SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction.
The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer and T-cell acute lymphoblastic leukaemia (T-ALL). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL, validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun, Myc, cyclin E and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth, overexpression of Jun, Myc or notch 1 can also induce programmed cell death. Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SCF(FBW7) (a SKP1-cullin-1-F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FBW7 and has implications for the targeted treatment of patients with FBW7-deficient T-ALL.


Ebstein's anomaly. Genetic study of 26 families.
The families of 26 patients with Ebstein's anomaly were examined. There were 120 first-degree relatives, 100 of whom were living, and 93 of these were examined. Information was available on 14 of the 20 who had died. No case of Ebstein's anomaly was found among the first-degree relatives, but 2 had ventricular septal defects and another, who died at 7 months, was said to have had congenital heart disease. In more distant relatives there were 6 with congenital heart disease, including 2 with ventricular septal defects and 2 with Fallot's tetralogy.


Comparative genomics of cyclic-di-GMP signalling in bacteria: post-translational regulation and catalytic activity.
Cyclic-di-GMP is a bacterial second messenger that controls the switch between motile and sessile states. It is synthesized by proteins containing the enzymatic GGDEF domain and degraded by the EAL domain. Many bacterial genomes encode several copies of proteins containing these domains, raising questions on how the activities of parallel c-di-GMP signalling systems are segregated to avoid potentially deleterious cross-talk. Moreover, many 'hybrid' proteins contain both GGDEF and EAL domains; the relationship between the two apparently opposing enzymatic activities has been termed a 'biochemical conundrum'. Here, we present a computational analysis of 11 248 GGDEF- and EAL-containing proteins in 867 prokaryotic genomes to address these two outstanding questions. Over half of these proteins contain a signal for cell-surface localization, and a majority accommodate a signal-sensing partner domain; these indicate widespread prevalence of post-translational regulation that may segregate the activities of proteins that are co-expressed. By examining the conservation of amino acid residues in the GGDEF and EAL catalytic sites, we show that there are predominantly two types of hybrid proteins. In the first, both sites are intact; an additional regulatory partner domain, present in most of these proteins, might determine the balance between the two enzymatic activities. In the second type, only the EAL catalytic site is intact; these--unlike EAL-only proteins--generally contain a signal-sensing partner domain, suggesting distinct modes of regulation for EAL activity under different sequence contexts. Finally, we discuss the role of proteins that have lost GGDEF and EAL catalytic sites as potential c-di-GMP-binding effectors. Our findings will serve as a genomic framework for interpreting ongoing molecular investigations of these proteins.


Sonographic differentiation of thyroid nodules with eggshell calcifications.
The purpose of this study was to assess the role of known suspicious sonographic findings and to find other additional sonographic findings to differentiate benign and malignant thyroid nodules with "eggshell" calcifications. Our Institutional Review Board approved this retrospective study, and informed consent was not required. We reviewed sonographic findings of thyroid nodules in 795 patients who underwent thyroid surgery in our institution between August 2006 and February 2007. Ninety-three thyroid nodules with eggshell calcifications in 92 patients were included in this study. Each lesion was evaluated for known suspicious sonographic criteria, including marked hypoechogenicity, irregular or microlobulated margins, and a taller-than-wide shape, as well as 2 additional sonographic findings: a hypoechoic halo and disruption of eggshell calcifications (halo and disrupted calcification rim). The sensitivity and specificity based on the sonographic criteria were calculated and compared among the 2 types of criteria. Among the 93 thyroid nodules, 59 were malignant and 34 were benign. The halo and disrupted calcification rim showed higher sensitivity (62.7% and 76.3%, respectively) than any of the known suspicious sonographic criteria (40.7%, 35.6%, and 55.9%). The combination of both the halo and the disrupted calcification rim showed significantly higher sensitivity (93.2%) than the combination of the known suspicious sonographic criteria (78%; P < .05), although both had the same specificity (64.7%). In thyroid nodules with eggshell calcifications but no other calcifications, the findings of a peripheral halo and disruption of the eggshell calcifications may be more useful sonographic predictors of malignancy than hypoechogenicity, microlobulated margins, and a taller-than-wide shape.


Molecular self-assembly under nanoconfinement: indigo carmine scroll structures entrapped within polymeric capsules.
Molecular self-assembly forms structures of well-defined organization that allow control over material properties, affording many advanced technological applications. Although the self-assembly of molecules is seemingly spontaneous, the structure into which they assemble can be altered by carefully modulating the driving forces. Here we study the self-assembly within the constraints of nanoconfined closed spherical volumes of polymeric nanocapsules, whereby a mixture of polyester-polyether block copolymer and methacrylic acid methyl methacrylate copolymer forms the entrapping capsule shell of nanometric dimensions. We follow the organization of the organic dye indigo carmine that serves as a model building unit due to its tendency to self-assemble into flat lamellar molecular sheets. Analysis of the structures formed inside the nanoconfined space using cryogenic-transmission electron microscopy (cryo-TEM) and cryogenic-electron tomography (cryo-ET) reveal that confinement drives the self-assembly to produce tubular scroll-like structures of the dye. Combined continuum theory and molecular modeling allow us to estimate the material properties of the confined nanosheets, including their elasticity and brittleness. Finally, we comment on the formation mechanism and forces that govern self-assembly under nanoconfinement.


Dysbiosis of oral microbiome persists after dental treatment-induced remission of periodontal disease and dental caries.
We characterized the oral conditions, salivary microbiome, and metabolome after dental treatment by investigating the state after treatment completion and transition to self-care. Dental treatment improved oral health conditions, resulting in oral disease remission; however, the imbalanced state of the salivary microbiome continued even after remission. Although the results of this study are preliminary, owing to the small number of participants in each group when compared to larger cohort studies, they indicate that the risk of disease may remain higher than that of healthy participants, thereby demonstrating the importance of removing dental plaque containing disease-related bacteria using appropriate care even after treatment completion. We also identified bacterial species with relative abundances that differed from those of healthy participants even after remission of symptoms, which may indicate that the maturation of certain bacterial species must be controlled to improve the oral microbiome and reduce the risk of disease recurrence.


