α,β-Unsaturated aldehyde of hyaluronan--Synthesis, analysis and applications.
Hyaluronic acid (HA) modified with an aldehyde group (HA-CHO or HA-aldehyde) has been extensively used for various biomedical applications. The main advantage of the aldehyde moieties is the ability to react with a wide range of amino compounds under physiological conditions. Reactions of aldehydes with primary amines in water are reversible and equilibrium is thoroughly shifted towards starting aldehyde and amine. This work presents an unique modification of HA: α,β-unsaturated aldehyde of HA (4,5-anhydro-6(GlcNAc)-oxo HA or ΔHA-CHO), which allows the primary amines to be attached to HA more effectively in comparison to the saturated HA-CHO. Higher hydrolytic stability is caused by the conjugation of imine with an adjacent --C=C-- double bond. Two strategies for the preparation of unsaturated HA-aldehyde were developed and chemical structures were studied in details. Cross-linked materials prepared from this precursor are biocompatible and suitable for applications in drug delivery and regenerative medicine.


[Histology-agnostic tumor treatment - a farewell to tumor entities?]
Considerable efforts concerning the molecular characterization and targeted treatment of cancer have significantly improved treatment options and prognosis of tumor patients. Nevertheless, in tumor entities without recurrent genetic alterations the application of molecular testing for potentially targetable lesions remains heterogeneous and, in most cases, the approval of targeted therapies is still restricted to defined tumor entities harboring corresponding predictive biomarkers.The broad genomic analysis of different tumor entities including rare cancers within several genome sequencing initiatives and precision oncology programs has revealed the occurrence of addressable molecular alterations across many tumor entities, although their incidence may differ significantly in the context of the underlying cancer type. The treatment of molecularly defined patient cohorts demonstrated an impressive tumor-agnostic efficacy of certain therapeutics such as NTRK inhibitors, while the outcome of other targeted therapies, such as ERBB or BRAF inhibitors, varied in the context of the underlying disease.In the meantime, a handful targeted therapeutics addressing NRTK and RET fusions, the BRAF V600E mutation or different features of defective DNA mismatch repair and high tumor mutational burden has been approved for histology-agnostic treatment of tumors harboring these target lesions. Ongoing molecularly stratified basket trials will further investigate the tumor-agnostic efficacy of different targeted treatment approaches.


Association between Active Travel to School and Depressive Symptoms among Early Adolescents.
Although much evidence has demonstrated the positive relationship of active school travel (AST) and physical health, little is known about the relationship of AST and mental health indicators among early adolescents, especially in Chinese populations. Thus, this study aimed to investigate the relationship of AST with depressive symptoms and its sex as well as age difference among early adolescents from Shanghai urban areas, China. 6478 adolescents (mean age = 13.6) in urban area were recruited, of whom boys accounted for 46.2%. A self-reported questionnaire in Chinese was used to collect data on AST and depressive symptoms, and other control variables. Multivariable logistic regression analyses were used to explore the relationships of AST with depressive symptoms. Of all included participants, 53.2% of adolescents reported being active in AST without sex difference. The prevalence of depressive symptoms was 19.2% without sex difference. AST was associated with reporting no depressive symptoms in adolescents (adjusted OR = 1.20, 95%CI: 1.06-1.36). However, the relationship was significant in boys (adjusted OR = 1.34, 95%CI: 1.11-1.60), in those who were grade 8 (adjusted OR = 1.25, 95%CI: 1.01-1.55) and 9 (adjusted OR = 1.29, 95%CI: 1.01-1.65) adolescents. AST may play an important role in preventing depressive symptoms among early adolescents. However, the relationship of AST with depressive symptoms differed by sex and age. More research is encouraged to explore the mechanism linking AST and depressive symptoms among adolescents, especially in different contexts.


Clinical and biochemical profile of monoclonal gammopathies in Caribbean patients in a resource-limited setting.
Multiple myeloma is the most common malignant plasma cell dyscrasia and ranks second among primary haematological malignancies. This study describes the epidemiologic, clinical and pathologic profile of monoclonal gammopathies seen in the University Hospital of the West Indies (UHWI), a tertiary care referral centre. A retrospective analysis of 85 cases diagnosed at UHWI over the 5-year period 2003-2007 was conducted. The cases were identified from the bone marrow records as well as the computerized database of the Medical Records Department. Clinical presentation, family and personal history and demographic data were retrieved. Haematological and biochemical results were also analyzed. There were 85 patients diagnosed with monoclonal gammopathies. The M:F ratio was 1.2:1 and the mean age was 65.7±1.3 years. Eighty percent of the patients had skeletal pain and 40% experienced weight loss. Of the patients experiencing bone pain 56.7% had multiple lytic lesions, 26.7% had pathological fractures and 26.7% had compression fractures. Seventy-four patients (87.1%) had a haemoglobin level <12.0 g/dL with 52.9% having values <8.0 g/dL. Renal impairment was evident at diagnosis in 36.5% . Hypercalcemia was seen in 26.5% and hyperuricemia in 45.9%. Of the 79 patients who had serum protein electrophoresis performed, 77.2% had at least one monoclonal band and of these 24.6% had a monoclonal protein also present on urine protein electrophoresis. The demographic profile in this group of patients is largely similar to other studies in predominantly Caucasian populations; however there was a notable increase in prevalence of severe disease at presentation, with the majority of patients presenting at the most advanced stage. It is probable that these differences reflect socioeconomic factors and not merely inherent ethnic variation in disease biology.


Late Intraluminal Stent Application in Strictures due to Corrosive Esophagitis: Our Preliminary Experiences.
Household chemicals result in corrosive esophageal burns in the developing third world countries, and most of them cause esophageal strictures. There is no standard treatment for esophageal strictures. Here, we present our preliminary experience with intraluminal esophageal stents for stricture treatment. The files of the patients who had stenosis due to corrosive esophagitis in our clinic were evaluated retrospectively. Stricture lengths were between 30 and 130 mm. Stents were self-expandable, made of nitinol alloy that was covered with silicone, and they were cylindrical in shape with a conical tip. The lengths varied between 60 and 170 mm and the diameters were between 10-20 mm. The stent application was made under general anaesthesia. There were seven patients (four girls and three boys). After stent application, all patients experienced constant or temporary pain, vomiting, and difficulty in swallowing. Bleeding occurred in one patient. Sudden death occurred in one patient, probably as a complication of chest infection. All stents had to be removed in mean 38 days because of embedding of the stent, development of granulation tissue and intolerance. More research is needed to determine the type, length and diameter of the stent, the timing and the duration of the application, the length and level of the stricture suitable for stent application and medications during treatment.


[The pathology, diagnosis and therapy on osteoporosis].
The increase of elderly population in Japan suggests the importance of the prevention of osteoporotic fracture. Falls and fractures account for around 10% of the causes for requiring care services in Japan. The Japanese criteria for initiating pharmacological treatment to prevent fragility fracture were revised in 2011. There are many kinds of anti-osteoporosis drugs including bisphosphonates, SERM, teriparatide, and denosumab that have been proven to reduce fractures. Thus, it is important to select drugs appropriate for each osteoporotic patients considering the mechanisms of drug action, their efficacy and side effects. In this article, we review pathophysiology, diagnosis and treatment of osteoporosis.


Tick-borne encephalitis virus in Clethrionomys glareolus in the Czech Republic.
A total of 474 specimens from 157 rodents caught at the military training area of Boletice in the south of the Czech Republic from May to November 1999 were screened for TBEV by nested PCR. TBEV-specific RNA was amplified from lung, kidney, and spleen derived from one Clethrionomys glareolus in the first RT-PCR round. Sequence analysis revealed a 100% identity to the TBEV strain Neudoerfl. TBEV presence in the sample was confirmed by mouse brain passage of backup samples and cell culture. The results support the observation that hantaviruses and TBEV transmission can occur sympatrically in the same rodent population.


Fairness emergence from zero-intelligence agents.
Fairness plays a key role in explaining the emergence and maintenance of cooperation. Opponent-oriented social utility models were often proposed to explain the origins of fairness preferences in which agents take into account not only their own outcomes but are also concerned with the outcomes of their opponents. Here, we propose a payoff-oriented mechanism in which agents update their beliefs only based on the payoff signals of the previous ultimatum game, regardless of the behaviors and outcomes of the opponents themselves. Employing adaptive ultimatum game, we show that (1) fairness behaviors can emerge out even under such minimalist assumptions, provided that agents are capable of responding to their payoff signals, (2) the average game payoff per agent per round decreases with the increasing discrepancy rate between the average giving rate and the average asking rate, and (3) the belief update process will lead to 50%-50% fair split provided that there is no mutation in the evolutionary dynamics.


The relationship of luteinizing hormone secretion to sleep in women during the early follicular phase: effects of sleep reversal and a prolonged three-hour sleep-wake schedule.
The relationship of luteinizing hormone (LH) secretion to sleep in adult women was investigated in two ways: an acute 180 degrees sleep-wake cycle reversal in a group of six women and a schedule in which a young woman engaged in a three hour sleep-wake cycle (two hours awake, one hour allowed for sleep continuously for ten days--the study was carried out on the eighth day). Each subject in the reversal study had a baseline period during which plasma samples were collected every twenty minutes for twenty-four hours and nocturnal sleep was monitored electrophysiologically during the early follicular phase of the menstrual cycle. During a succeeding cycle, the study was repeated after sleep-wake reversal. LH secretory patterns were analyzed by comparing the 24-hour mean plasma LH concentration with the hourly averages in percentage terms, using Stage 2 sleep onset as the zero point. LH secretion was depressed to approximately the same degree in both the baseline and reversal studies. The average hourly percentage difference from the 24-hour mean for the four-hour period following sleep onset was -13.4% and -13.1% for the baseline and reversal, respectively. These percentage deviations represented practically the entire negative deviation for the 24-hour period in both studies. The difference between the first four-hour period after sleep onset and the second was significant. The subject on a three-hour cycle had a baseline in which a large decrease in LH secretion occurred after sleep onset (-52.2% during the third hour). Her LH secretory pattern during the three-hour sleep-wake schedule was characterized by a fall during sleep periods, particularly when slow wave sleep (SWS) predominated. However, no correlation was found between specific sleep stages and LH secretion in the six women of the reversal study. These results confirm a relationship of LH secretion to sleep in adult women, one which is different from that described during puberty.


