL/min/1.73 m(2) , which decreased to 16% after RNU (P < 0.001); 72% of patients had a preoperative eGFR ≥ 45 mL/min/1.73 m(2) , which decreased to 52% after RNU (P < 0.001). The distributions were similar when analyses were restricted to patients with locally advanced disease (pT3-pT4) and/or lymph node metastasis. Patients older than the median age of 70 years were more likely to have a decrease in eGFR after RNU (P < 0.001). None of the renal function variables was associated with clinical outcomes such as disease recurrence, cancer-specific and overall mortality; however, when analyses were restricted to patients who had no adjuvant chemotherapy and did not experience disease recurrence (n = 431), a preoperative eGFR ≥ 60 mL/min/1.73 m(2) (P = 0.03) and a postoperative eGFR ≥ 45 mL/min/1.73 m(2) (P = 0.04) were associated with better overall survival in univariable analyses. In patients who had UTUC, eGFR was low and furthermore, it significantly decreased after RNU. Renal function did not affect cancer-specific outcomes after RNU.


Intramolecular singlet-singlet energy transfer in antenna-substituted azoalkanes.
Two novel azoalkane bichromophores and related model compounds have been synthesised and photophysically characterised. Dimethylphenylsiloxy (DPSO) or dimethylnaphthylsiloxy (DNSO) serve as aromatic donor groups (antenna) and the azoalkane 2,3-diazabicyclo[2.2.2]oct-2-ene (DBO) as the acceptor. The UV spectral window of DBO (250-300 nm) allows selective excitation of the donor. Intramolecular singlet-singlet energy transfer to DBO is highly efficient and proceeds with quantum yields of 0.76 with DPSO and 0.99 with DNSO. The photophysical and spectral properties of the bichromophoric systems suggest that energy transfer occurs through diffusional approach of the donor and acceptor within a van der Waals contact at which the exchange mechanism is presumed to dominate. Furthermore, akin to the behaviour of electron-transfer systems in the Marcus inverted region, a rate of energy transfer 2.5 times slower was observed for the system with the more favourable energetics, i.e. singlet-singlet energy transfer from DPSO proceeded slower than from DNSO, although the process is more exergonic for DPSO (-142 kJ mol(-1) for DPSO versus-67 kJ mol(-1) for DNSO).


[Prevention of ischemic heart disease: a feasibility study of health education in the primary school].
To verify the level of participation of children and teachers in an educational program, the reliability of the program itself and to determine whether children can modify family's behavioral patterns, a feasibility study was undertaken among the pupils of a primary school. Seventy-two children, belonging to different socio-economic classes, were studied. Children were given a questionnaire before and after the course, which was held by previously trained teachers. Very good participation of children and teachers in the program was observed. On the contrary very low involvement of the parents was achieved. This experience emphasizes the difficulties arising when actions to modify adult's life styles are attempted. On the contrary, a standardized education program, lasting for a whole school year, could be a feasible, useful and not too costly program not only for the primary prevention of coronary artery disease, but for any program of extensive health care.


Application of Fourier transform mid-infrared photoacoustic spectroscopy for rapid assessment of phosphorus availability in digestates and digestate-amended soils.
Digestate is the anaerobic digestion by-product of biogas production that can be used as a phosphorus (P) fertilizer. To achieve the efficient utilization of digestate as a P fertilizer and evaluate P availability in digestate-amended soils, it is necessary to assess both available P in different digestates and digestate-amended soils. In this study, Fourier transform mid-infrared photoacoustic spectroscopy (FTIR-PAS) combined with multivariate analysis was applied to predict water-extractable P (WEP) in digestates and plant-available P in digestate-amended soils. The plant-available P was determined by the diffusive gradients in thin films (DGT) technique. 45 digestate samples were collected both from laboratory-scale digesters (26 samples) and operating biogas plants (19 samples) in Denmark for WEP determination. Three soils amended with the collected 19 digestate samples from biogas plants (that results to 57 digestate-amended soil samples in total) were deployed for DGT measurement of plant- available P. The WEP predicting model had a coefficient of determination (R2) of 0.80 and a root mean square error of 0.78 g kg-1 while the plant-available P predicting model exhibited an R2 of 0.70 and a root mean square error of 134.09 μg P L-1. Furthermore, regression coefficients with a significant contribution of the plant-available P predicting model were identified, indicating that FTIR-PAS is capable for correlating spectra information with plant-available P related chemical bonds. In conclusion, FTIR-PAS can be used as a faster and non-destructive alternative for the assessment of both WEP in digestates and plant-available P in digestate-amended soils.