Sleep Health amongst Patients Attending Adult Neurology Clinic in Abakaliki, Nigeria.
Sleep health indicates how well an individual or population sleeps. Good sleep health is characterized by subjective satisfaction, sustained alertness during waking hours, appropriate timing, high efficiency, and adequate duration. Poor sleep health is associated with many short-term and long-term health consequences. There are limited data on the pattern of sleep health in Nigeria. Against this backdrop, we embarked on this study to determine the Pattern of Sleep Health among patients attending the Adult Neurology clinic in a Federal Teaching Hospital, in Abakaliki, Nigeria. This is a cross-sectional observational hospital-based study undertaken at the Adult Neurology clinic of the Alex Ekwueme Federal University Teaching Hospital Abakaliki, Nigeria from July to September 2022. Out of the 267 patients recruited for the study, 19% had good sleep health with SATED scores of 8 to 10 while 81% had poor sleep health. The absence of alcohol abuse, cigarette smoking, and neurological diagnosis were statistically associated with poor sleep health with no sex and age predilection. The mean sleep duration was 7.5± 1.5 hours (male = 7.6 hours, female = 7.3 hours, 18- 64 years= 7.4 hours, ≥ 65 years =7.9 hours). Timing of sleep (mean= 0.97) was the least rated while sleep satisfaction (mean= 1.54) was the best-rated sleep dimension. Sleep health is very poor amongst patients attending the adult Neurology clinic at Abakaliki Nigeria and it is associated with smoking, absence of alcohol abuse, and neurological diagnosis. La santé du sommeil indique à quel point un individu ou une population dort. Une bonne santé du sommeil se caractérise par une satisfaction subjective, une vigilance soutenue pendant les heures d'éveil, un timing approprié, une efficacité élevée et une durée adéquate. Une mauvaise santé du sommeil est associée à de nombreuses conséquences sanitaires à court et à long terme. Il existe des données limitées sur le schéma de santé du sommeil au Nigéria. Dans ce contexte, nous avons entrepris cette étude pour déterminer le schéma de santé du sommeil parmi les patients fréquentant la clinique de neurologie pour adultes dans un hôpital d'enseignement fédéral à Abakaliki, Nigeria. Il s'agissait d'une étude observationnelle transversale réalisée à la clinique de neurologie pour adultes de l'hôpital universitaire fédéral Alex Ekwueme àAbakaliki, Nigeria, de juillet à septembre 2022. Sur les 267 patients recrutés pour l'étude, 19 % avaient une bonne santé du sommeil avec des scores SATED de 8 à 10, tandis que 81 % avaient une mauvaise santé du sommeil. L'absence d'abus d'alcool, de tabagisme et de diagnostic neurologique était statistiquement associée à une mauvaise santé du sommeil, sans prédilection pour le sexe et l'âge. La durée moyenne du sommeil était de 7,5 ± 1,5 heures (homme = 7,6 heures, femme = 7,3 heures, 18-64 ans = 7,4 heures, ≥ 65 ans = 7,9 heures). Le timing du sommeil (moyenne = 0,97) était la dimension la moins bien notée, tandis que la satisfaction du sommeil (moyenne = 1,54) était la dimension la mieux notée. La santé du sommeil est très mauvaise chez les patients fréquentant la clinique de neurologie pour adultes à Abakaliki, au Nigéria, et elle est associée au tabagisme, à l'absence d'abus d'alcool et au diagnostic neurologique. :Santé du sommeil, Clinique de neurologie,Abakaliki, Nigeria.


[A protocol of assessment, follow-up and nutritional action at a nursing home].
1) To assess the nutritional status of able elderly, institutionalized at a nursing home; 2) To propose the required nutritional interventions; 3) To establish a consensus protocol for nutritional assessment and follow-up at the Center. Cross-sectional study on all able residents, carrying out: 1) Mini Nutritional Assessment Test; 2) Anthropometrical assessment; 3) Biochemical assessment; and 4) an additional questionnaire (gathering information on dental prostheses, swallowing difficulties, and special diets or oral supplements). Analysis of these data to implement appropriate recommendations and elaborating a nutritional protocol. The mean age of the 50 residents assessed was 84 years [66-97], mean weight 62 kg [35-87], mean height 154 cm [140-175], mean body mass index 26 [15.6-36], mean tricipital fold 18.1 mm [4-36], and mean muscle arm circumference 20.6 cm [14.7-27.1]. By using the Mini Nutritional Assessment Test we identified 3/50 (6% [95% CI: 1-16]) malnourished residents, and 6/50 (12% [95% CI: 4-24]) residents at risk for malnourishment. The body mass index allowed to identify 11/50 (22% [95% CI: 11-35]) overweighed residents-body mass index 27-29-, 10/50 (20% [95% CI: 10-33]) with grade I obesity -body mass index 30-35 and 1/50 (2% [95% CI: 0-10]) with grade II obesity-body mass index > 35-. None of them presented values below the 5th percentile for both the tricipital fold and the muscle arm circumference. Values above the 95th percentile were found in 10/50 (20% [95% CI: 10-33]) residents for the tricipital fold and in 7/50 (14% [95% CI: 5-26]) for the muscle arm circumference, both criteria being present in 3 residents. In all of them the body mass index mayor was > 27. When analyzing the biochemical parameters, the results were not concordant, since laboratory workups analyzed were not always done at the same time as the interview. After analyzing the data obtained, a nutritional assessment and follow-up protocol was elaborated in collaboration with the physicians in charge of the Center, in which five categories were defined according to the nutritional status. 1) 3/50 malnourished residents were identified, 6/50 at risk for malnourishment, and 22/50 with overweight. 2) We proposed the performance of a whole laboratory work-up in these residents, reviewed their dietary habits in order to correct them or prescribe oral supplements, and recommended adapted physical exercise. 3) A nutritional assessment and follow-up protocol was elaborated.


[Age-related force distribution at the proximal end of the femur in normally growing children].
In a group of normally developed children and adolescents the age dependent distribution of forces at the proximal end of the femur was to be described. The results should explain why the shape of the proximal end of the femur changes significantly during the time of growth and why the neck shaft angle decreases. The method applied was the biomechanical computation analyzing in the coronal plane according to Pauwels' biomechanical hip model. The necessary age relevant data was derived from 675 anteroposterior pelvis radiographs of healthy children of both sexes and of varying age. The following can be put down as a result: 1. The proximal end of the femur is stressed by two resultant forces: the hip resultant force R controls the growth of the capital growth plate, the trochanteric resultant force RT regulates the growth of the greater trochanter growth plate. 2. During the growing period the hip resultant force R adjusts itself less vertically: during the second year of life it inclines at an average of 11,6 degrees towards the vertical, towards the end of the growing period it is incident with an inclination angle of 20 degrees. With the older child the magnitude of the hip resultant force R decreases in relation to the exerting body weight. 3. During the time of growth the trochanteric resultant force RT maintains its direction stability with inclination angles of 50-52 degrees towards the vertical. Its magnitude increases significantly (in relation to the exerting body weight). 4. From age 2 to 10 the projected neck shaft angle decreases from an average of 148.2 degrees to 133.7 degrees and usually remains stable. It can be concluded that the shape of the proximal end of the femur is determined by the muscle forces stimulating the greater trochanter apophysis and by gravity. With increasing age the growth of the greater trochanter apophysis shifts the insertions of abductor muscles laterally. As a result the directions of the hip abductors and the hip resultant force R incline. The neck shaft angle decreases consecutively.


[Electroconvulsive therapy in the third trimester of pregnancy: a case report].
Electroconvulsive or electroshock therapy is an effective psychiatric treatment. The need for effective psychotherapy in the pregnant patient and the need to limit application of psychotropic drugs have encouraged the use of electroshock therapy in the past 50 years. We report the case of a 35-year-old woman at 30 weeks' gestation who was hospitalized with severe depression. When her condition worsened after initiation of medical treatment, electroshock therapy was considered. She received a total of 9 sessions (3 per week). During treatments the patient received general anesthesia with propofol and succinylcholine with insertion of a tracheal tube. Significant variations in the hemodynamic variables of mother and fetus were not observed; nor were there signs of fetal distress. The patient experienced clear improvement and 2 days after the last treatment spontaneous labor commenced. A healthy boy was born by vaginal delivery.


Beneficial effect of fish oil on blood viscosity in peripheral vascular disease.
Reports suggest that the low incidence of ischaemic heart disease in Greenlandic Eskimos is related to the effect of a diet rich in eicosapentaenoic acid on platelet reactivity and plasma lipid concentrations. A double blind randomised investigation was therefore conducted of the effects on blood viscosity of dietary supplementation with an oil rich in this fatty acid (1.8 g/day, given as fish oil) and an eicosapentaenoic acid poor oil (as corn/olive oil) in patients with peripheral arterial disease. A statistically significant reduction in whole blood viscosity was observed at seven weeks in those patients receiving the eicosapentaenoic acid rich oil. No changes in plasma viscosity, haemoglobin concentration, packed cell volume, or platelet count were seen. A significant fall in plasma triglyceride concentration was also noted only in the patients receiving oil rich in eicosapentaenoic acid; plasma concentrations of cholesterol and high density lipoprotein cholesterol were unchanged. It is concluded that rheological changes that result from a diet rich in eicosapentaenoic acid may contribute to the suggested protective effects of such a diet against arterial disease and that such changes are of potential therapeutic importance in established arterial disease.