Phosphorus Over-Fertilization and Nutrient Misbalance of Irrigated Tomato Crops in Brazil.
Over the past 20 years, the use of center-pivot irrigation has increased tomato (Solanum lycopersicum L.) yields in Brazil from 42 Mg ha-1 to more than 80 Mg ha-1. In the absence of field trials to support fertilizer recommendations, substantial amounts of phosphorus (P) have been applied to crops. Additional P dosing has been based on an equilibrated nutrient P budget adjusted for low-P fertilizer-use efficiency in high-P fixing tropical soils. To document nutrient requirements and prevent over-fertilization, tissue samples and crop yield data can be acquired through crop surveys and fertilizer trials. Nevertheless, most tissue diagnostic methods pose numerical difficulties that can be avoided by using the nutrient balance concept. The objectives of this study were to model the response of irrigated tomato crops to P fertilization in low- and high-P soils and to provide tissue diagnostic models for high crop yield. Three P trials, arranged in a randomized block design with six P treatments (0-437 kg P ha-1) and three or four replications, were established on a low-P soil in 2013 and high-P soils in 2013 and 2014, totaling 66 plots in all. Together with crop yield data, 65 tissue samples were collected from tomato farms. We found no significant yield response to P fertilization, despite large differences in soil-test P (coefficient of variation, 24%). High- and low-yield classes (cutoff: 91 Mg fruits ha-1) were classified by balance models with 78-81% accuracy using logit and Cate-Nelson partitioning models. The critical Mahalanobis distance for the partition was 5.31. Tomato yields were apparently not limited by P but were limited by calcium. There was no evidence that P fertilization should differ between center-pivot-irrigated and rain-fed crops. Use of the P budget method to arrive at the P requirement for tomato crops proved to be fallacious, as several nutrients should be rebalanced in Brazilian tomato cropping systems.


A clinical use case to evaluate the i2b2 Hive: predicting asthma exacerbations.
To evaluate the i2b2 Hive as a tool to query, visualize, and extract clinical data, we selected a use case from the i2b2 airways diseases driving biology project: asthma exacerbations prediction. We analyzed the cohort selection and the extraction of the clinical data used by this asthma exacerbations prediction study. The structured data included the asthma diagnosis, birthdate, age, race, sex, height, weight, and BMI. The smoking status is typically only mentioned in clinical notes, and we evaluated the Natural Language Processing (NLP) application embedded in the i2b2 NLP cell to extract the smoking status from history and physical exam reports.Querying structured data was possible with the i2b2 workbench for about half the clinical data elements. The remaining had to be queried using a commercial database management system client. The automated extraction of the smoking status reached a mean precision of 0.79 and a mean specificity of 0.90.


Pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first-episode schizophrenia: Japanese Society of Clinical Neuropsychopharmacology treatment algorithms.
There are only a few treatment algorithms for first-episode schizophrenia. Moreover, all the algorithms apply to acute treatment, but not maintenance treatment. Therefore, we aimed to develop acute and maintenance treatment algorithms for first-episode schizophrenia. The algorithm committee of the Japanese Society of Clinical Neuropsychopharmacology developed pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first-episode schizophrenia. The acute treatment algorithm focuses on drug-naïve patients with first-episode schizophrenia who are not old or very agitated and recommends first-line treatment with aripiprazole, second- or third-line treatment with risperidone/paliperidone or olanzapine, and fourth-line treatment with clozapine. Long-acting injection of the current antipsychotic agent can be used for poor medication adherence or based on patient preference. The agitation treatment algorithm recommends first-line treatment with lorazepam and second- or third-line treatment with quetiapine or levomepromazine and clearly instructs that the medication used for agitation should be reduced and then discontinued after remission of agitation. The maintenance treatment algorithm recommends the gradual reduction of antipsychotics to the minimum effective dose after remission of positive symptoms. We hope that our unique algorithms will be used broadly and will contribute to minimizing patients' burden related to antipsychotic treatment.


Effect of dietary lipid on benzo(a)pyrene metabolism by perfused rat liver.
Male Holtzman albino rats weighing 60-75 gm were fed purified synthetic diets containing casein (18%), alphacel (4%), wheat starch (44%), sucrose (26%), Jones Foster salt mix (4%), and vitamin mix (4%) for three weeks. The diet for group I contained no fat, whereas corn oil (10%) substituted for 10% sucrose in the diet for group II. All animals were administered 3-methylcholanthrene [20 mg/kg intraperitoneally (ip) in 0.5% methylcellulose solution] for two successive days prior to sacrifice in order to increase the activity of the mixed function oxidase (MFO) responsible for metabolizing benzo(a)pyrene [B(a)P]. After 21 days on diet, livers were perfused with benzo(a)pyrene in blood-free Krebs Henseleit bicarbonate buffer containing 100 mg glucose plus 200 units of heparin per 100 ml. Aliquots of perfusate were removed at five, ten, 20, 30, 40, and 60 minutes for analysis of B(a)P metabolites. Higher concentrations of B(a)P-9, 10-dihydrodiol; B(a)P-4,5-dihydrodiol; B(a)P-7,8-dihydrodiol; and 3-hydroxy B(a)P were recovered from livers of rats fed the diet containing 10% corn oil than from livers of rats fed the fat-free diet. The concentrations of 9-hydroxy B(a)P except the 9,10-dihydrodiol were recovered from bile along with two unidentified metabolites. Following the perfusion period, homogenized and extracted livers from rats fed the diet containing corn oil retained significantly higher concentration of the three dihydrodiols and two phenols than livers from rats fed the fat-free diet.


Nicotine favors osteoclastogenesis in human periodontal ligament cells co-cultured with CD4(+) T cells by upregulating IL-1β.
Periodontitis, which is the main cause of tooth loss, is one of the most common chronic oral diseases in adults. Tooth loss is mainly a result of alveolar bone resorption, which reflects an increased osteoclast formation and activation. Osteoclast formation in periodontal tissue is a multistep process driven by osteoclastogenesis supporting cells such as human periodontal ligament (PDL) cells and CD4(+) T cells. Inflammatory cytokines, such as interleukin-1β (IL-1β), can induce osteoclastogenesis by affecting the expression of receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) in human PDL cells. Nicotine, the major component in tobacco smoking and a specific agonist of the α7 nicotinic acetylcholine receptor (α7 nAChR), has been proven to regulate the expression of inflammatory cytokines in smoking-associated periodontitis. In this study, we investigated the mechanism(s) through which nicotine affects osteoclastogenesis in human PDL cells co-cultured/non-co-cultured with CD4(+) T cells. Human PDL cells were stimulated with nicotine (10-5 M) and/or α-bungarotoxin (α-BTX, specific antagonist of α7 nAChR, 10-8 M) before being co-cultured with CD4(+) T cells. Compared with mono-culture systems, stimulation with nicotine caused an increased secretion of IL-1β in serum of human PDL cell-CD4(+) T cell co-culture, and the expression of RANKL in human PDL cells was further upregulated co-cultured with CD4(+) T cells, while no differences were observed in the expression of OPG between the co-culture and mono-culture systems. Our data suggested that nicotine upregulated IL-1β secretion, further upregulated RANKL expression in smoking-associated periodontitis, which may aid in the better understanding of the relationship between nicotine and alveolar bone resorption.


Disseminated neuroblastoma with initial presentation as an intraoral mass: case report.
Neuroblastoma is an uncommon malignant neoplasm that derives from neural crest progenitor cells that normally give rise to the sympathetic nervous system. It represents 8 to 10% of all extracranial tumors in childhood. The purpose of this paper is to report a case in which a mandibular soft tissue mass was the initial presenting sign of disseminated neuroblastoma in a 2-year-old child, and to discuss the clinicopathologic features and biologic behavior of neuroblastoma.


Refugees, trade, and FDI.
Humanitarian policies aimed at welcoming forced migrants may yield unexpected economic dividends. This article focuses on the trade and investment links forged by refugees between their countries of resettlement and the origins they fled. We document how such immigrant-links differ in the case of refugees, focusing on why their opportunity sets might differ and the difficulties in establishing economic connections against a backdrop of civil conflict and political unrest. We conclude by discussing a range of policies aimed at engaging refugee diasporas to foster development at refugees' origins.


Soluble TNF-alpha receptors are constitutively shed and downregulate adhesion molecule expression in malignant gliomas.
The regulation of adhesion molecule expression in malignant gliomas by tumor necrosis factor-alpha (TNF) and soluble TNF receptors (TNFR) was examined in the malignant glioma cell line A-172 and in 2 primary glioblastoma cell cultures (LA-492 and LA-567). A-172 cells expressed only the p55 TNF receptor transcripts and protein. The 2 primary cell cultures expressed both the p55 and p75 TNF receptors. In A-172 cells and in 1 of 2 primary glioma cell cultures, TNF upregulated the expression of ICAM-1 and VCAM-1, A-172 and both primary glioma cultures also shed their TNF receptors in the absence of activation by stimulating agents. Soluble p55 (sp55) receptors, but not soluble p75 (sp75) receptors, were found to reduce the TNF induced VCAM-1 and ICAM-1 expression in both the glioma cell line and the primary cell culture. Immunostaining of malignant glioma sections confirmed the presence of soluble TNFR and adhesion molecule expression in glioma cells in situ. These data suggest that soluble TNF receptors may play a role in the mechanism by which malignant gliomas downregulate the effects of infiltrating immune-competent cells.


Sound production in Onuxodon fowleri (Carapidae) and its amplification by the host shell.
Onuxodon species are well known for living inside pearl oysters. As in other carapids, their anatomy highlights their ability to make sounds but sound production has never been documented in Onuxodon. This paper describes sound production in Onuxodon fowleri as well as the anatomy of the sound production apparatus. Single-pulsed sounds and multiple-pulsed sounds that sometimes last more than 3 s were recorded in the field and in captivity (Makemo Island, French Polynesia). These pulses are characterized by a broadband frequency spectrum from 100 to 1000 Hz. Onuxodon fowleri is mainly characterized by its ability to modulate the pulse period, meaning that this species can produce pulsed sounds and tonal-like sounds using the same mechanism. In addition, the sound can be remarkably amplified by the shell cavity (peak gain can exceed 10 dB for some frequencies). The sonic apparatus of O. fowleri is characterized by a rocker bone in front of the swimbladder, modified vertebrae and epineurals, and two pairs of sonic muscles, one of which (primary sonic muscle) inserts on the rocker bone. The latter structure, which is absent in other carapid genera, appears to be sexually dimorphic suggesting differences in sound production in males and females. Sound production in O. fowleri could be an example of adaptation where an animal exploits features of its environment to enhance communication.