IL-17A is implicated in lipopolysaccharide-induced neuroinflammation and cognitive impairment in aged rats via microglial activation.
Neuroinflammation is considered a risk factor for impairments in neuronal function and cognition that arise with trauma, infection, and/or disease. IL-17A has been determined to be involved in neurodegenerative diseases such as multiple sclerosis. Recently, IL-17A has been shown to be upregulated in lipopolysaccharide(LPS)-induced systemic inflammation. This study aims to explore the role of IL-17A in LPS-induced neuroinflammation and cognitive impairment. Male Sprague-Dawley (SD) rats were injected intraperitoneally with LPS (500 μg/kg), and IL-17A expression in serum and in the hippocampus was examined 6, 12, 24, and 48 h later. Then, we investigated whether IL-17A-neutralizing antibodies (IL-17A Abs, 1 mg/kg) prevented neuroinflammation and memory dysfunction in aged rats that received LPS (500 μg/kg) injection. In addition, the effect of IL-17A on microglial activation in vitro was determined using ELISA and immunofluorescence. LPS injection increased the expression of IL-17A in serum and in the hippocampus. IL-17A Abs improved LPS-induced memory impairment. In addition, IL-17A Abs prevented the LPS-induced expression of TNF-α, IL-6 and inflammatory proteins, and of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as the activation of microglia in the brain. IL-17A Abs also inhibited the expression of amyloid precursor protein (APP) and BACE1 and increased the expression of the synaptic marker PSD95 in the aged rats treated with LPS. In an in vitro study, we found that recombinant IL-17A could simulate microglial activation and increase production of pro-inflammatory cytokines. Taken together, our results suggest that IL-17A was involved in LPS-induced neuroinflammation and cognitive impairment in aged rats via microglial activation. Anti-IL-17A may represent a new therapeutic strategy for the treatment of endotoxemia-induced neuroinflammation and cognitive dysfunction.


The Diabetes Education Study: a controlled trial of the effects of intensive instruction of internal medicine residents on the management of diabetes mellitus.
The Diabetes Education Study was a controlled trial of the effects of physician and patient education. This article describes an educational program for internal medicine residents and its effects on ambulatory diabetes management practices. Forty-five of 86 residents practicing in the general medicine clinic of a university-affiliated city/county hospital were assigned randomly to receive a multifaceted program intended to 1) provide specific care recommendations, 2) teach necessary skills, and 3) make the professional and institutional environment more supportive. During the subsequent 11 months, 323 diabetic patients were interviewed and their records audited for evidence of changes in care. Experimental residents utilized fasting blood glucose determinations more often than controls (i.e., during 40% of visits vs. 31%, p = 0.004). Experimental residents also engaged more frequently in a variety of recommended dietary management recommendations. Isolated differences in monitoring/management of chronic complications also were found (e.g., lipid screening: 70% of experimental residents' patients vs. 58%, p = 0.016). Intensive, multifaceted programs of this nature are concluded to result in improvements in diabetes care, over and above that which is attainable through routine methods of clinical training for residents.