Seminal, adventitious and lateral root growth and physiological responses in rice to upland conditions.
Understanding the growth and physiological responses of rice to upland conditions would be helpful for designing treatments to improve the tolerance of rice under a rainfed system. The objective of this study was to investigate the initiation,elongation and membrane stability of seminal, lateral and adventitious roots of upland rice after 9-d upland condition treatment. Compared with control roots under waterlogged conditions, upland water deficiency conditions favor seminal and lateral root growth over adventitious root growth by accelerating seminal root elongation, promoting lateral root initiation and elongation, and reducing the elongation and number of adventitious roots. Enhanced total root number and length resulted in increase of total root dry weight and thereby increasing the root-to-shoot ratio. Organic compound leakage from seminal root tips and adventitious roots increased progressively to some extent with upland culture duration, while significant increases in seminal root tips were the consequence of loss of membrane integrity caused by the upland-condition enhanced growth.


The electronic structure of UCoGe by ab initio calculations and XPS experiment.
The crystal and electronic structures of the orthorhombic compound UCoGe are presented and discussed. It has been either refined by the x-ray diffraction on a single crystal or computed within the local spin density functional theory, employing the fully relativistic version of the full-potential local-orbital band structure code, respectively. We particularly give our attention to investigating the Fermi surface and de Haas-van Alphen quantities of UCoGe. The calculated electronic density is then examined by x-ray photoelectron spectroscopy (XPS). Fairly good agreement is achieved between theoretical and experimental XPS results in the paramagnetic state. A small difference in the position (in energy scale) of the U 5f bands is caused by the electron localization effect observed in the experimental XPS. There is also some discrepancy for the Co 3d electron contributions below E(F). The Fermi surface in the non-magnetic state is of a semimetallic type while that in the ferromagnetic state, with the ordered moment of -0.47 μ(B)/f.u. along the c axis, is more metallic, with nesting properties that may favour superconductivity.


Sorption and aging of corn and soybean pesticides in tropical soils of Brazil.
The efficacy and fate of pesticides in soil strongly depend on sorption reversibility that is known to decrease with increasing contact time (aging). We elucidated the aging dynamics of eight different pesticides in two contrasting agricultural soils of tropical Brazil (Ustox and Psamments), using batch equilibrium experiments and sequential extractions of field samples. Adsorption was best described by Langmuir isotherms for the entire and by Freundlich equations for the lower concentration range. In field samples, water extractable pesticide fractions mostly dissipated at least twice as fast as did the solvent extractable fractions. Hence, in comparison to 0 days K(OC) values, measured field K(OC) values were higher by a factor of 2.6-38 for the clayey Ustox and 2.1-72 for the sandy Psamments toward the end of the experimental period at 80 days after application. The extent of such aging basically increased with increasing polarity of the pesticide. An absolute enrichment of polar pesticides within the final exhaustive acetone--ethyl acetate--water extracts was observed during the experimental period, so that we may deduce that pesticides had redistributed into stronger sorption sites. The time course of the K(OC) development was well-described using a semiempirical equation, which had been employed for temperate soils before.


Memory in the B-cell compartment: antibody affinity maturation.
In the humoral arm of the immune system, the memory response is not only more quickly elicited and of greater magnitude than the primary response, but it is also different in quality. In the recall response to antigen, the antibodies produced are of higher affinity and of different isotype (typically immunoglobulin G rather than immunoglobulin M). This maturation rests on the antigen dependence of B-cell maturation and is effected by programmed genetic modifications of the immunoglobulin gene loci. Here we consider how the B-cell response to antigen depends on the affinity of the antigen receptor interaction. We also compare and draw parallels between the two processes, which underpin the generation of secondary-response antibodies: V gene somatic hypermutation and immunoglobulin heavy-chain class switching.


Dancing with Deterrents: Understanding the Role of Abuse-Deterrent Opioid Formulations and Naloxone in Managing Cancer Pain.
Prescription opioids are commonly prescribed for the relief of many kinds of pain syndromes, including cancer pain. In order to combat the growing rates of abuse and misuse of prescription opioids, the Centers for Disease Control and Prevention, along with the U.S. Food and Drug Administration and multiple pharmaceutical companies, have implemented many risk mitigation strategies. Abuse-deterrent drug delivery technology and more consistent prescribing of the opioid antagonist, naloxone, are two of the mechanisms of reducing harm in patients on chronic opioid therapy. Abuse-deterrent technology is implemented into different commercially available opioid products with the intent of discouraging manipulation of the opioid or making the use of the manipulated opioid less appealing. Use of the opioid antagonist, naloxone, for reversal of intentional or unintentional opioid overdose is a safe and effective means to reduce potential risk in patients who are on opioids for pain management. These mechanisms have multiple advantages and limitations that influence their practical use specifically in patients with cancer pain. Patients with cancer pain have unique therapeutic needs and goals, and their balance of treatment risks and benefits differs from that of other kinds of chronic pain disorders. This article provides an overview of the advantages and limitations of these specific harm-reduction strategies and provides guidance on how to practically utilize them when caring for patients with cancer pain. IMPLICATIONS FOR PRACTICE: Treating cancer pain has important and unique considerations compared with other chronic, noncancer pain disorders. The use of risk mitigation strategies for opioid prescribing as promoted by the Centers for Disease Control and Prevention does not translate seamlessly to patients with cancer. It is crucial to be wary of the advantages and pitfalls of all risk mitigation strategies related to opioid use in patients with cancer pain. Careful examination of patient-specific risks and benefits should always be considered when implementing pharmacologic treatment and harm-reduction strategies for the management of cancer pain.


Field cancerization in the intestinal epithelium of patients with Crohn's ileocolitis.
Tumors that develop in patients with Crohn's disease tend be multifocal, so field cancerization (the replacement of normal cells with nondysplastic but tumorigenic clones) might contribute to intestinal carcinogenesis. We investigated patterns of tumor development from pretumor intestinal cell clones. We performed genetic analyses of multiple areas of intestine from 10 patients with Crohn's disease and intestinal neoplasia. Two patients had multifocal neoplasia; longitudinal sections were collected from 3 patients. Individual crypts were microdissected and genotyped; clonal dependency analysis was used to determine the order and timing of mutations that led to tumor development. The same mutations in KRAS, CDKN2A(p16), and TP53 that were observed in neoplasias were also present in nontumor, nondysplastic, and dysplastic epithelium. In 2 patients, carcinogenic mutations were detected in nontumor epithelium 4 years before tumors developed. The same mutation (TP53 p.R248W) was detected at multiple sites along the entire length of the colon from 1 patient; it was the apparent founder mutation for synchronous tumors and multiple dysplastic areas. Disruption of TP53, CDKN2A, and KRAS were all seen as possible initial events in tumorigenesis; the sequence of mutations (the tumor development pathway) differed among lesions. Pretumor clones can grow extensively in the intestinal epithelium of patients with Crohn's disease. Segmental resections for neoplasia in patients with Crohn's disease might therefore leave residual pretumor disease, and dysplasia might be an unreliable biomarker for cancer risk. Characterization of the behavior of pretumor clones might be used to predict the development of intestinal neoplasia.