Temperature dependence of the photodissociation of CO2 from high vibrational levels: 205-230 nm imaging studies of CO(X1Σ+) and O(3P, 1D) products.
The 205-230 nm photodissociation of vibrationally excited CO2 at temperatures up to 1800 K was studied using Resonance Enhanced Multiphoton Ionization (REMPI) and time-sliced Velocity Map Imaging (VMI). CO2 molecules seeded in He were heated in an SiC tube attached to a pulsed valve and supersonically expanded to create a molecular beam of rotationally cooled but vibrationally hot CO2. Photodissociation was observed from vibrationally excited CO2 with internal energies up to about 20 000 cm-1, and CO(X1Σ+), O(3P), and O(1D) products were detected by REMPI. The large enhancement in the absorption cross section with increasing CO2 vibrational excitation made this investigation feasible. The internal energies of heated CO2 molecules that absorbed 230 nm radiation were estimated from the kinetic energy release (KER) distributions of CO(X1Σ+) products in v″ = 0. At 230 nm, CO2 needs to have at least 4000 cm-1 of rovibrational energy to absorb the UV radiation and produce CO(X1Σ+) + O(3P). CO2 internal energies in excess of 16 000 cm-1 were confirmed by observing O(1D) products. It is likely that initial absorption from levels with high bending excitation accesses both the A1B2 and B1A2 states, explaining the nearly isotropic angular distributions of the products. CO(X1Σ+) product internal energies were estimated from REMPI spectroscopy, and the KER distributions of the CO(X1Σ+), O(3P), and O(1D) products were obtained by VMI. The CO product internal energy distributions change with increasing CO2 temperature, suggesting that more than one dynamical pathway is involved when the internal energy of CO2 (and the corresponding available energy) increases. The KER distributions of O(1D) and O(3P) show broad internal energy distributions in the CO(X1Σ+) cofragment, extending up to the maximum allowed by energy but peaking at low KER values. Although not all the observations can be explained at this time, with the aid of available theoretical studies of CO2 VUV photodissociation and O + CO recombination, it is proposed that following UV absorption, the two lowest lying triplet states, a3B2 and b3A2, and the ground electronic state are involved in the dynamical pathways that lead to product formation.


The structural neuroimaging of bipolar disorder.
There is an increasing body of literature fuelled by advances in high-resolution structural MRI acquisition and image processing techniques which implicates subtle neuroanatomical abnormalities in the aetiopathogenesis of bipolar disorder. This account reviews the main findings from structural neuroimaging research into regional brain abnormalities, the impact of genetic liability and mood stabilizing medication on brain structure in bipolar disorder, and the overlapping structural deviations found in the allied disorders of schizophrenia and depression. The manifold challenges extant within neuroimaging research are highlighted with accompanying recommendations for future studies. The most consistent findings include preservation of total cerebral volume with regional grey and white matter structural changes in prefrontal, midline and anterior limbic networks, non-contingent ventriculomegaly and increased rates of white matter hyperintensities, with more pronounced deficits in juveniles suffering from the illness. There is increasing evidence that medication has observable effects on brain structure, whereby lithium status is associated with volumetric increase in the medial temporal lobe and anterior cingulate gyrus. However, research continues to be confounded by the use of highly heterogeneous methodology and clinical populations, in studies employing small scale, low-powered, cross-sectional designs. Future work should investigate larger, clinically homogenous groups of patients and unaffected relatives, combining both categorical and dimensional approaches to illness classification in cross-sectional and longitudinal designs in order to elucidate trait versus state mechanisms, genetic effects and medication/illness progression effects over time.


The Parkinson's Active Living (PAL) Program.
Apathy, one of the most common neuropsychiatric symptoms in Parkinson's disease (PD), has been associated with reduced daily functioning, cognition, treatment compliance, quality of life, and increased caregiver burden and distress, among other outcomes. The purpose of the present study was to develop and gather pilot data on the feasibility, acceptability, and efficacy of the Parkinson's Active Living (PAL) program, to our knowledge, the first behavioral treatment specifically designed to target apathy in patients with PD. The Parkinson's Active Living is a primarily telephone-based, 6-week activity scheduling and monitoring intervention that incorporates external cueing to target disease-related self-generational deficits to reduce levels of apathy in nondemented, highly apathetic patients with PD. Participants aged 44 to 86 years (mean = 66, SD [standard deviation] = 10.7) ranging in disease duration from <1 to 23 years with elevated apathy (Apathy Evaluation Scale >35) were enrolled in a 1-arm trial and tested at 3 time points (baseline, posttest, and 1-month follow-up). Feasibility aspects (ie, acceptability, demand, implementation, practicality, adaptation, integration, and expansion) and efficacy of PAL program are reported. Matched pairs t tests showed a medium to large effect of treatment on patient apathy (52% showing ≥1 SD improvement), depression (33% showing ≥1 SD improvement), and quality of life at posttest, with improvements in apathy and depression maintained at follow-up. The program may hold promise as an effective nonpharmacological intervention for apathy in PD. Implications and future directions are discussed. Randomized controlled trials are needed.


Endogenous factors regulating neuronal death induced by radical stress.
Neurons in the central nervous system (CNS) are vulnerable to radical stress caused by reactive oxygen species, including nitric oxide (NO). Those radicals play crucial roles in glutamate neurotoxicity associated with ischemic brain injury and a wide range of neurodegenerative disorders. In our previous studies, we have shown evidence suggesting that glutamate neurotoxicity is regulated by certain endogenous substances such as neurotrophins, nicotinic acetylcholine, prostanoids and vitamins. Based on those findings, we have used the term 'neuroprotective factor' for endogenous substances possessing protective activity against glutamate neurotoxicity, and have further searched for a candidate with unique structure. We isolated a novel neuroprotective substance named 'serofendic acid' derived from fetal calf serum. The compound exhibited potent protective action against neurotoxicity induced by glutamate and by an NO donor without inhibiting glutamate receptors. Electron spin resonance analysis demonstrated that serofendic acid had no direct scavenging activity on NO, but was capable of inhibiting the generation of a hydroxyl radical, a presumed 'executor' radical in the nitric oxide-mediated neurotoxic cascade. The chemical structure was determined by mass spectrometry and nuclear magnetic resonance spectroscopy, and was confirmed by synthesis. The structure was unique among known endogenous substances because the compound was a sulfur-containing atisane type diterpenoid. The discovery of serofendic acid may provide a new scope for the investigation of low-molecular weight bioactive factors promoting the survival of CNS neurons.


Nanocomposite conductive hydrogels with Robust elasticity and multifunctional responsiveness for flexible sensing and wound monitoring.
Flexible biosensors made from conductive hydrogels have shown tremendous potential in health management and human-machine interfaces. Nevertheless, it remains challenging to fabricate conductive hydrogels with robust resilience and long-term stability. Herein, we report a nanocomposite conductive hydrogel prepared through one-pot radical polymerization of 3-acrylamidophenylboronic acid (APBA) and acrylamide (AM) in the presence of LAPONITE® XLG nanosheet (XLG) stabilized carbon nanotubes (CNTs). Owing to the existence of various non-covalent interactions within the network (B-N coordination, hydrogen bond, and polymer chain entanglement), the hydrogels feature splendid mechanical properties with a tensile strength of 252-323 kPa, fracture strain of 880-1200%, Young's modulus of 48-50 kPa and fracture energy of 911-1078 J m-2, and exhibit robust elasticity and fatigue resistance during 1000 consecutive tensile and compressive cycles. The hydrogels show remarkable sensing performances (gauge factor up to 9.43) and a broad sensing range of strain (1-300%) and pressure (1-80 kPa), enabling reliable and accurate monitoring of large and tiny motions in daily human life. Moreover, the conductive hydrogels could not only accelerate skin incision healing but also act as smart wearable sensors to monitor the skin wound healing process by detection of local temperature changes.


Arbutin reduces cognitive deficit and oxidative stress in animal model of Alzheimer's disease.
Objectives: Recent evidences have shown the beneficial effects of natural products for treating of Alzheimer's disease (AD). Arbutin is derived from Pyrus biossieriana and exerts a wide range of pharmacological activities including anti-inflammatory and anti-oxidant effects. The present study was designed to examine the protective effects of arbutin on streptozotocin (STZ)-induced neurotoxicity in rats. Materials and methods: The spatial memory impairment was induced by intracerebroventricular (i.c.v) microinjection of STZ (3 mg/kg, 10 μL). Animals received the pretreatment of arbutin (50 mg/kg) for 21 days before STZ injection. The Morris Water maze (MWM) task was used to study the spatial learning and memory. The levels of oxidative stress markers including malondialdehyde (MDA), nitrite and carbonyl were measured in serum and hippocampus samples. In addition, antioxidant level was assessed by ferric reducing antioxidant power (FRAP) test. Results: The obtained result indicated that administration of STZ is led to memory impairment and increases the levels of oxidative stress markers in the hippocampus tissues. Conversely, arbutin improves spatial memory and reduces oxidative and nitrosative stress, as evidenced by a significant decrease in the amount of MDA and nitrite in the serum and hippocampus. In addition, an increase in FRAP levels of hippocampus was observed in arbutin receiving animals. The protein carbonyl content was not reduced in arbutin receiving animals. Conclusion: It could be concluded that arbutin protects the brain against STZ-induced memory impairment and oxidative damage in the hippocampus. The neuroprotective effect of arbutin might be mediated through its antioxidant and free radical scavenging effects.


Prevalence and in-hospital outcomes of patients with malignancies undergoing de novo cardiac electronic device implantation in the USA.
To study the outcomes of cancer patients undergoing cardiac implantable electronic device (CIED) implantation. De novo CIED implantations (2004-15; n = 2 670 590) from the National Inpatient Sample were analysed for characteristics and in-hospital outcomes, stratified by presence of cancer (no cancer, historical and current cancers) and further by current cancer type (haematological, lung, breast, colon, and prostate). Current and historical cancer prevalence has increased from 3.3% to 7.8%, and 5.8% to 7.8%, respectively, between 2004 and 2015. Current cancer was associated with increased adjusted odds ratio (OR) of major adverse cardiovascular events (MACE) [composite of all-cause mortality, thoracic and cardiac complications, and device-related infection; OR 1.26, 95% confidence interval (CI) 1.23-1.30], all-cause mortality (OR 1.43, 95% CI 1.35-1.50), major bleeding (OR 1.38, 95% CI 1.32-1.44), and thoracic complications (OR 1.39, 95% CI 1.35-1.43). Differences in outcomes were observed according to cancer type, with significantly worse MACE, mortality and thoracic complications with lung and haematological malignancies, and increased major bleeding in colon and prostate malignancies. The risk of complications was also different according to CIED subtype. The prevalence of cancer patients amongst those undergoing CIED implantation has significantly increased over 12 years. Overall, current cancers are associated with increased mortality and worse outcomes, especially in patients with lung, haematological, and colon malignancies whereas there was no evidence that historical cancer had a negative impact on outcomes.