Whole exome sequencing is an alternative method in the diagnosis of mitochondrial DNA diseases.
Mitochondrial disease (MD) is genetically a heterogeneous group of disorders with impairment in respiratory chain complexes or pathways associated with the mitochondrial function. Nowadays, it is still a challenge for the genetic screening of MD due to heteroplasmy of mitochondrial genome and the complex model of inheritance. This study was designed to investigate the feasibility of whole exome sequencing (WES)-based testing as an alternative option for the diagnosis of MD. A Chinese Han cohort of 48 patients with suspect MD features was tested using nanoWES, which was a self-designed WES technique that covered the complete mtDNA genome and 21,019 nuclear genes. Fourteen patients were identified with a single genetic variant and three with single deletion in mtDNA. The heteroplasmy levels of variants in mitochondrial genome range from 11% to 100%. NanoWES failed to identify multiple deletions in mtDNA compared with long range PCR and massively parallel sequencing (LR-PCR/MPS). However, our testing showed obvious advantages in identifying variations in nuclear DNA. Based on nanoWES, we identified two patients with nuclear DNA variation. One of them showed Xp22.33-q28 duplication, which indicated a possibility of Klinefelter syndrome. NanoWES yielded a diagnostic rate of 35.4% for MD. With the rapid advances of next generation sequencing technique and decrease in cost, we recommend the usage of nanoWES as a first-line method in clinical diagnosis.


Parentification and family responsibility in the family of origin of adult children of alcoholics.
The present study examined parentification and family responsibility in the families of origin of 103 female college students who met criteria for being Adult Children of Alcoholics (ACOAs) as compared to 233 women who did not. The gender of the parent with an alcohol problem (mother only, father only, both parents, neither) was also examined in relation to family roles. Participants completed the Parentification Questionnaire-Adult (PQ-A; Sessions, M. W., and Jurkovic, G. J. (1986). Parentification Questionnaire-Adult (PQ-A). Unpublished document. Department of Psychology, Georgia State University, Atlanta, GA), the Filial Responsibility Scale-Adult (FRS-A; Jurkovic, G. J., and Thirkield, A. (1999). Filial Responsibility Scale-Adult (FRS-A). Unpublished document. Department of Psychology, Georgia State University, Atlanta, GA), the Children of Alcoholics Screening Test (CAST; Jones, J. W. (1983). The Children of Alcoholics Screening Test: Test manual. Chicago: Camelot), and indicated whether they suspected their mother/father of a drinking problem. ACOAs reported more parentification, instrumental caregiving, emotional caregiving, and past unfairness in their families of origin as compared to non-ACOAs. However, as compared to ACOAs who indicated that their father was the alcohol-abusing parent or non-ACOAs, respondents who thought their mothers had an alcohol problem reported greater past unfairness. In addition, ACOAs who thought their mothers had a problem with alcohol abuse reported more parentification and emotional caretaking than did non-ACOAs.


N-(Pyrrolidin-1-ylcarbothio-yl)benzamide.
In the title compound, C(12)H(14)N(2)OS, the pyrrolidine ring adopts an envelope conformation with the C atom at the 3-position as the flap and makes a dihedral angle of 65.80 (9)° with the benzene ring. In the crystal, N-H⋯O hydrogen bonds join c-glide related mol-ecules into chains extended along [001] that are further connected into (100) layers via C-H⋯O inter-actions.


Renal resistive index as a new independent risk factor for new-onset diabetes mellitus after kidney transplantation.
Pulse pressure and urinary albumin excretion were recently identified as risk factors of new-onset diabetes after renal transplantation (NODAT), suggesting that microvascular injury may be implicated in NODAT. However, the relationship between of microvascular injury and NODAT is unknown. In the present long-term (median follow-up: 5.7years; observation period: 4908 patient-years) retrospective study in 656 renal transplant recipients, the association between baseline renal resistance index (RI, used as a marker of widespread microvascular damage) and the incidence of NODAT was assessed. The incidence of NODAT was 11.2% and 14.6% at 5 and 10years, respectively, after transplantation. RI at 3months was a risk factor for NODAT [hazard ratio (HR) per 0.1: 2.19 (1.55-3.09), P<0.0001]. RI >0.75 (vs. 0≤0.75) was a potent a predictor of NODAT [HR: 3.29 (1.91-5.67), P<0.0001], even after adjustments [HR: 3.29 (1.50-7.24), P=0.0030] on age, weight, glucose, nephropathy, and arterial pressure. Similar results were observed when RI was measured at 1month [HR per 0.1:1.74 (1.33-2.27), P<0.0001] and 12months [HR per 0.1:1.74 (1.33-2.27), P<0.0001] after transplantation. High RI early after renal transplantation is a long-term risk factor for NODAT, and could be used to refine the individual risk of NODAT.