Submilliwatt, ultrafast and broadband electro-optic silicon switches.
We present a broadband 2x2 electro-optic silicon switch with an ultralow switching power and fast switching time based on a Mach-Zehnder interferometer (MZI). Forward-biased p-i-n junctions are employed to tune the phase of silicon waveguides in the MZI, to achieve a π-phase switching power of 0.6 mW with a drive voltage 0.83 V with a MZI arm length of 4 mm. The 10%-90% switching time is demonstrated to be 6 ns. Optical crosstalk levels lower than -17 dB are obtained for an optical bandwidth of 60 nm. The free carrier induced silicon refractive index change is extracted from the experimental results for the concentration range from 10(16) to 10(17) cm(-3). We find that at the concentration of 10(16) cm(-3), the index change is about twice that calculated by the commonly used index change equation.


Dynamics of expression of the mRNA for cytokines and inducible nitric synthase in a murine model of the Parkinson's disease.
The inflammatory reaction and oxidative stress has been linked with PD. Proinflammatory cytokines promote neurodegeneration or neuroprotection in different animal models. In addition, these cytokines have been reported to increase iNOS expression. With the RT-PCR method we evaluated mRNA levels for IL 1beta, IL6, TNF, IFNgamma, IL-10 and iNOS in the striatum of C57BL/6 mice after MPTP intoxication. The IL1beta mRNA expression rapidly increased and peaked at 6 h. The first increase of mRNA for TNFalpha and IFNgamma was noticed at 6-24 h and the second at the 7th day after MPTP intoxication. Two peaks of IL10 mRNA were seen, immediately (6 h) and at the 3 day post MPTP injection. The peak of mRNA level for IL6 was observed at the 7th day. Expression of mRNA for iNOS peaked at 24 h, started decreasing on the 3rd day, but was still present till the 14th day. Those findings suggest that cytokine network and iNOS may be involved in the development of immune changes accompanying degeneration of the nigrostriatal system.


How well are we doing addressing disability in America? Examining the status of adults with chronic disabling conditions, 1995 and 2005.
Despite laws like the Americans with Disabilities Act (ADA), (1992), and The Ticket to Work Act, (TTWA), (2001), working age adults who develop chronic disabling conditions often find themselves faced with a choice of leaving the labor market in order to qualify for public health insurance or continuing to work, often on a "hit and miss" basis, disqualifying them from employee health benefits. Federal and state policy makers continue to struggle to find solutions addressing the needs of working age adults with disabling conditions and illnesses. In this study we examine the work status of working age adults using two National Health Interview Surveys conducted a decade apart (1995 & 2005) to investigate and compare adults who have chronic, disabling conditions and self-reported rates of work. Specifically, this research investigates whether reported work activity among working age adults who report chronic health conditions has improved in the decade between 1995 and 2005. The effects of racial/ethnic differences, age, and region of residence on one's work status are also examined.


[Erythrocyte morphology in anemia after artificial circulation (based on scanning electron microscopic data)].
Erythrocyte stereo-ultrastructure of 58 patients operated under the conditions of extracorporeal circulation was studied by scanning electron microscopy. It is established that after the operation with extracorporeal circulation the hemoglobin level is always decreasing, 3 mg% on the average; hemoglobin decrease up to 10 mg% and less was considered as anemia, this occurring according to the approximate calculations, in 10-11% of cases. The causes of anemia in an early postoperative period are as follows: mechanical trauma of erythrocytes in the system of extracorporeal circulation; disturbance of the osmotic balance; alteration of the erythrocyte membrane plasticity due to the change of its enzyme-lipid component. Anemia in the late postoperative period is due to the purulent inflammatory processes. Morphological substrate of anemia is represented by the iron-deficient, target-like, two-pit erythrocytes, spherocytes, lacerated erythrocytes and other forms.


An integrated clinical computer system: implications for a medical information services department.
The hybrid record--both paper and electronic--is a cumbersome byproduct of the evolution to the computer-based patient record. Nancy Walker describes how William Beaumont Hospital managed its information services with this mixed media record. Her article provides practical solutions for health information managers including downtime procedures, report distribution plans, release of information steps, and audit procedures for maintaining confidentiality.


The SMAC mimetic LCL-161 displays antitumor activity in preclinical models of rituximab-resistant B-cell lymphoma.
Clinical observations suggest the existence of shared resistance pathways between rituximab and chemotherapy agents. To explore the mechanisms of rituximab resistance, our group created rituximab-resistant cell lines (RRCLs), which display altered expression of several inhibitor of apoptosis (IAP) family proteins. Here, we provide evidence to support pharmacologically targeting IAPs in lymphoma with LCL-161, a small molecule mimetic of the second mitochondria-derived activator of caspases (SMAC). The antitumor effect of LCL-161 was determined using luminescent adenosine triphosphate assays, flow cytometry, SCID mouse xenografts, and ex vivo patient biopsy sample studies. In vitro exposure to LCL-161 also resulted in a dose-dependent decrease in IAP levels, along with synergistic enhancement of the antitumor effect of cytotoxic chemotherapy, in rituximab-sensitive cell lines and RRCLs. In addition, LCL-161 increased the cytotoxic effect of the proteasome inhibitor carfilzomib in ex vivo lymphoma patient samples. The combination of LCL-161 with the chemotherapy regimen rituximab, gemcitabine, and vinorelbine (RGV) improved in vivo survival compared with RGV alone in severe combined immunodeficient mice implanted with RRCLs but not in animals implanted with rituximab-sensitive cell lines. In summary, LCL-161 exhibits synergistic antitumor activity in both in vitro and in vivo models of resistant lymphoma. Our data support further preclinical investigation of LCL-161 as a novel antilymphoma agent.


Gravity signal transduction in primary roots.
The molecular mechanisms that correlate with gravity perception and signal transduction in the tip of angiosperm primary roots are discussed. Gravity provides a cue for downward orientation of plant roots, allowing anchorage of the plant and uptake of the water and nutrients needed for growth and development. Root gravitropism involves a succession of physiological steps: gravity perception and signal transduction (mainly mediated by the columella cells of the root cap); signal transmission to the elongation zone; and curvature response. Interesting new insights into gravity perception and signal transduction within the root tip have accumulated recently by use of a wide range of experimental approaches in physiology, biochemistry, genetics, genomics, proteomics and cell biology. The data suggest a network of signal transduction pathways leading to a lateral redistribution of auxin across the root cap and a possible involvement of cytokinin in initial phases of gravicurvature. These new discoveries illustrate the complexity of a highly redundant gravity-signalling process in roots, and help to elucidate the global mechanisms that govern auxin transport and morphogenetic regulation in roots.


Role of radiation therapy in primary central nervous system lymphoma : KROG 14-20 Collaborative Study of Brain and Lymphoma Committee.
We analyzed patterns of care and outcomes for patients with primary central nervous system lymphoma (PCNSL) in this multi-institutional retrospective study. Between January 2000 and December 2011, 220 patients with PCNSL received radiotherapy (RT). Among these patients, 26 patients received RT alone; 179 patients were treated with chemotherapy and radiotherapy; the rest of the patients (N = 15) initially underwent chemotherapy alone, then received RT as a salvage treatment. Most of the patients (N = 188) received methotrexate-based chemotherapy. The median follow up duration was 38 months (range 3-179 months). The median RT dose and whole brain RT (WBRT) dose were 45.0 Gy (range 20.0-59.4) and 30.6 Gy (range 18.0-45.0), respectively. Seventy-seven (35%) patients received WBRT alone, and 143 patients (65%) underwent WBRT plus boost RT. Total RT dose and WBRT dose decreased during the study period. The median survival was 64 months and actuarial 5-year overall survival was 51.4%. In multivariate analysis, age (P < 0.001), ECOG performance status (P = 0.036), deep structure involvement (P = 0.011) and treatment response (P = 0.001) were significant prognosticators. RT combined with chemotherapy is effective modality for treatment of PCNSL. The survival outcome improved in spite of total radiation dose and whole brain RT (WBRT) dose having been decreased over the study period, indicating that low-dose WBRT could be effective.