Gene-environment interaction in panic disorder and posttraumatic stress disorder.
Gene-environment interaction is a form of causal interplay, whereby genetic effects on phenotypic variation change as a function of environmental exposure. While conceptually appealing, there is still much debate on the veracity and the relevance of this form of etiological interdependence for psychiatric disorders. By focusing on panic disorder (PD) and posttraumatic stress disorder (PTSD), this article outlines why gene-environment interaction is controversial, why it can be important for both researchers and clinicians, and how it is investigated by quantitative genetic, molecular genetic, and genomic strategies. It is suggested that gene-environment interaction effects are more reliable and meaningful when they can be harnessed to pinpoint specific biological pathways and mechanisms. In psychiatry, this can be guided by phenotypic dissection and realized by adopting intermediate phenotypes of a physiological nature, such as carbon dioxide sensitivity for PD, or gene expression profiling after stress for PTSD. A developmental framework of reference and the possibility of transferring the investigation to animal models are additional key elements in this debate.


Experimental evidence for previously unclassified calcium phosphate structures in the casein micelle.
1H-31P Cross-polarization magic angle spinning (CP-MAS) measurements of 40-d-old Mozzarella cheese and 20 mM EDTA-treated casein micelles revealed that each sample had immobile phosphorus with the same spectral pattern, which did not match that of native casein micelles. To identify the immobile phosphorus bodies, 1H-31P CP-MAS spectra and cross-polarization kinetics measurements were undertaken on native casein micelles, EDTA-chelated casein micelles, and reference samples of β-casein and hydroxyapatite. The results showed that the immobile phosphorus bodies in the mature Mozzarella cheese had the following characteristics: they are immobile phosphoserine residues (not colloidal calcium phosphate); they are not the product of phosphoserine to colloidal calcium phosphate bridging; the phosphate is complexed to calcium; their rigidity is localized to a phosphorus site; their rigidity and bond coupling is unaffected by protein hydration; and the immobile bodies share a narrow range of bond orientations. Combining these observations, the best explanation of the immobile phosphorus bodies is that bonding structures of phosphorus-containing groups and calcium exist within the casein micelle that are not yet clearly classified in the literature. The best candidate is a calcium-bridged phosphoserine-to-phosphoserine linkage, either intra- or inter-protein.


The effect of depressive symptoms on disability-free survival in healthy older adults: A prospective cohort study.
Gerontology and ageing research are increasingly focussing on healthy life span (healthspan), the period of life lived free of serious disease and disability. Late-life depression (LLD) is believed to impact adversely on physical health. However, no studies have examined its effect on healthspan. This study investigated the effect of LLD and subthreshold depression on disability-free survival, a widely accepted measure of healthspan. This prospective cohort study used data from the ASPirin in Reducing Events in the Elderly study. Participants were aged ≥70 years (or ≥65 years for African-American and Hispanic participants) and free of dementia, physical disability and cardiovascular disease. Depressive symptoms were measured using the 10-item Centre for Epidemiological Studies Depression Scale (CES-D-10). LLD and subthreshold depression were defined as CES-D-10 scores ≥8 and 3-7, respectively. Disability-free survival was defined as survival free of dementia and persistent physical disability. A total of 19,110 participants were followed up for a maximum of 7.3 years. In female participants, LLD was associated with lower disability-free survival adjusting for sociodemographic and lifestyle factors, medical comorbidities, polypharmacy, physical function and antidepressant use (HR, 1.50; 95% CI, 1.23-1.82). In male participants, LLD was associated with lower disability-free survival adjusting for sociodemographic and lifestyle factors (HR, 1.30; 95% CI, 1.03-1.64). Subthreshold depression was also associated with lower disability-free survival in both sexes. LLD may be a common and important risk factor for shortened healthspan.


Ontogeny and senescence of salivary immunity.
The objective of the present study was to evaluate the capacity for secretory immune responses throughout life. This was done by measuring, by single radial immunodiffusion, the concentrations of IgA and IgA1 subclass in saliva samples of subjects who ranged in age from two months to 91 years. The presence of salivary IgA antibodies to two nearly ubiquitous mucosal antigens, Streptococcus mutans glucosyltransferase (GTF) and killed poliovirus (Types 1, 2, and 3), was measured in an enzyme-linked immunosorbent assay in this population. Whole saliva from 2-5-month-old infants contained significantly less IgA than did parotid saliva of any adult group. Also, a significantly higher proportion of the total salivary IgA was IgA1 in infants' saliva than was found in parotid saliva of adults. Salivary IgA and IgA1 subclass levels in parotid saliva of young and old (70-91 years) adults did not differ. Salivary IgA antibody levels to GTF were negligible in most saliva samples of children less than five years old, while 40% of children older than one year had detectable levels of salivary antibody to poliovirus (PV). This differences between response to GTF and PV antigens may reflect differences in antigenic challenge. Parotid saliva of the oldest group (70-91 years) had narrowly distributed and uniformly low levels of IgA antibody to both antigens. Since their IgA immunoglobulin levels were the same as in younger adults, the low antibody levels in this oldest group may be associated with changes in the number or function of T or B lymphocytes or antigen-processing cells, and/or may result from diminished levels of challenge with these antigens.


COLOR-PATTERN VARIATION IN LAKE ERIE WATER SNAKES: THE ROLE OF GENE FLOW.
In an effort to clarify the evolutionary processes influencing color-pattern variation in Lake Erie island water snake (Nerodia sipedon) populations, rates of gene flow among island and mainland populations were estimated from patterns of allozymic variation detected using electrophoresis. Rates of gene flow were high with Nm, the number of migrants per generation, averaging 25.5 among island sites, 9.2 between the Ontario mainland and the islands, and 3.6 between the Ohio mainland and the islands. Based on estimates of current population size from mark-recapture work and of past population size extrapolated from the extent of shoreline habitat, values of m between island and mainland populations ranged from 0.0008-0.01. Synthesis of estimates of the rate of gene flow with information on inheritance of color pattern, the strength of natural selection, and population history supports the hypothesis that color-pattern variation in island populations results from a balance between gene flow and natural selection. However, depending on the mode of inheritance of color pattern, stochastic processes such as drift may have been important in the initial stages of differentiation between island and mainland populations.


Endovascular stenting treatment for drug-refractory hypertension due to ostial stenosis of transplanted renal artery.
Transplanted renal artery stenosis (TRAS) is one of the major causes of poor blood pressure control, progressive renal dysfunction and finally renal graft failure in uremic patients receiving renal allograft transplantation. Percutaneous transluminal balloon angioplasty (PTA) with stenting is an effective treatment for TRAS but has rarely had validation for the ostial lesions of TRAS. We reported 2 patients developing drug-refractory hypertension along with impaired renal function who received PTA plus stent deployment therapy for severe ostial stenosis of graft renal artery. Both of the patients had improved allograft function gradually, and satisfactory blood pressure control after 3 months follow-up. In conjugation with balloon angioplasty, stenting could provide a safe and effective revascularization strategy in conjunction with balloon angioplasty for ostial lesions of TRAS.


In silico and immunoinformatics based multiepitope subunit vaccine design for protection against visceral leishmaniasis.
Visceral leishmaniasis (VL) is a vector-borne neglected tropical protozoan disease with high fatality and no certified vaccine. Conventional vaccine preparation is challenging and tedious. Here in this work, we created a global multiepitope subunit vaccination against VL utilizing innovative immunoinformatics technique based on the extensively conserved epitopic regions of the PrimPol protein of Leishmania donovani consisting of four subunits which were analyzed and studied, out of which DNA primase large subunit and DNA polymerase α subunit B were evaluated as antigens by Vaxijen 2.0. The multiepitope vaccine design includes a single adjuvant β-defensins, eight CTL epitopes, eight HTL epitopes, seven linear BCL epitopes and one discontinuous BCL epitope to induce innate, cellular and humoral immune responses against VL. The Expasy ProtParam tool characterized the physiochemical parameters of the vaccine. At the same time, SOLpro evaluated our vaccine constructs to be soluble upon expression. We also modeled the stable tertiary structure of our vaccine construct through Robetta modeling for molecular docking studies with toll-like receptor proteins through HADDOCK 2.4. Simulations based on molecular dynamics revealed an intact vaccine and TLR8 complex, supporting our vaccine design's immunogenicity. Also, the immune simulation of our vaccine by the C-ImmSim server demonstrated the potency of the multiepitope vaccine construct to induce proper immune response for host defense. Codon optimization and in silico cloning of our vaccine further assured high expression. The outcomes of our study on multiepitope vaccine design significantly produced a potential candidate against VL and can potentially eradicate the disease in the future after clinical investigations.Communicated by Ramaswamy H. Sarma.


NEO-five factor personality traits as predictors of response to two forms of group psychotherapy.
The relationships between patient personality variables and outcome for 107 psychiatric outpatients with complicated grief who completed either interpretive or supportive short-term group therapy were investigated. The personality variables were assessed prior to treatment with the NEO-Five Factor Inventory (NEO-FFI). For patients in both forms of therapy, extraversion, conscientiousness, and openness were directly associated with favorable treatment outcome. In contrast, neuroticism was inversely related to favorable outcome for patients in both forms of therapy. Agreeableness was directly related to favorable improvement in grief symptomatology for patients in interpretive therapy, but not for those in supportive therapy. The results highlight the importance of assessing patient personality in order to predict response to short-term group therapy. Possible explanations and clinical implications of these findings are discussed.


Double- and triple-consecutive O-insertion into tert-butyl and triarylmethyl structures.
[reaction: see text] The concecutive Criegee rearrangement reactions were studied for tert-butyl trifluoroacetate, triarylcarbinols, and benzophenone ketales with trifluoroperacetic acid (TFPAA) in trifluoroacetic acid (TFA). The formation of methyl acetate and methyl trifluoroacetate indicates that the consecutive double-O-insertion process has taken place for tert-butyl trifluoroacetate. The intermediate dimethoxymethylcarbonium ion was detected below 5 degrees C. A consecutive triple-O-insertion process has been observed for triarylmethanols and benzophenone ketals. A new high yield method of corresponding diaryl carbonates synthesis was developed.


A comparison of central and peripheral effects of cetirizine and loratadine.
In a double-blind, crossover, randomized clinical pharmacological study performed on 10 healthy volunteers, peripheral and central effects of 10 mg cetirizine and 10 and 40 mg loratadine were compared. Cetirizine (10 mg) significantly (P less than 0.001) inhibited 10 or 100 mg/ml histamine-induced weals 2 and 6 h after drug intake. Cetirizine was more potent than 10 mg loratadine after 2 and 6 h, and was even more potent than 40 mg loratadine after 6 h. Neither drug affected subjective evaluation of central effects and cetirizine was completely devoid of electro-encephalographic (EEG) changes, whereas 10 and 40 mg loratadine induced only slight and limited EEG changes.