Evaluation of Fine Feeding System and Angioarchitecture of Giant Pituitary Adenoma--Implications for Establishment of Surgical Strategy.
Giant pituitary adenomas carry higher surgical risks despite recent advances in microsurgical and/or endoscopic surgery, and postoperative acute catastrophic changes without major vessel disturbance are still extremely difficult to predict, may manifest as postoperative pituitary apoplexy, and are associated with poor outcomes. Eight males and 4 females aged 31-72 years (mean 50.7 years) with giant pituitary adenomas underwent preoperative investigation of fine angioarchitecture using C-arm cone-beam computed tomography with a flat-panel detector. Angiographical findings were used to decide the surgical routes and compared with clinical outcome. Feeding arteries were verified in 10 of 12 patients, whereas no feeding arteries were evident in 2 patients. The patients were divided into the faint tumor staining group and the significant staining group, which was reconfirmed by region of interest analysis. The former group had faint supply from the ipsilateral superior hypophyseal arteries and meningohypophyseal trunk, and the latter group had significant supply from the meningohypophyseal and inferolateral trunks, which passed centrifugally from the inferoposterior pole of the tumor. All patients were treated through the extended transsphenoidal approach. Intraoperative bleeding was significantly greater in the latter group (P = 0.013). All patients had improvement of neurologic deficit and were released from the intensive care unit within a few days. Major blood supply of giant pituitary adenomas originates from branches of the infraclinoidal portion of the internal carotid artery, different from the normal anterior pituitary gland. Surgical route should depend on not only tumor shape and extension but also feeding systems.


Celecoxib and a novel COX-2 inhibitor ON09310 upregulate death receptor 5 expression via GADD153/CHOP.
Cyclooxygenase-2 (COX-2) inhibitors are promising anticancer agents but their long-term use at high doses is associated with adverse cardiovascular events. The molecular mechanisms underlying the anticancer or toxic cardiovascular effects of COX-2 inhibitors remain unknown. Here we report that COX-2-selective celecoxib and a novel COX-2 inhibitor ON09310 upregulate death receptor 5 (DR5) and cooperate with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), the ligand for DR5, to induce apoptosis in COX-2-positive and -negative cancer cells. We also show that both agents engage GADD153/CHOP to transcriptionally upregulate DR5 expression; GADD153/CHOP is a C/EBP homologous transcription factor implicated in cellular stress response and apoptosis. Based on our results, we propose that (1) these agents appear to mediate their effects, at least in part, by engaging GADD153/CHOP to activate DR5-dependent apoptotic pathway and (2) their regulation of GADD153/CHOP and DR5 expression appears to occur independent of their COX-2 inhibitory effects. Our results also indicate that ON09310 is generally more potent than celecoxib and, at lower concentration, strongly cooperates with TRAIL to induce apoptosis. Taken together, our findings form the basis for future in-depth studies to further explore the utility of TRAIL and/or agonistic anti-DR5 antibodies in combination with low-dose COX-2 inhibitors as a rational approach for cancer prevention and treatment.


Seasonal variations of cellular stress response in the heart and gastrocnemius muscle of the water frog (Pelophylax ridibundus).
The present study aimed to investigate the seasonal cellular stress response in the heart and the gastrocnemius muscle of the amphibian Pelophylax ridibundus (former name Rana ridibunda) during an 8 month acclimatization period in the field. Processes studied included heat shock protein expression and protein kinase activation. The cellular stress response was addressed through the expression of Hsp70 and Hsp90 and the phosphorylation of stress-activated protein kinases and particularly p38 mitogen-activated protein kinase (p38 MAPK), the extracellular signal-regulated kinases (ERK-1/2) and c-Jun N-terminal kinases (JNK1/2/3). Due to a general metabolic depression during winter hibernation, the induction of Hsp70 and Hsp90 and the phosphorylation of p38 MAPK, JNKs and ERKs are retained at low levels of expression in the examined tissues of P. ridibundus. Recovery from hibernation induces increased levels of the specific proteins, probably providing stamina to the animals during their arousal.