Management of failed spinal anaesthesia for caesarean section.
Failed spinal anaesthesia for caesarean section (CS) may be partial or complete and the subsequent discomfort is the most commonly cited cause of litigation in obstetric anaesthesia. To determine if there is a standardised approach to: (i) testing the level of block of spinal anaesthesia; and (ii) the management of failed spinal anaesthesia for CS. A structured questionnaire to ascertain the current practice of testing the level of block and management of three different scenarios of failed spinal anaesthesia was distributed to 51 government hospitals in KwaZulu-Natal, South Africa (SA). All obstetric anaes-thetic service providers, ranging from interns to specialist anaesthetists, were invited to complete the questionnaire. A total of 375 responses were received from 42 of the 51 hospitals surveyed. Specialist anaesthetists managed failure of spinal anaesthesia significantly differently than other anaesthetic service providers. Specialists were more likely to convert to a general anaesthetic (GA), while others were more likely to repeat spinal anaesthesia or administer intravenous ketamine, midazolam and opioids. Only 212 respondents (56%) tested the level of block and there was no difference between the groups with regard to the method of assessment of height (p=0.15). Non-specialists, however, accepted a significantly lower level of block, using pinprick, than specialists (p=0.027), which could lead to a higher failure rate. More than one-third of non-specialists did not consider themselves competent to perform a GA and >90% of respondents agreed that a 'failed' spinal algorithm would be useful. There is a need for standardised assessment of the adequacy of spinal anaesthesia for CS in SA, as well as a failed spinal algorithm.


Eclipse of coxsackievirus infectivity: the restrictive event for a non-fusing myogenic cell line.
Coxsackieviruses A2, A5 and B3 did not replicate in L8CL3-U cells (a non-fusing variant of the rat L8 myogenic cell line) although these cells possessed a common receptor for coxsackieviruses A2 and A5, and a different receptor for coxsackievirus B3. The restriction in replication was identified as a block in viral eclipse, since 6 M-LiCl treatment permitted recovery of the coxsackievirus A2 inoculum from L8CL3-U cells after 2 h at 37 degrees C, and the cells could be transfected by viral RNA. Cellular fusion which was induced in L8CL3-U cultures by herpes simplex virus type 1 (HF strain) facilitated coxsackievirus A2 and A5 replication. Differentiating myogenic L8 cells acquired full susceptibility to infection concurrently with the appearance of acetylcholine receptors, the muscle-specific isoenzyme of creatine phosphokinase, prominent myotube formation and the acquired capacity of the cells to eclipse virus.


[Seeding rates of atypical mycobacterium in patients at L'vov regional phthisiopulmonological center].
Mycobacterial seeding rates were retrospectively analyzed in patients from 1986 to 1995 by the results obtained by the Centralized Bacteriological Laboratory, Lvov Regional Phthisiopulmonological Center, and the Laboratory of Bacteriology and Immunology, Department of Tuberculosis and the Research Laboratory of the Lvov Research Institute of Epidemiology and Hygiene. The findings suggest that in the past decade there has been a rise in the rate of isolation of atypical Mycobacteria, as well as an undulatory dynamics in their seeding with a stable upward tendency for the ratio of isolated atypical Mycobacteria to the total number of Mycobacteria in new cases.


Synergistic effect between erlotinib and MEK inhibitors in KRAS wild-type human pancreatic cancer cells.
The combination of erlotinib and gemcitabine has shown a small but statistically significant survival advantage when compared with gemcitabine alone in patients with advanced pancreatic cancer. However, the overall survival rate with the erlotinib and gemcitabine combination is still low. In this study, we sought to identify gene targets that, when inhibited, would enhance the activity of epidermal growth factor receptor (EGFR)-targeted therapies in pancreatic cancer cells. A high-throughput RNA interference (RNAi) screen was carried out to identify candidate genes. Selected gene hits were further confirmed and mechanisms of action were further investigated using various assays. Six gene hits from siRNA screening were confirmed to significantly sensitize BxPC-3 pancreatic cancer cells to erlotinib. One of the hits, mitogen-activated protein kinase (MAPK) 1, was selected for further mechanistic studies. Combination treatments of erlotinib and two MAP kinase kinase (MEK) inhibitors, RDEA119 and AZD6244, showed significant synergistic effect for both combinations (RDEA119-erlotinib and AZD6244-erlotinib) compared with the corresponding single drug treatments in pancreatic cancer cell lines with wild-type KRAS (BxPC-3 and Hs 700T) but not in cell lines with mutant KRAS (MIA PaCa-2 and PANC-1). The enhanced antitumor activity of the combination treatment was further verified in the BxPC-3 and MIA PaCa-2 mouse xenograft model. Examination of the MAPK signaling pathway by Western blotting indicated effective inhibition of the EGFR signaling by the drug combination in KRAS wild-type cells but not in KRAS mutant cells. Overall, our results suggest that combination therapy of an EGFR and MEK inhibitors may have enhanced efficacy in patients with pancreatic cancer.


Human monoclonal antiphospholipid antibodies disrupt the annexin A5 anticoagulant crystal shield on phospholipid bilayers: evidence from atomic force microscopy and functional assay.
The antiphospholipid (aPL) syndrome is an autoimmune condition that is marked by recurrent pregnancy losses and/or systemic vascular thrombosis in patients who have antibodies against phospholipid/co-factor complexes. The mechanism(s) for pregnancy losses and thrombosis in this condition is (are) not known. Annexin A5 is a potent anticoagulant protein, expressed by placental trophoblasts and endothelial cells, that crystallizes over anionic phospholipids, shielding them from availability for coagulation reactions. We previously presented data supporting the hypothesis that aPL antibody-mediated disruption of the anticoagulant annexin A5 shield could be a thrombogenic mechanism in the aPL syndrome. However, this has remained a subject of controversy. We therefore used atomic force microscopy, a method previously used to study the crystallization of annexin A5, to image the effects of monoclonal human aPL antibodies on the crystal structure of the protein over phospholipid bilayers. In the presence of the aPL monoclonal antibodies (mAbs) and beta(2)-GPI, the major aPL co-factor, structures presumed to be aPL mAb-antigen complexes were associated with varying degrees of disruption to the annexin A5 crystallization pattern over the bilayer. In addition, measurements of prothrombinase activity on the phospholipid bilayers showed that the aPL mAbs reduced the anti-coagulant effect of annexin A5 and promoted thrombin generation. These data provide morphological evidence that support the hypothesis that aPL antibodies can disrupt annexin A5 binding to phospholipid membranes and permit increased generation of thrombin. The aPL antibody-mediated disruption of the annexin A5 anticoagulant shield may be an important prothrombotic mechanism in the aPL syndrome.


Cinematic Rendering With Positive Oral Contrast: Virtual Fluoroscopy.
Recently, a novel 3-dimensional visualization methodology for volumetric computed tomography data has become available. This method, known as cinematic rendering, uses an advanced lighting model to create photorealistic images from standard computed tomography acquisition data composed of isotropic voxels. We have observed that cinematic rendering visualizations in which patients have been administered dense, positive oral contrast do not have any substantive visual artifacts and can be used to demonstrate bowel pathology to advantage (ie, "virtual fluoroscopy"). In this technical note, we describe our acquisition and visualization parameters, and we also include demonstrative examples.