Fast-to-slow conversion following chronic low-frequency activation of medial gastrocnemius muscle in cats. I. Muscle and motor unit properties.
This study of cat medial gastrocnemius (MG) muscle and motor unit (MU) properties tests the hypothesis that the normal ranges of MU contractile force, endurance, and speed are directly associated with the amount of neuromuscular activity normally experienced by each MU. We synchronously activated all MUs in the MG muscle with the same activity (20 Hz in a 50% duty cycle) and asked whether conversion of whole muscle contractile properties is associated with loss of the normal heterogeneity in MU properties. Chronically implanted cuff electrodes on the nerve to MG muscle were used for 24-h/day stimulation and for monitoring progressive changes in contractile force, endurance, and speed by periodic recording of maximal isometric twitch and tetanic contractions under halothane anesthesia. Chronic low-frequency stimulation slowed muscle contractions and made them weaker, and increased muscle endurance. The most rapid and least variable response to stimulation was a decline in force output of the muscle and constituent MUs. Fatigue resistance increased more slowly, whereas the increase in time to peak force varied most widely between animals and occurred with a longer time course than either force or endurance. Changes in contractile force, endurance, and speed of the whole MG muscle accurately reflected changes in the properties of the constituent MUs both in extent and time course. Normally there is a 100-fold range in tetanic force and a 10-fold range in fatigue indexes and twitch time to peak force. After chronic stimulation, the range in these properties was significantly reduced and, even in MU samples from single animals, the range was shown to correspond with the slow (type S) MUs of the normal MG. In no case was the range reduced to less than the type S range. The same results were obtained when the same chronic stimulation pattern of 20 Hz/50% duty cycle was imposed on paralyzed muscles after hemisection and unilateral deafferentation. The findings that the properties of MUs still varied within the normal range of type S MUs and were still heterogeneous despite a decline in the variance in any one property indicate that the neuromuscular activity can account only in part for the wide range of muscle properties. It is concluded that the normal range of properties within MU types reflects an intrinsic regulation of properties in the multinucleated muscle fibers.


[T-proteins of Streptococcus pyogenes. III. Communication: purification of T-proteins extracted with trypsin, pepsin and C-phage-associated lysin by means of immunochromatography (author's transl)].
T-proteins of Streptococcus pyogenes type 1 were extracted by enzymatic treatment of cells with trypsin, pepsin or C-phage-associated lysin and subsequently purified by ion exchange chromatography on DEAE cellulose as well as by immuno-adsorption on immobilized anti-T-type 1 antibodies. Immunochromatographical purified T1-proteins which were extracted by the different enzymes showed different properties in immuno-electrophoresis, SDS-electrophoresis and amino acid composition although a serological reaction of identity was found in Ouchterlony precipitation. Tryptic and peptic digestion was efficient for extraction of T protein while the extraction with C-phage-associated lysin was unsuitable for isolation of T-protein. The release of T-protein after treatment of cells with this lysin was very low and the preparation purified by this way exhibited cross-reaction with non-absorbed antisera of other types.


Overstaying their welcome: defective CX3CR1 microglia eyed in macular degeneration.
Age-related macular degeneration (AMD), the most common cause of blindness in the elderly, is characterized by degeneration of the macula and can lead to loss of fine color vision. Alterations in inflammatory and immune system pathways, which arise from genetic differences, predispose individuals to AMD. Yet the mechanism of disease progression with respect to inflammation is not fully understood. In this issue of the JCI, the study by Combadière and colleagues shows that CX3C chemokine receptor 1-deficient (CX3CR1-deficient) mice have abnormal microglia that accumulate beneath the retina and contribute to the progression of AMD.


Nitrofurantoin: mechanism of action and implications for resistance development in common uropathogens.
Nitrofurantoin is an effective urinary tract antibacterial to which no clinically significant resistance development has occurred. We have previously shown that nitrofurantoin susceptibility in bacteria correlates with the presence of bacterial nitroreductases which convert nitrofurantoin to highly reactive electrophilic intermediates. These intermediates were shown to attack bacterial ribosomal proteins non-specifically, causing complete inhibition of protein synthesis. In the present study, we confirm previous reports that low concentrations of nitrofurantoin specifically inhibit inducible enzyme synthesis in bacteria, and show that this inhibition occurs at levels equivalent to the MICs of nitrofurantoin for several bacterial species. Our previous studies had shown that nitrofurantoin at different concentrations interacts with bacterial ribosomal proteins in qualitatively the same fashion; we now report that quantitative differences are seen in the labelling observed at different nitrofurantoin concentrations and discuss these differences as they may relate to the inhibition of inducible enzyme synthesis. In addition, we have now demonstrated the existence of a novel mechanism of action for nitrofurantoin which does not require the production of reactive nitrofurantoin metabolites by bacterial reductases. The lack of clinically significant bacterial resistance development to nitrofurantoin is likely due to the combination of nitrofurantoin's multiple sites of attack and multiple mechanisms of action.


Development of Polyelectrolyte Complexes for the Delivery of Peptide-Based Subunit Vaccines against Group A Streptococcus.
Peptide subunit vaccines hold great potential compared to traditional vaccines. However, peptides alone are poorly immunogenic. Therefore, it is of great importance that a vaccine delivery platform and/or adjuvant that enhances the immunogenicity of peptide antigens is developed. Here, we report the development of two different systems for the delivery of lipopeptide subunit vaccine (LCP-1) against group A streptococcus: polymer-coated liposomes and polyelectrolyte complexes (PECs). First, LCP-1-loaded and alginate/trimethyl chitosan (TMC)-coated liposomes (Lip-1) and LCP-1/alginate/TMC PECs (PEC-1) were examined for their ability to trigger required immune responses in outbred Swiss mice; PEC-1 induced stronger humoral immune responses than Lip-1. To further assess the adjuvanting effect of anionic polymers in PECs, a series of PECs (PEC-1 to PEC-5) were prepared by mixing LCP-1 with different anionic polymers, namely alginate, chondroitin sulfate, dextran, hyaluronic acid, and heparin, then coated with TMC. All produced PECs had similar particle sizes (around 200 nm) and surface charges (around + 30 mV). Notably, PEC-5, which contained heparin, induced higher antigen-specific systemic IgG and mucosal IgA titers than all other PECs. PEC systems, especially when containing heparin and TMC, could function as a promising platform for peptide-based subunit vaccine delivery for intranasal administration.


The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group: past activities, current status and future direction.
The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group was organized in 1986. Initially, 26 collaborative institutions participated. In the early period, the Lung Cancer Surgical Study Group focused on combined modality therapies and conducted nine trials, including JCOG9101: adjuvant chemotherapy for resected small-cell lung cancer, and JCOG9806: induction chemoradiotherapy followed by surgery for superior sulcus tumor, which greatly impacted the treatment strategies for some special kinds of lung cancer. Since the 2000s, the Lung Cancer Surgical Study Group has defined radiologically noninvasive adenocarcinoma: JCOG0201 and investigated adequate modes of surgical resection for small-sized non-small cell lung cancer: JCOG0802, JCOG0804 and JCOG1211. The accrual of these trials is now complete and we are waiting for the maturation of follow-up data. In addition, two adjuvant trials have been conducted: JCOG0707; a Phase III study of adjuvant chemotherapy for resected pathological stage I (T1 > 2 cm) non-small cell lung cancer, and JCOG1205; a Phase III study of adjuvant chemotherapy for completely resected pulmonary high-grade neuroendocrine tumor. The accrual of JCOG0707 is complete and we are waiting for the maturation of follow-up data. At present, 44 institutions are active members of the Lung Cancer Surgical Study Group. In addition to thoracic surgeons, medical oncologists, pathologists and radiotherapists are participating in the Lung Cancer Surgical Study Group. The Lung Cancer Surgical Study Group continues to conduct various clinical trials in an effort to improve survival in patients with lung cancer. In this review, we provide an overview of the past 30 years, as well as the present status and future direction of the Lung Cancer Surgical Study Group.


[Long-term acting insulin analogues and the risks of hypoglycemic incidence].
As recommendation for treatment of type 2 diabetes mellitus, incorporating individualization of therapeutic targets for patients with co-morbidities, for whom hypoglycemia increases the risk of complications. The sufficient target value is 60 mmol/mol of HbA1c under the guidelines of Czech Diabetesl Society. Insulin therapy becomes essential for a whole line of patients, including those of advanced age, in relation to duration of diabetes and progression of the disease. The Diabetes and Aging Study observed patients of 60 years age with diabetes, in which hypoglycemia ranked among the most frequent side effects of therapy and where incidence increased with age. It is necessary to select simple insulin regimens which are in accordance with the associated diseases and the age of the person. A therapy of basal insulin analogues, linked to a low risk rate of hypoglycemic incidence, enables combination with oral antidiabetic drugs and GLP-1 receptor agonists.Key words: basal insulin analogues - hypoglycemia - type 2 diabetes mellitus.


Tellurium: A High-Performance Cathode for Magnesium Ion Batteries Based on a Conversion Mechanism.
Magnesium ion batteries (MIBs), due to the low redox potential of Mg, high theoretical capacity, dendrite-free magnesiation, and safe nature, have been recognized as a post-lithium energy storage system. However, an ongoing challenge, sluggish Mg2+ kinetics in the small number of available cathode materials of MIBs, restricts its further development. The existing cathodes mostly deliver unsatisfactory capacity with poor cycling life based on the traditional ion-intercalation mechanism. Herein, we fabricated a conversion-type Mg∥Te battery based on a reversible two-step conversion reaction (Te to MgTe2 to MgTe). High discharge capacities (387 mAh g-1) and rate capability (165 mAh g-1 at 5 A g-1) can be achieved. The diffusivity of Mg2+ can reach 3.54 × 10-8 cm2 s-1, enabled by the high electrical conductivity of Te and increased surface conversion sites. Subsequently, ab initio molecular dynamics simulation was also carried out to further confirm the conversion mechanism and fast Mg2+ transportation kinetics.