An innovative sewage sludge reduction by using a combined mesophilic anaerobic and thermophilic aerobic process with thermal-alkaline treatment and sludge recirculation.
Lab-scale High Efficiency Digestion (HED) systems containing a Mesophilic Anaerobic Reactor (MAR), Thermophilic Aerobic Reactor (TAR), liquid/solid separation unit, and thermal-alkaline treatment were developed to evaluate the efficiencies of sludge reduction and methane production. The HED process was divided into three phases to examine the influence of sludge pretreatment and pretreated sludge recirculation using TCOD and VSS reduction, COD solubilization, and methane production. The VSS removal with a solid/liquid separation unit, sludge recirculation, and thermal-alkaline treatment drastically increased up to 95% compared to the feed concentration. In addition, the results of COD solubilization and VSS/TSS showed that the solubilization of cells and organic matters by the thermal-alkaline treatment was highly increased, which was also consistent with the SEM images. In particular, the methane production rate increased 24-fold when the feed sludge and recirculated sludge were pretreated together. Collectively, the HED experiments performed with sludge recirculation and thermal-alkaline treatment demonstrated that the HED systems can be successfully employed for highly efficient sewage sludge reduction and methane gas production.


Evaluation of a novel aminopeptidase N inhibitor, in vitro, using two assay systems.
The activities of the novel aminopeptidase N inhibitor (APNI), beta-Amino-alpha-Hydroxyl-Phenyl butanic acid-Valine (AHPA-Val), were compared with APNI (amastatin). AHPA-Val and amastatin produced competitive inhibition of the hydrolysis of Tyr-Gly in the guinea-pig striatal membrane preparation, with K(i) equal to 14.06 microM and 12.48 microM respectively. Met-enkephalin-induced twitch inhibition of the guinea-pig ileum preparation was enhanced by AHPA-Val and amastatin with pA(1/2) values (the negative logarithm concentration of APNI that decreased the IC(50) of Met-enkephalin by half), of 7.08 and 7.79 respectively. These results suggest that AHPA-Val has good activity as an APNI and that these two assay systems are useful for evaluating the potency of novel APNIs.


Conservation of corneal tissue with wavefront-guided laser in situ keratomileusis.
To determine whether corneal tissue can be conserved with wavefront-guided ablation compared to conventional surgery with a larger ablation zone for attempted prevention of glare and halo. Department of Ophthalmology, Ilsan Paik Hospital, Inje University, Korea. This prospective study was composed of 2 parts: First, 40 eyes of 20 patients were studied to determine whether a larger optical ablation could be beneficial in prevention of glare after conventional laser in situ keratomileusis (LASIK) surgery. One eye in each patient was treated with a 6.00 mm optical zone, and the other with a 6.25 mm optical zone. Second, 20 eyes of 10 patients with a higher-order root mean square (RMS) value of 0.3 or greater were evaluated to learn whether a wavefront-guided ablation could be as effective as a larger conventional optical ablation. One eye in each patient was treated by conventional LASIK surgery with a 6.25 mm optical zone, and the other eye was treated by wavefront-guided LASIK surgery with a 6.00 mm optical zone. All patients were analyzed with a WASCA analyzer (Carl Zeiss Meditec) preoperatively, and 1 month and 3 months after surgery. Higher-order aberrations including coma, spherical aberration, and higher-order RMS were statistically significantly increased after conventional surgery with both a 6.00 mm and 6.25 mm optical zone. High-order aberrations including comaer- and spherical aberration after conventional surgery with 6.25 mm zone were statistically significantly increased. However, coma and higher-order RMS did not show a statistically significant increase between pre-LASIK and post-LASIK in wavefront-ablated eyes with a 6.00 mm optical zone. Wavefront ablation showed less increase of coma and higher-order RMS regardless of a smaller optical zone. This finding might provide a clinical clue for an advantage of wavefront-guided ablation from the standpoint of corneal tissue conservation.