Genetic determinants of urolithiasis.
Urolithiasis affects approximately 10% of individuals in Western societies by the seventh decade of life. The most common form, idiopathic calcium oxalate urolithiasis, results from the interaction of multiple genes and their interplay with dietary and environmental factors. To date, considerable progress has been made in identifying the metabolic risk factors that predispose to this complex trait, among which hypercalciuria predominates. The specific genetic and epigenetic factors involved in urolithiasis have remained less clear, partly owing to the candidate gene and linkage methods that have been available until now, being inherently low in their power of resolution and in assessing modest effects in complex traits. However, together with investigations of rare, Mendelian forms of urolithiasis associated with various metabolic risk factors, these methods have afforded insights into biological pathways that seem to underlie the development of stones in the urinary tract. Monogenic diseases account for a greater proportion of stone formers in children and adolescents than in adults. Early diagnosis of monogenic forms of urolithiasis is of importance owing to associated renal injury and other potentially treatable disease manifestations, but diagnosis is often delayed because of a lack of familiarity with these rare disorders. In this Review, we will discuss advances in the understanding of the genetics underlying polygenic and monogenic forms of urolithiasis.


Pharmacokinetic comparison of intravenous and oral chloramphenicol in patients with Haemophilus influenzae meningitis.
The pharmacokinetics of chloramphenicol following intravenous and oral administration were studied in 14 infants with Haemophilus influenzae meningitis. Following five days of treatment with intravenous chloramphenicol (100 mg/kg/day every six hours), oral chloramphenicol was substituted at the same dose. Multiple serum levels of chloramphenicol were determined after an intravenous dose on day 4 and after an oral dose on day 10. CSF levels were measured six hours after intravenous or oral chloramphenicol dose on those days (CSF trough). Following intravenous administration, the mean peak serum level of 15.0 micrograms/ml was reached at 45 minutes. In comparison, after oral chloramphenicol in the same dosage, the mean peak serum level of 18.5 micrograms/ml was achieved at two to three hours. The mean serum half-life of the drug (6.5 hours) was significantly longer after oral administration than after intravenous chloramphenicol (4.0 hours) (P less than .001). The increased serum half-life following orally administered chloramphenicol was occasionally associated with drug accumulation. In addition, mean trough CSF levels were somewhat higher when the patient received oral medication (6.6 micrograms/ml) compared to intravenous administration (4.2 micrograms/ml) (P less than .001). For any treatment regimen for H influenzae meningitis that includes a period of oral chloramphenicol therapy the patient should be hospitalized to ensure compliance. Because of the wide range of individual variation in serum half-life that may result in accumulation, periodic monitoring of serum chloramphenicol levels is also recommended.


Natural history and survival of 14 patients with corticobasal degeneration confirmed at postmortem examination.
To analyse the natural history and survival of corticobasal degeneration by investigating the clinical features of 14 cases confirmed by postmortem examination. Patients with definite corticobasal degeneration were selected from the research and clinical files of seven tertiary medical centres in Austria, the United Kingdom, and the United States. Clinical features were analysed in detail. The sample consisted of eight female and six male patients; mean age at symptom onset was 63 (SD 7.7) years, and mean disease duration was 7.9 (SD 2.6) years. The most commonly reported symptom at onset included asymmetric limb clumsiness with or without rigidity (50%) or tremor (21%). At the first neurological visit, on average 3.0 (SD 1.9) years after symptom onset, the most often encountered extrapyramidal features included unilateral limb rigidity (79%) or bradykinesia (71%), postural imbalance (45%), and unilateral limb dystonia (43%). Ideomotor apraxia (64%), and to a lesser extent cortical dementia (36%), were the most common cortical signs present at the first visit. During the course of the disease, virtually all patients developed asymmetric or unilateral akinetic rigid parkinsonism and a gait disorder. No patient had a dramatic response to levodopa therapy. Median survival time after onset of symptoms was 7.9 (SD 0.7) (range, 2.5-12.5) years, and, after the first clinic visit, 4.9 (SD 0.7) (range, 0.8-10) years. Early bilateral bradykinesia, frontal syndrome, or two out of tremor, rigidity, and bradykinesia, predicted a shorter survival. The results confirm that unilateral parkinsonism unresponsive to levodopa and limb ideomotor apraxia are the clinical hallmarks of corticobasal degeneration, and only a minority of patients with corticobasal degeneration present with dementia. The study also suggests that a focal cognitive and extrapyramidal motor syndrome is indicative of corticobasal degeneration. Survival in corticobasal degeneration was shortened by the early presence of (more) widespread parkinsonian features or frontal lobe syndrome.


The effect of surface material and roughness on bone screw stability.
To evaluate the effects of osteointegration ability and surface texture on bone screw interface stability in three different groups of titanium screws. Sixty titanium tapered screws were used: twenty screws were polished, uncoated (Group A); twenty screws were rough, coated with titanium (Group B); and twenty screws were rough, coated with fluor-hydroxyapatite (Group C). Thirty screws, ten per group, were implanted in the femurs and tibiae of two sheep, which were euthanized one month after surgery. The remaining thirty screws, ten per group, were implanted in the femurs and tibiae of another two sheep, which were euthanized three months after surgery. At one month, extraction torque of Group C was higher than that of Group A (p = 0.042). At three months, extraction torque of Group C was higher than that of Group A (p < 0.0001) and Group B (p < 0.0001). At three months, extraction torque of Group C was higher compared with the corresponding insertion torque (p < 0.0001) and compared with the corresponding extraction torque at one month (p < 0.0001). At one and three months, a high percentage of bone-screw contact was observed histologically in Groups B and C. A continuous gap with fibrous tissue encapsulation was observed in Group A. This study shows that the osteointegration ability provided by the type of coating is a very important parameter for optimizing the bone-screw stability. Surface texture is also important. By using screws with optimal osteointegration ability, very positive clinical consequences can be expected.


Relative clause comprehension in Cantonese-speaking children with and without developmental language disorder.
Developmental Language Disorder (DLD), present in 2 out of every 30 children, affects primarily oral language abilities and development in the absence of associated biomedical conditions. We report the first experimental study that examines relative clause (RC) comprehension accuracy and processing (via looking preference) in Cantonese-speaking children with and without DLD, testing the predictions from competing domain-specific versus domain-general theoretical accounts. We compared children with DLD (N = 22) with their age-matched typically-developing (TD) children (AM-TD, N = 23) aged 6;6-9;7 and language-matched (and younger) TD children (YTD, N = 21) aged 4;7-7;6, using a referent selection task. Within-subject factors were: RC type (subject-RCs (SRCs) versus object-RCs (ORCs); relativizer (classifier (CL) versus relative marker ge3 RCs). Accuracy measures and looking preference to the target were analyzed using generalized linear mixed effects models. Results indicated Cantonese children with DLD scored significantly lower than their AM-TD peers in accuracy and processed RCs significantly slower than AM-TDs, but did not differ from the YTDs on either measure. Overall, while the results revealed evidence of a SRC advantage in the accuracy data, there was no indication of additional difficulty associated with ORCs in the eye-tracking data. All children showed a processing advantage for the frequent CL relativizer over the less frequent ge3 relativizer. These findings pose challenges to domain-specific representational deficit accounts of DLD, which primarily explain the disorder as a syntactic deficit, and are better explained by domain-general accounts that explain acquisition and processing as emergent properties of multiple converging linguistic and non-linguistic processes.