Release of substance P from rat hypothalamus and pituitary by endothelin.
Endothelin-1 is a 21 amino acid peptide originally isolated from porcine aortic endothelium and has recently been localized within the central nervous system. We have administered endothelin-1 in a dynamic perfusion system in order to study its possible effects on the rat hypothalamus and anterior pituitary. Tissue (hypothalami or quartered pituitaries) was placed into plastic chambers and was perfused with oxygenated Krebs-bicarbonate solution. After an interval to establish stable basal peptide release, endothelin-1 was administered at two doses (0.1 and 1 microM) and the release of substance P, vasoactive intestinal peptide, 7B2, and somatostatin was measured, the last being detectable only in hypothalamic perfusates. Both concentrations of endothelin-1 led to a significant increase (P less than 0.01) in the release of substance P from the hypothalamus and pituitary, but not of vasoactive intestinal peptide, 7B2, or somatostatin. Thus after the 0.1 microM and 1 microM endothelin-1 perfusion substance P release from the hypothalamus increased by 125 +/- 5% and 215 +/- 15% (mean +/- SEM) of basal and from the pituitary by 168 +/- 8% and 276 +/- 15% (mean +/- SEM). No change occurred in the output of ACTH or other pituitary hormones. The release of substance P from hypothalamus or pituitary after stimulation with endothelin-1 was not blocked when a calcium free medium was used. Endothelin-1 binding sites were identified on rat pituitary cell membranes. These findings suggest the possibility that endothelin may act as a paracrine substance, neurotransmitter, or neuromodulator in the hypothalamo-pituitary axis.


Detection of ETV6 and RUNX1 gene rearrangements using fluorescence in situ hybridization in Mexican patients with acute lymphoblastic leukemia: experience at a single institution.
The t(12;21) produces the gene fusion ETV6/RUNX1 and is a frequent rearrangement in childhood ALL, associated with a good prognosis. In Mexico its prevalence has not been reported. This study evaluated a group of consecutive Mexican children with newly diagnosed ALL, to detect the fusion using fluorescence in situ hybridization (FISH). Seventy-one bone marrow samples were analyzed with FISH, using ETV6/RUNX1 DNA probes. Abnormalities of ETV6, RUNX1, or both were found in 31 of the 71 (44%) patients. Six showed ETV6/RUNX1 fusion and 17, with extra RUNX1 copies, presented an additional chromosome 21 or dup(21)(q22). Five patients had structural changes in ETV6, and three patients showed extra copies of ETV6 and RUNX1 from polysomy of chromosomes 12 and 21. Our results revealed a fusion in 8.5% of the 71 cases analyzed. This frequency is lower than that observed in other populations (9.5-32%). The structural rearrangements resulting in RUNX1 extra copies were found in 9.8% of patients, which is close to the range reported (1.5-9.7%) by other authors. Due to the prevalence of RUNX1 overrepresentation in our population and its unknown prognostic significance, further studies should be conducted in consecutive children with ALL, to correlate this abnormality with the patients' follow-up.


Helping bereaved children and parents.
When a child dies, or is bereaved of a parent or sibling, it changes a family for ever. Grief affects different family members in different ways and may prevent them from supporting one another effectively. An understanding and well informed approach from health professionals can help the family manage their grief and adjust to their new life without the person who has died.


High-resolution computed tomography findings in hantavirus pulmonary syndrome.
The hantavirus pulmonary syndrome (HPS) is an acute, rapidly progressive disease transmitted by rodent excreta, with endothelial damage playing a central role in the pathophysiology. It usually affects rural workers. The lung itself is the target organ and reflects all the patterns of endothelial involvement of this disease. The radiologic findings of HPS are vast and range from a mild interstitial involvement to total obliteration of the airspaces with or without pleural effusion. There are no specific findings on high-resolution computed tomography in HPS; nevertheless, findings of thickening of interlobular septa, ground-glass opacities, and occasionally small ill-defined nodular opacities have been described. The authors report a fulminant case of HPS and discuss its varied high-resolution computed tomography findings. To our knowledge, the "crazy-paving" pattern has not been seen previously in such cases.


Pharmacogenetics of coumarinic oral anticoagulants.
Coumarinic oral anticoagulants are life-saving drugs, but are also one of the leading causes of drug-induced major bleeding events. Moreover, there is substantial individual variation in response to coumarinic oral anticoagulants caused by several factors including variations in the CYP2C9 and VKORC1 genes. Several retrospective and a few small prospective clinical studies have shown that polymorphisms in CYP2C9 and VKORC1 genes together account for 35-50% of the variability in warfarin initiation and maintenance dose requirements. Large randomized clinical trials are currently underway to further solidify the safety, clinical utility and cost-effectiveness of pharmacogenetic-guided dosing algorithms for warfarin, acenocoumarol and phenprocoumon. By 2020, coumarinic oral anticoagulant pharmacogenetic testing will be part of routine clinical practice in anticoagulant therapy.


IVGTT-based simple assessment of glucose tolerance in the Zucker fatty rat: Validation against minimal models.
For the assessment of glucose tolerance from IVGTT data in Zucker rat, minimal model methodology is reliable but time- and money-consuming. This study aimed to validate for the first time in Zucker rat, simple surrogate indexes of insulin sensitivity and secretion against the glucose-minimal-model insulin sensitivity index (SI) and against first- (Φ1) and second-phase (Φ2) β-cell responsiveness indexes provided by C-peptide minimal model. Validation of the surrogate insulin sensitivity index (ISI) and of two sets of coupled insulin-based indexes for insulin secretion, differing from the cut-off point between phases (FPIR3-SPIR3, t = 3 min and FPIR5-SPIR5, t = 5 min), was carried out in a population of ten Zucker fatty rats (ZFR) and ten Zucker lean rats (ZLR). Considering the whole rat population (ZLR+ZFR), ISI showed a significant strong correlation with SI (Spearman's correlation coefficient, r = 0.88; P<0.001). Both FPIR3 and FPIR5 showed a significant (P<0.001) strong correlation with Φ1 (r = 0.76 and r = 0.75, respectively). Both SPIR3 and SPIR5 showed a significant (P<0.001) strong correlation with Φ2 (r = 0.85 and r = 0.83, respectively). ISI is able to detect (P<0.001) the well-recognized reduction in insulin sensitivity in ZFRs, compared to ZLRs. The insulin-based indexes of insulin secretion are able to detect in ZFRs (P<0.001) the compensatory increase of first- and second-phase secretion, associated to the insulin-resistant state. The ability of the surrogate indexes in describing glucose tolerance in the ZFRs was confirmed by the Disposition Index analysis. The model-based validation performed in the present study supports the utilization of low-cost, insulin-based indexes for the assessment of glucose tolerance in Zucker rat, reliable animal model of human metabolic syndrome.


Salvianolic Acid Exerts Cardioprotection through Promoting Angiogenesis in Animal Models of Acute Myocardial Infarction: Preclinical Evidence.
Radix Salviae miltiorrhizae, danshen root (danshen), is one of the widely used Chinese herbal medicines in clinics, containing rich phenolic compounds. Salvianolic acid is the main active compound responsible for the pharmacologic effects of danshen. Here, we aimed to evaluate the effects of salvianolic acid on cardioprotection through promoting angiogenesis in experimental myocardial infarction. Studies of salvianolic acid in animal models of myocardial infarction were obtained from 6 databases until April 2016. The outcome measures were vascular endothelium growth factor (VEGF), blood vessel density (BVD), and myocardial infarct size. All the data were analyzed using Rev-Man 5.3 software. Ultimately, 14 studies were identified involving 226 animals. The quality score of studies ranged from 3 to 6. The meta-analysis of six studies showed significant effects of salvianolic acid on increasing VEGF expression compared with the control group (P < 0.01). The meta-analysis of the two salvianolic acid A studies and three salvianolic acid B studies showed significantly improving BVD compared with the control group (P < 0.01). The meta-analysis of five studies showed significant effects of salvianolic acid for decreasing myocardial infarct size compared with the control group (P < 0.01). In conclusion, these findings demonstrated that salvianolic acid can exert cardioprotection through promoting angiogenesis in animal models of myocardial infarction.


Experimental and calculated parameters on particle phagocytosis by alveolar macrophages.
Phagocytosis of three types of fluorescein-labeled test particles by rat alveolar macrophages (AM) were studied: spherical silica (3.2 microm), heat-killed Candida albicans (3.8 microm), and heat-killed Cryptococcus neoformans (6.1 microm) opsonized with specific IgG. These particles should attach to scavenger, mannose, and Fc receptors, respectively. Both control AM and AM pretreated for 20 h with interferon-gamma (12.5 or 50 U/ml) were studied. The sum of the number of attached and ingested particles per AM (accumulated attachment) was used as a measure of the attachment process, and the number of ingested particles per AM divided by the accumulated attachment (ingested fraction) was used as a measure of the ingestion process. The average ingestion time (IT), which is also a measure of the ingestion process, was calculated from the experimental data. The ingestion process was independent of the attachment process. IT increased with the time of observation. This is explained by the fact that IT determined from observation times shorter than the whole distribution of IT for a certain particle results in a shorter IT than the real average IT. C. albicans (mannose receptor) had the fastest ingestion process, C. neoformans opsonized with specific IgG (Fc receptor) had ingestion that was nearly as fast, and the silica particles (scavenger receptors) had the slowest ingestion process. Treatment with interferon-gamma markedly impaired the attachment process for all three types of particles (and three types of receptors) but clearly impaired the ingestion process only for silica particles (scavenger receptors).


The mechanism of ipsilateral ataxia in lacunar hemiparesis: SPECT perfusion imaging.
Although ataxic hemiparesis is a common lacunar syndrome, the precise mechanism underlying hemiataxia is not clear. We attempted to identify ataxia-related, cerebral blood flow changes in patients presenting with ataxic hemiparesis after acute capsular infarct. We used 99mTc-ECD brain perfusion single-photon emission computed tomography to evaluate regional cerebral blood flow in 12 patients with ataxic hemiparesis caused by capsular infarct, and we compared the regional blood flow of these patients with that of 11 patients with pure motor hemiparesis caused by similar lesions. The ipsilateral red nucleus blood flow was significantly decreased in the ataxic hemiparesis patients, whereas the ipsilateral red nucleus blood flow was increased in the pure motor hemiparesis patients. Crossed cerebellar diaschisis (decreased contralateral cerebellar blood flow) was seen in ataxic hemiparesis patients; similarly, it was seen in pure motor hemiparesis patients. Our findings suggest that ataxia in hemiparetic patients with capsular infarct can be caused by ipsilateral red nucleus dysfunction secondary to cortico-rubral pathway disruption at the internal capsule.