[Measurement of corneal thickness in glaucoma patients].
For the past 5 decades, Goldmann's applanation tonometry has been the basis for measurement of intraocular pressure. In this process, it is assumed that the corneal architecture-and particularly corneal thickness-does not have significant influence on the applanation tonometry. The aim of this study was to assess central corneal thickness in patients with primary open angle glaucoma (POWG), normal tension glaucoma (NDG), and ocular hypertension (OHT) compared to the central corneal thickness of control subjects. In 200 consecutive glaucoma patients corneal pachymetry was performed with the Orbscan II system and a pachymetry map was obtained. Simultaneously, corneal pachymetry was also performed in 200 age- and sex-matched control subjects. To avoid diurnal variations the pachymetry measurements were performed at the same time of the day. The central corneal thickness (CCT) distribution turned out to be a near-Gaussian curve in patients with glaucoma and in the control subjects. The mean CCT in glaucoma patients was 561+/-49.4 micro m with a minimum of 448 micro m and a maximum of 732 micro m. In control subjects the mean CCT was 555.9+/-34.6 micro m with a minimum of 480 micro m and a maximum of 635 micro m. Further evaluation of CCT of glaucoma patients demonstrated that the CCT in patients with POWG was 559.5+/-43.5 micro m, in patients with NDG was 530.3+/-51.1 micro m and with OHT was 624.2+/-25.4 micro m. Central corneal thickness in patients with OHT was significantly greater, and in patients with NDG significantly lower, compared to control subjects. In defining the desired intraocular pressure in glaucoma patients, in the future CCT measurements should be considered along with intraocular pressure measurement and visual field analysis.


Introduction to Diagnostic and Therapeutic Spinal Angiography.
This article describes the basic principles of diagnostic and therapeutic spinal angiography as practiced by the author, including catheterization and radioprotection techniques, the selection of endovascular devices and embolization agents, and procedural complications.


Post-transplantation diabetes-state of the art.
With increasing success in overcoming the immunological and infectious challenges accompanying solid organ transplantation, susceptibility to post-transplant diabetes and cardiovascular disease has assumed increasing importance. Although some guidance is available from diabetes-related literature pertaining to the general population, some aspects are unique to solid organ allograft recipients. Both insulin resistance and β-cell dysfunction are generally agreed to contribute to development and manifestation of post-transplant diabetes, but controversy continues about which is most important and to what extent post-transplant diabetes is a distinct entity or simply a variant of type 2 diabetes with transplant-specific components. The optimum method and timing for detection and diagnosis of post-transplant diabetes remains an area of uncertainty. However, the greatest needs are to: address the absence of contemporary data for incidence and clinical outcomes associated with post-transplant diabetes; establish the role of glycaemic control; and assess the role of new diabetic therapies in prevention and management of post-transplant diabetes. We place the present knowledge base in the context of other advances in transplantation, challenge some existing ideas, and examine the potential role of emerging diabetes therapies. In highlighting existing deficiencies, we hope to provide direction for future research that will ultimately reduce incidence and improve management of post-transplant diabetes.


Process optimization, characterization and pharmacokinetic evaluation in rats of ursodeoxycholic acid-phospholipid complex.
The purpose of this research was to study whether the bioavailability of ursodeoxycholic acid could be improved by administering ursodeoxycholic acid-phospholipid complex (UDCA-PLC) orally to rats. A central composite design approach was used for process optimization in order to obtain the acceptable UDCA-PLC. The physicochemical properties of the complex obtained by optimal parameters were investigated by means of scanning electron microscopy and X-ray diffraction. The pharmacokinetic parameters and bioavailability studies were conducted in rats of UDCA after oral administration of UDCA-PLC and UDCA tablet. Multiple linear regression analysis for process optimization revealed that the acceptable UDCA-PLC was obtained wherein the optimal values of X(1), X(2) and X(3) were 3, 60 degrees C and 3 h, respectively. The XRD studies of UDCA-PLC obtained by the optimal parameters demonstrated that UDCA and phospholipids in the UDCA-PLC were combined by non-covalent bonds, not form new compounds. But pharmacokinetic parameters of the complex in rats were T(max) 1.6 h, C(max) 0.1346 microg/ml, AUC(0-infinity) 11.437 microg x h/ml, respectively. The relative bioavailability of UDCA of UDCA-PLC was increased by 241%,compared with the reference ursodeoxycholic acid tablet.