Portal to the interior: viral pathogenesis and natural compounds that restore mucosal immunity and modulate inflammation.
Most antigens, particularly viruses, enter the body through the mucosal epithelia where they are carried by afferent lymphatics to regional lymph nodes for presentation to the immune system. Although they share immunological similarities, immune processes that protect the mucosa are distinct from innate and acquired immunity. The barrier formed by the intestinal mucosa is the most studied, with its microenvironment having a marked influence on both local and systemic immune responses. A healthy microenvironment and resilient neighboring tissue provide protection against inflammation known to dampen mucosal immunity, promote carcinogenesis, contribute to systemic inflammatory processes, and result in autoimmune diseases. Numerous natural substances improve this microenvironment and thereby enhance immunity against microbial infections. Since mucosal immunity forms the first line of defense against many commonly transmitted pathogens, restoring and maintaining mucosal immunity is critical for disease prevention and intervention. This article discusses the nature of mucosal immunity and its relationship to viral infections and other conditions, and reviews natural compounds that help restore mucosal immunity.


Development of an activity assay for characterizing deoxyhypusine synthase and its diverse reaction products.
Deoxyhypusine synthase transfers an aminobutyl moiety from spermidine to the eukaryotic translation initiation factor 5A (eIF5A) in the first step of eIF5A activation. This exclusive post-translational modification is conserved in all eukaryotes. Activated eIF5A has been shown to be essential for cell proliferation and viability. Recent reports have linked the activation of eIF5A to several human diseases. Deoxyhypusine synthase, which is encoded by a single gene copy in most eukaryotes, was duplicated in several plant lineages during evolution, the copies being repeatedly recruited to pyrrolizidine alkaloid biosynthesis. However, the function of many of these duplicates is unknown. Notably, deoxyhypusine synthase is highly promiscuous and can catalyze various reactions, often of unknown biological relevance. To facilitate in-depth biochemical studies of this enzyme, we report here the development of a simple and robust in vitro enzyme assay. It involves precolumn derivatization of the polyamines taking part in the reaction and avoids the need for the previously used radioactively labeled tracers. The derivatized polyamines are quantified after high-performance liquid chromatography coupled to diode array and fluorescence detectors. By performing kinetic analyses of deoxyhypusine synthase and its paralog from the pyrrolizidine alkaloid-producing plant Senecio vernalis, we demonstrate that the assay unequivocally differentiates the paralogous enzymes. Furthermore, it detects and quantifies, in a single assay, the side reactions that occur in parallel to the main reaction. The presented assay thus provides a detailed biochemical characterization of deoxyhypusine synthase and its paralogs.


Atypical Human Effector/Memory CD4+ T Cells With a Naive-Like Phenotype.
The induction of adaptive immunological memory, mediated by T and B cells, plays an important role in protective immunity to pathogens induced by previous infections or vaccination. Naive CD4+ T cells that have been primed by antigen develop into memory or effector cells, which may be distinguished by their capability to exert a long-term and rapid response upon re-challenge by antigen, to produce distinct cytokines and surface marker expression phenotypes such as CD45RA/RO, CD27, CD62L, and CCR7. Moreover, a distinct lineage of memory T cells populates tissues (tissue-resident memory T cells or TRM cells) which orchestratea the response to pathogens re encountered at tissue sites. Recent evidence, however, has highlighted that CD4+ naive T cells are much more heterogeneous that previously thought, and that they harbor diversity in phenotypes, differentiation stages, persistence, functions, and anatomic localizations. These cells represent cellular subsets that are extremely heterogeneous and multifunctional at their very initial stages of differentiation, with the potential to become "atypical" memory and effector cells. In this mini review, we focus on recently obtained data from studies in humans, in which this newly recognized heterogeneity in the naive T cell pool was discovered in terms of surface marker expression, cytokine production, or transcriptomic profiles. The deep analysis of immune functions at the single cell level combined with a better understanding of the generation and maintenance of the various atypical memory CD4+ T cell subsets with a naive-like phenotype will be important in immune-monitoring of vaccination and immunotherapies in infectious diseases.


Preventing hypothermia: comparison of current devices used by the US Army in an in vitro warmed fluid model.
The purpose of this study was to develop an in vitro torso model constructed with fluid bags and to determine whether this model could be used to differentiate between the heat prevention performance of devices with active chemical or radiant forced-air heating systems compared with passive heat loss prevention devices. We tested three active (Hypothermia Prevention Management Kit [HPMK], Ready-Heat, and Bair Hugger) and five passive (wool, space blankets, Blizzard blankets, human remains pouch, and Hot Pocket) hypothermia prevention products. Active warming devices included products with chemically or electrically heated systems. Both groups were tested on a fluid model warmed to 37 degrees C versus a control with no warming device. Core temperatures were recorded every 5 minutes for 120 minutes in total. Products that prevent heat loss with an actively heated element performed better than most passive prevention methods. The original HPMK achieved and maintained significantly higher temperatures than all other methods and the controls at 120 minutes (p < 0.05). None of the devices with an actively heated element achieved the sustained 44 degrees C that could damage human tissue if left in place for 6 hours. The best passive methods of heat loss prevention were the Hot Pocket and Blizzard blanket, which performed the same as two of the three active heating methods tested at 120 minutes. Our in vitro fluid bag "torso" model seemed sensitive to detect heat loss in the evaluation of several active or passive warming devices. All active and most passive devices were better than wool blankets. Under conditions near room temperature, passive warming methods (Blizzard blanket or the Hot Pocket) were as effective as active warming devices other than the original HPMK. Further studies are necessary to determine how these data can translate to field conditions in preventing heat loss in combat casualties.


Structural and Practical Identifiability Issues of Immuno-Epidemiological Vector-Host Models with Application to Rift Valley Fever.
In this article, we discuss the structural and practical identifiability of a nested immuno-epidemiological model of arbovirus diseases, where host-vector transmission rate, host recovery, and disease-induced death rates are governed by the within-host immune system. We incorporate the newest ideas and the most up-to-date features of numerical methods to fit multi-scale models to multi-scale data. For an immunological model, we use Rift Valley Fever Virus (RVFV) time-series data obtained from livestock under laboratory experiments, and for an epidemiological model we incorporate a human compartment to the nested model and use the number of human RVFV cases reported by the CDC during the 2006-2007 Kenya outbreak. We show that the immunological model is not structurally identifiable for the measurements of time-series viremia concentrations in the host. Thus, we study the non-dimensionalized and scaled versions of the immunological model and prove that both are structurally globally identifiable. After fixing estimated parameter values for the immunological model derived from the scaled model, we develop a numerical method to fit observable RVFV epidemiological data to the nested model for the remaining parameter values of the multi-scale system. For the given (CDC) data set, Monte Carlo simulations indicate that only three parameters of the epidemiological model are practically identifiable when the immune model parameters are fixed. Alternatively, we fit the multi-scale data to the multi-scale model simultaneously. Monte Carlo simulations for the simultaneous fitting suggest that the parameters of the immunological model and the parameters of the immuno-epidemiological model are practically identifiable. We suggest that analytic approaches for studying the structural identifiability of nested models are a necessity, so that identifiable parameter combinations can be derived to reparameterize the nested model to obtain an identifiable one. This is a crucial step in developing multi-scale models which explain multi-scale data.