The actin-binding protein Lasp promotes Oskar accumulation at the posterior pole of the Drosophila embryo.
During Drosophila oogenesis, Oskar mRNA is transported to the posterior pole of the oocyte, where it is locally translated and induces germ-plasm assembly. Oskar protein recruits all of the components necessary for the establishment of posterior embryonic structures and of the germline. Tight localization of Oskar is essential, as its ectopic expression causes severe patterning defects. Here, we show that the Drosophila homolog of mammalian Lasp1 protein, an actin-binding protein previously implicated in cell migration in vertebrate cell culture, contributes to the accumulation of Oskar protein at the posterior pole of the embryo. The reduced number of primordial germ cells in embryos derived from lasp mutant females can be rescued only with a form of Lasp that is capable of interacting with Oskar, revealing the physiological importance of the Lasp-Oskar interaction.


Alveolar soft-part sarcoma of the urinary bladder with urethral recurrence: a unique case with emphasis on differential diagnoses and diagnostic utility of an immunohistochemical panel including TFE3.
Alveolar soft-part sarcoma (ASPS) is a rare, clinically, morphologically, ultrastructurally, and cytogenetically distinctive malignant mesenchymal tumor that most classically occurs in the extremities of adolescents and young adults, but has also been described in a number of unusual sites. The molecular signature of ASPS is a specific der(17)t(X;17)(p11.2;q25) translocation, which results in the fusion of TFE3 transcription factor gene (from Xp11) with ASPL at 17q25. The ASPL-TFE3 fusion protein encoded by the fusion transcript can be detected immunohistochemically with commercially available antibodies to the carboxy terminus of TFE3. Herein, we report a unique case of ASPS presenting in the bladder with subsequent urethral recurrence in a 25-year-old woman. We emphasize the differential diagnoses engendered by ASPS including common, not-so-common, and rare tumors involving the urinary bladder that have a nested architecture, and both clear and eosinophilic cytoplasm, and demonstrate the utility of a broad immunohistochemistry panel including TFE3 for diagnosis.


Reversible inhibition of mitochondrial protein synthesis during linezolid-related hyperlactatemia.
The objective of the present study was to determine the mitochondrial toxicity mechanisms of linezolid-related hyperlactatemia. Five patients on a long-term schedule of linezolid treatment were studied during the acute phase of hyperlactatemia and after clinical recovery and lactate normalization following linezolid withdrawal. Mitochondrial studies were performed with peripheral blood mononuclear cells and consisted of measurement of mitochondrial mass, mitochondrial protein synthesis homeostasis (cytochrome c oxidase [COX] activity, COX-II subunit expression, COX-II mRNA abundance, and mitochondrial DNA [mtDNA] content), and overall mitochondrial function (mitochondrial membrane potential and intact-cell oxidative capacity). During linezolid-induced hyperlactatemia, we found extremely reduced protein expression (16% of the remaining content compared to control values [100%], P < 0.001) for the mitochondrially coded, transcribed, and translated COX-II subunit. Accordingly, COX activity was also found to be decreased (51% of the remaining activity, P < 0.05). These reductions were observed despite the numbers of COX-II mitochondrial RNA transcripts being abnormally increased (297%, P = 0.10 [not significant]) and the mitochondrial DNA content remaining stable. These abnormalities persisted even after the correction for mitochondrial mass, which was mildly decreased during the hyperlactatemic phase. Most of the mitochondrial abnormalities returned to control ranges after linezolid withdrawal, lactate normalization, and clinical recovery. Linezolid inhibits mitochondrial protein synthesis, leading to decreased mitochondrial enzymatic activity, which causes linezolid-related hyperlactatemia, which resolves upon discontinuation of linezolid treatment.


Vancomycin-resistant enterococcus: a review from a Singapore perspective.
Vancomycin-resistant enterococcus (VRE) can cause serious infections in vulnerable, immunocompromised patients. In this article, we summarise current data on epidemiology, detection, treatment and prevention of VRE. VRE was first isolated in Singapore in 1994 and until 2004 was only sporadically encountered in our public hospitals. After 2 outbreaks in 2004 and in 2005, VRE has become established in our healthcare institutions. Multiple studies have shown that VRE spreads mainly via contaminated hands, cloths and portable equipment carried by healthcare workers. Only a comprehensive programme (consisting of active surveillance, isolation of colonised/infected patients, strict adherence to proper infection control practices and anti-microbial stewardship) can limit the spread of these organisms. In addition to monitoring the compliance with traditional infection control measures, new strategies that merit consideration include pre-emptive isolation of patients in high-risk units and molecular techniques for the detection of VRE.


The L-coding region of the DA strain of Theiler's murine encephalomyelitis virus causes dysfunction and death of myelin-synthesizing cells.
The DA strain and other members of the TO subgroup of Theiler's murine encephalomyelitis virus (TMEV) induce an early transient subclinical neuronal disease followed by a chronic progressive inflammatory demyelination, with persistence of the virus in the central nervous system (CNS) for the life of the mouse. Although TMEV-induced demyelinating disease (TMEV-IDD) is thought to be immune mediated, there is also evidence that supports a role for the virus in directly inducing demyelination. In order to clarify the function of DA virus genes, we generated a transgenic mouse that had tamoxifen-inducible expression of the DA L-coding region in oligodendrocytes (and Schwann cells), a cell type in which the virus is known to persist. Tamoxifen-treated young transgenic mice usually developed an acute progressive fatal paralysis, with abnormalities of the oligodendrocytes and Schwann cells and demyelination, but without significant lymphocytic infiltration; later treatment led to transient weakness with demyelination and persistent expression of the recombined transgene. These findings demonstrate that a high level of expression of DA L can cause the death of myelin-synthesizing cells and death of the mouse, while a lower level of L expression (which can persist) can lead to cellular dysfunction with survival. The results suggest that expression of DA L plays an important role in the pathogenesis of TMEV-IDD. Virus-induced infection and death of oligodendrocytes may play a part in the demyelination of other diseases in which an immune-mediated mechanism has been stressed, including multiple sclerosis.


Correlated heart/limb anomalies in Mendelian syndromes provide evidence for a cardiomelic developmental field.
Coordinated development of heart and limbs is suggested by a review of human abortus, chromosomal, and teratogenic syndromes, and characterized by an analysis of Mendelian disorders that affect the limbs, heart, or both (672, 202, or 107, respectively). Mendelian syndromes with altered limb patterns often include cardiac anomalies, as shown by limb duplications (34%), deficiencies (30%), hypoplasias (23%), or dysplasias (9.3%). Syndromes with particular cardiac anomalies, illustrated by VSD (85%) or ASD (90%), frequently include limb defects. Positional correlations of anterior (preaxial/conotruncal), posterior (postaxial/atrial), or lateral (mirror hand/atrial isometry) heart/limb anomalies are consistent with the existence of a cardiomelic developmental field. Vertebrate comparisons suggest an early D-V limb-heart gradient, influenced by the neural crest, with distal limb segments (80% of syndromic defects) at its dorsal extreme. The proposed cardiomelic field relates the genetic heterogeneity of disorders such as Holt-Oram syndrome to a cascade of molecules, including the brachyury, sonic hedgehog, bone morphogenetic protein, retinoic acid receptor, and transforming growth factor-beta families.


Regulation of pentitol metabolism by aerobacter aerogenes. II. Induction of the ribitol pathway.
The incubation of Aerobacter aerogenes PRL-R3 with ribitol resulted in the induction of ribitol dehydrogenase and d-ribulokinase, coordinately controlled enzymes of the pathway of ribitol catabolism. A dehydrogenase-negative mutant was unable to induce d-ribulokinase activity following incubation with ribitol. Similar experiments using a kinase-negative mutant resulted in normal induction of ribitol dehydrogenase, as compared to the wild-type PRL-R3 strain. Constitutive or induced cells for l-fucose isomerase were capable of catalyzing the isomerization of d-arabinose to d-ribulose. In contrast to the experiments using ribitol as the substrate, the isomerization of d-arabinose resulted in the induction of d-ribulokinase with dehydrogenase-negative cells. These data indicated that d-ribulose, rather than ribitol, acts as the inducer of the enzymes for ribitol degradation.


Lead concentrations in semen of healthy men without occupational exposure to lead.
Lead analyses were performed by atomic absorption spectrometry of semen and blood specimens from 21 medical students and technicians (ages 19 to 41 years) who had no occupational or avocational exposure to lead (Pb). Seminal Pb concentrations averaged 5.9 (S.D. +/- 2.7) microgram per dl (range = 1.0 to 11), and blood Pb concentrations averaged 13.1 (S.D. +/- 3.5) microgram per dl (range = 7.0 to 19). Sperm counts averaged 54 X 10(6) (S.D. +/- 29 X 10(6)) sperm per ml (range = 13 X 10(6) to 120 X 10(6)). Seminal protein concentrations averaged 2.9 (S.D. +/- 0.5) g per dl (range = 2.0 to 4.0). No significant correlations were found between seminal Pb concentrations and blood Pb concentrations or between seminal Pb concentrations and sperm counts. In each subject, the concentration of seminal Pb was less than or equal to the concentration of blood Pb. These measurements are the first published data on seminal Pb concentrations in healthy men, and they serve as reference values for measurements of Pb in semen from Pb-poisoned men.


Sensorineural hearing loss enhances auditory sensitivity and temporal integration for amplitude modulation.
Amplitude-modulation detection thresholds (AMDTs) were measured at 40 dB sensation level for listeners with mild-to-moderate sensorineural hearing loss (age: 50-64 yr) for a carrier frequency of 500 Hz and rates of 2 and 20 Hz. The number of modulation cycles, N, varied between two and nine. The data were compared with AMDTs measured for young and older normal-hearing listeners [Wallaert, Moore, and Lorenzi (2016). J. Acoust. Soc. Am. 139, 3088-3096]. As for normal-hearing listeners, AMDTs were lower for the 2-Hz than for the 20-Hz rate, and AMDTs decreased with increasing N. AMDTs were lower for hearing-impaired listeners than for normal-hearing listeners, and the effect of increasing N was greater for hearing-impaired listeners. A computational model based on the modulation-filterbank concept and a template-matching decision strategy was developed to account for the data. The psychophysical and simulation data suggest that the loss of amplitude compression in the impaired cochlea is mainly responsible for the enhanced sensitivity and temporal integration of temporal envelope cues found for hearing-impaired listeners. The data also suggest that, for AM detection, cochlear damage is associated with increased internal noise, but preserved short-term memory and decision mechanisms.


"Identifying and Describing Emotions": Measuring the Effectiveness of a Brief, Alexithymia-Specific, Intervention for a Sex Offender Population.
Certain individuals who sexually offend may have difficulty differentiating, identifying, and articulating emotions. These clients may prove challenging for therapists when engaging with them in treatment. Such clients may suffer from alexithymia. There has been a dearth of research regarding specific psychotherapeutic interventions for alexithymia in both the clinical and forensic fields. The present study provides results from a pilot study on the efficacy of a brief, four-session, alexithymia-specific intervention with adults who have sexually offended. The intervention also aimed to increase emotional awareness and psychological mindedness. The intervention was comprised of both mindfulness and mentalization treatment components. Thirty-two men (Mage = 41.8 years, SD = 11.9) convicted of sexual offences completed the intervention group. When compared with a matched control condition (n = 27; Mage = 39, SD = 10.8), the intervention was effective in decreasing alexithymia characteristics and increasing psychological mindedness. Results suggest that the intervention was an effective means of increasing emotional awareness in this population. These provisional results must be tempered by the limitations of the study. However, the positive findings warrant future investigation. Clinical implications and ideas for future work are also discussed.


Biopolymer-mediated suramin chemotherapy in the treatment of experimental brain tumours.
Suramin inhibits tumour growth and neoangiogenesis by blocking several growth factor receptors. In this study the toxicity and efficacy of intralesional delivery of suramin incorporated in a controlled-release polymer were assessed in a rat 9L tumour model. Initially, the toxicity of the compound was evaluated in adult Fisher 344 rats. The animals were intracerebrally implanted with an ethylene vinyl acetate copolymer. These experiments showed early toxicity in the rats implanted with a 50% load-polymer and 100% mortality within 48 h, whereas in rats implanted with a 33% load-polymer only transient behavioural changes were observed. In a second experiment the rats were stereotactically implanted with 9L cells in the frontal region. Two days after inoculation of cells, the animals were divided into two groups: one group received a 33% suramin load-biopolymer at the tumour implantation site, while the control group received polymer implants only. The interstitial release of suramin in the brain did not produce any improvement in survival of 9L tumour-bearing rats, with a mean survival of 14.2 +/- 1 days for the suramin-treated group versus 13.8 +/- 2 for the control group (p = 0.82). We conclude that intralesional polymer-mediated chemotherapy with suramin does not prolong survival in rats with intracerebral 9L tumours.


Late presentation of metastatic pheochromocytoma: a problem case solved by I-131 MIBG scintigraphy.
A patient presented with recurrent pheochromocytoma 10 years following the apparently successful surgical cure of a right adrenal pheochromocytoma. Conventional medical imaging techniques, (chest radiograph, abdominal ultrasound, and abdominal CT) suggested local recurrence for which surgery was planned. I-131 MIBG scintigraphy revealed disseminated metastatic disease that rendered attempts at surgical cure futile. The patient was treated with three therapeutic doses of I-131 MIBG with good symptomatic palliation and improvement of some biochemical parameters.


Introduction to the special issue: drugs, wars, military personnel, and veterans.
This special issue examines major structural, sociocultural, and behavioral issues surrounding substance use and misuse among U.S. military personnel and veterans who served in recent military conflicts in Iraq and Afghanistan. This introduction provides a brief historical review of the US's experiences of the linkages between war and substance use, misuse, and abuse. It then describes how the various topics covered in this issue span the military-veteran life course and explains the significance of each contribution.


Physiology of thrombospondin.
Thrombospondin is a large, multifunctional glycoprotein released from activated platelets and secreted by growing cells. It binds to components of the cell surface and extracellular milieu. Thrombospondin probably modulates a number of processes, including aggregation of platelets, formation and lysis of fibrin, adhesion and migration of cells, and progression of cells through the growth cycle. Studies relating thrombospondin to disease processes are just beginning.


Retromer and Its Role in Regulating Signaling at Endosomes.
The retromer complex is a key element of the endosomal protein sorting machinery being involved in trafficking of proteins from endosomes to the Golgi and also endosomes to the cell surface. There is now accumulating evidence that retromer also has a prominent role in regulating the activity of many diverse signaling proteins that traffic through endosomes and this activity has profound implications for the functioning of many different cell and tissue types from neuronal cells to cells of the immune system to specialized polarized epithelial cells of the retina. In this review, the protein composition of the retromer complex will be described along with many of the accessory factors that facilitate retromer-mediated endosomal protein sorting to detail how retromer activity contributes to the regulation of several distinct signaling pathways.


Cdk9 is an essential kinase in Drosophila that is required for heat shock gene expression, histone methylation and elongation factor recruitment.
Phosphorylation of the large RNA Polymerase II subunit C-terminal domain (CTD) is believed to be important in promoter clearance and for recruiting protein factors that function in messenger RNA synthesis and processing. P-TEFb is a protein kinase that targets the (CTD). The goal of this study was to identify chromatin modifications and associations that require P-TEFb activity in vivo. We knocked down the catalytic subunit of P-TEFb, Cdk9, in Drosophila melanogaster using RNA interference. Cdk9 knockdown flies die during metamorphosis. Phosphorylation at serine 2 and serine 5 of the CTD heptad repeat were both dramatically reduced in knockdown larvae. Hsp 70 mRNA induction by heat shock was attenuated in Cdk9 knockdown larvae. Both mono- and trimethylation of histone H3 at lysine 4 were dramatically reduced, suggesting a link between CTD phosphorylation and histone methylation in transcribed chromatin in vivo. Levels of the chromo helicase protein CHD1 were reduced in Cdk9 knockdown chromosomes, suggesting that CHD1 is targeted to chromosomes through P-TEFb-dependent histone methylation. Dimethylation of histone H3 at lysine 36 was significantly reduced in knockdown larvae, implicating CTD phosphorylation in the regulation of this chromatin modification. Binding of the RNA Polymerase II elongation factor ELL was reduced in knockdown chromosomes, suggesting that ELL is recruited to active polymerase via CTD phosphorylation.


Multicenter double-blind study of ticlopidine in the treatment of intermittent claudication and the prevention of its complications.
In this multicenter trial 169 patients with chronic intermittent claudication due to obstructive peripheral vascular disease were randomized in a double-blind fashion into two parallel groups receiving either 250 mg ticlopidine or placebo, twice daily. At entry, the two groups (83 ticlopidine, 86 placebo) were well matched for the major clinical features apart from an excess of women in the ticlopidine group. At six months, 167 patients were alive, 2 having died of malignant disease (1 from each group). At this stage, 39 patients from the ticlopidine group and 29 from the placebo group (p = 0.04) had increased their walking distance by more than 50% of baseline values. For the groups as a whole pain-free and total walking distance were greater in the ticlopidine group than in the placebo group (194 vs 124 meters, p = 0.03 and 236 vs 170 meters, p = 0.04, respectively). Two patients from the ticlopidine group vs 9 patients from the placebo group (p = 0.03) developed significant cardiovascular events during the study. These results indicate that ticlopidine has a beneficial effect both in the treatment of the symptoms and the prevention of vascular complications in patients with intermittent claudication.


Total hip replacement for Paget's disease of the hip.
We reviewed our experience with total hip replacement for coxarthrosis due to Paget's disease. The clinical and radiographic results in twenty-one patients who had a total hip replacement between October 1972 and February 1982 were analyzed. The ages of the patients averaged 68.6 years (range, fifty-seven to eighty years) and there were twelve women and nine men. The follow-up averaged five years and two months (range, two years to eleven years and four months). A good or excellent result was achieved in eighteen patients. Of the other three patients, two required a revision operation at two and one-half and five years postoperatively for symptomatic mechanical loosening of the femoral component. The remaining patient had a fair result because of activity of the Paget's disease. Special problems that we encountered included varus deformity of the proximal end of the femur predisposing to varus placement of the femoral component, protrusio acetabuli, increased blood loss, sclerotic bone that made reaming difficult, and heterotopic ossification.


Effect of hydrostatic pressure on water penetration and rotational dynamics in phospholipid-cholesterol bilayers.
The effect of high hydrostatic pressure on the lipid bilayer hydration, the mean order parameter, and rotational dynamics of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) cholesterol vesicles has been studied by time-resolved fluorescence spectroscopy up to 1500 bar. Whereas the degree of hydration in the lipid headgroup and interfacial region was assessed from fluorescence lifetime data using the probe 1-(4-trimethylammonium-phenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH), the corresponding information in the upper acyl chain region was estimated from its effect on the fluorescence lifetime of and 3-(diphenylhexatrienyl)propyl-trimethylammonium (TMAP-DPH). The lifetime data indicate a greater level of interfacial hydration for DPPC bilayers than for POPC bilayers, but there is no marked difference in interchain hydration of the two bilayer systems. The addition of cholesterol at levels from 30 to 50 mol% to DPPC has a greater effect on the increase of hydrophobicity in the interfacial region of the bilayer than the application of hydrostatic pressure of several hundred to 1000 bar. Although the same trend is observed in the corresponding system, POPC/30 mol% cholesterol, the observed effects are markedly less pronounced. Whereas the rotational correlation times of the fluorophores decrease in passing the pressure-induced liquid-crystalline to gel phase transition of DPPC, the wobbling diffusion coefficient remains essentially unchanged. The wobbling diffusion constant of the two fluorophores changes markedly upon incorporation of 30 mol% cholesterol, and increases at higher pressures, also in the case of POPC/30 mol% cholesterol. The observed effects are discussed in terms of changes in the rotational characteristics of the fluorophores and the phase-state of the lipid mixture. The results demonstrate the ability of cholesterol to adjust the structural and dynamic properties of membranes composed of different phospholipid components, and to efficiently regulate the motional freedom and hydrophobicity of membranes, so that they can withstand even drastic changes in environmental conditions, such as high external hydrostatic pressure.


IgH gene rearrangements on the unexpressed allele in rabbit B cells.
VDJ genes are assembled in two sequential DNA recombination steps, rearrangement of D and J(H) gene segments followed by rearrangement of a V(H) gene segment. In mouse and human, VDJ gene rearrangements occur in a regulated step in which D rearranges to J(H) on both alleles before V(H) rearranges to DJ. To determine how VDJ gene rearrangements are regulated in the rabbit, we studied the IgH gene rearrangements in rabbit B cells by examining the gene rearrangement on the unexpressed allele in rabbit hybridomas. By Southern blot analysis with probes from the J(H) and 3'V(H)1 regions, we found that approximately 50% of the hybridomas had DJ gene rearrangements on the unexpressed allele, whereas the remaining 50% did not rearrange either J(H) or V(H) genes. Unexpectedly, we found a VD gene rearrangement on the unexpressed allele of a rabbit B cell line, so we PCR-amplified the VD gene rearrangements from splenocyte DNA and found a few VD gene rearrangements in normal B cells as well. The data taken together show that IgH gene rearrangements in rabbit B cells are regulated differently than those in the mouse, and we hypothesize that in some B cells, VDJ gene rearrangements proceed through a VD intermediate rather than through a DJ intermediate.