Self-reactive CFTR T cells in humans: implications for gene therapy.
Cystic fibrosis (CF) is one of the most common autosomal recessive lethal disorders affecting white populations of northern European ancestry. To date there is no cure for CF. Life-long treatments for CF are being developed and include gene therapy and the use of small-molecule drugs designed to target specific cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. Irrespective of the type of molecular therapy for CF, which may include gene replacement, exon skipping, nonsense suppression, or molecular correctors, because all of these modulate gene expression there is an inherent risk of activation of T cells against the wild-type version of CFTR. Here we report the validation of the human interferon-γ enzyme-linked immunospot assay and its application for the analysis of CFTR-specific T cell responses in patients with CF and in non-CF subjects. We found non-CF subjects with low levels of self-reactive CFTR-specific T cells in the United States and several patients with CF with low to high levels of self-reactive CFTR-specific T cells in both the United States and the United Kingdom.


Putting brain training to the test.
'Brain training', or the goal of improved cognitive function through the regular use of computerized tests, is a multimillion-pound industry, yet in our view scientific evidence to support its efficacy is lacking. Modest effects have been reported in some studies of older individuals and preschool children, and video-game players outperform non-players on some tests of visual attention. However, the widely held belief that commercially available computerized brain-training programs improve general cognitive function in the wider population in our opinion lacks empirical support. The central question is not whether performance on cognitive tests can be improved by training, but rather, whether those benefits transfer to other untrained tasks or lead to any general improvement in the level of cognitive functioning. Here we report the results of a six-week online study in which 11,430 participants trained several times each week on cognitive tasks designed to improve reasoning, memory, planning, visuospatial skills and attention. Although improvements were observed in every one of the cognitive tasks that were trained, no evidence was found for transfer effects to untrained tasks, even when those tasks were cognitively closely related.


A Virtual Joy-Stick Study of Emotional Responses and Social Motivation in Children with Autism Spectrum Disorder.
A new virtual reality task was employed which uses preference for interpersonal distance to social stimuli to examine social motivation and emotion perception in children with Autism Spectrum Disorders. Nineteen high function children with higher functioning Autism Spectrum Disorder (HFASD) and 23 age, gender, and IQ matched children with typical development (TD) used a joy stick to position themselves closer or further from virtual avatars while attempting to identify six emotions expressed by the avatars, happiness, fear, anger, disgust, sadness, and surprise that were expressed at different levels of intensity. The results indicated that children with HFASD displayed significantly less approach behavior to the positive happy expression than did children with TD, who displayed increases in approach behavior to higher intensities of happy expressions. Alternatively, all groups tended to withdraw from negative emotions to the same extent and there were no diagnostic group differences in accuracy of recognition of any of the six emotions. This pattern of results is consistent with theory that suggests that some children with HFASD display atypical social-approach motivation, or sensitivity to the positive reward value of positive social-emotional events. Conversely, there was little evidence that a tendency to withdraw from social-emotional stimuli, or a failure to process social emotional stimuli, was a component of social behavior task performance in this sample of children with HFASD.


Prevention of leg length discrepancy in young children with pauciarticular juvenile rheumatoid arthritis by treatment with intraarticular steroids.
To determine if intraarticular (i.a.) injection of triamcinolone hexacetonide (steroids) used early in the course of pauciarticular juvenile rheumatoid arthritis (pauci JRA) is associated with less leg length discrepancy (LLD) or thigh circumference discrepancy (TCD). Children with pauci JRA who had asymmetric lower-extremity arthritis diagnosed before age 7 years in Seattle, Washington (WA; n = 16) and in Chapel Hill and Durham, North Carolina (NC; n = 14) were retrospectively identified. WA children were given i.a. steroids within 2 months of diagnosis; the injections were repeated if synovitis recurred in the same joint or in a different joint. These children were compared with NC children who were not treated with i.a. steroids. Thigh circumference was measured at 10 cm above the patella, and leg length was measured from the anterior superior iliac spine to the mid-medial malleolus, by a single observer. LLD and TCD are reported as the percentage of difference between leg measurements in each subject. The WA and NC subjects had comparable disease severity and duration of followup (in months). Twelve WA children had subsequent i.a. steroid injections (mean 3.25 injections per child over mean +/- SD 42 +/- 11 months). The WA subjects had significantly less LLD (P = 0.005, by Student's 2-sided t-test) and prescriptions for shoe lifts (P = 0.002, by Fisher's 2-sided exact test). There was not a significant difference in TCD between the 2 groups (P = 0.139, by Student's 2-sided t-test). Similar findings were obtained when the analysis was limited to children with monarticular knee arthritis. Early and continued use of i.a. steroids may be associated with less LLD in young children with pauci JRA. This may indicate decreased duration of synovitis.


Cholinergic synaptic transmissions were altered after single sevoflurane exposure in Drosophila pupa.
. Sevoflurane, one of the most used general anesthetics, is widely used in clinical practice all over the world. Previous studies indicated that sevoflurane could induce neuron apoptosis and neural deficit causing query in the safety of anesthesia using sevoflurane. The present study was designed to investigate the effects of sevoflurane on electrophysiology in Drosophila pupa whose excitatory neurotransmitter is acetylcholine early after sevoflurane exposure using whole brain recording technique. Wide types of Drosophila (canton-s flies) were allocated to control and sevoflurane groups randomly. Sevoflurane groups (1% sevoflurane; 2% sevoflurane; 3% sevoflurane) were exposed to sevoflurane and the exposure lasted 5 hours, respectively. All flies were subjected to electrophysiology experiment using patch clamp 24 hours after exposure. The results showed that, 24 hours after sevoflurane exposure, frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) was significantly reduced (P < 0.05). Furthermore, we explored the underlying mechanism and found that calcium currents density, which partially regulated the frequency of mEPSCs, was significantly reduced after sevoflurane exposure (P < 0.05). All these suggested that sevoflurane could alter the mEPSCs that are related to synaptic plasticity partially through modulating calcium channel early after sevoflurane exposure.


Postdeployment suicidal ideations and trajectories of posttraumatic stress disorder in Danish soldiers: a 3-year follow-up of the USPER study.
Suicidal ideation in veterans is of great concern. The objective of this study is to examine how heterogeneous posttraumatic stress disorder (PTSD) trajectories are associated with postdeployment suicidal ideation in veterans 2.5 years postdeployment to a combat zone in Afghanistan. If PTSD trajectories are associated with postdeployment suicidal ideations, then the accumulative knowledge on what characterizes veterans falling into different PTSD trajectories may provide better opportunities for early identification of suicidal high-risk veterans. In this prospective study of 743 Danish soldiers deployed to Afghanistan from February to August in 2009, we collected data at 6 time points from 6 weeks before deployment to 2.5 years after homecoming (total for this study: 456). At all assessments, the soldiers responded to a comprehensive questionnaire including measures of PTSD (measured by the PTSD Checklist, Civilian Version) and other mental and physical health variables, demographics, and social and combat-related factors. Suicidal ideation was measured by an item from the European Parasuicide Study Interview Schedule II. In a previous study based on soldiers from this cohort, we identified 6 PTSD trajectories using latent growth mixture modeling, which we have extracted and applied as independent variables in this study. Adjusted multivariable logistic regression analyses were applied to examine whether deployed soldiers with certain PTSD symptom trajectories were more likely to report suicidal ideation 2.5 years after homecoming. Two PTSD trajectories with high PTSD symptom level 2.5 years after return were significantly associated with suicidal ideation 2.5 years after homecoming. Thus, a relieved-worsening class, described by initial decreasing PTSD symptom levels followed by a steep increase in symptoms had higher risk of suicidal ideation (OR = 7.84; 95% CI, 1.68-36.6), which was also the case for a late-onset class (OR 5.2; 95% CI, 2.21-12.24) when compared to a low-stable class. Heterogeneous PTSD trajectories are associated with suicidal ideation in veterans 2.5 years after homecoming.


N-propionylated group B meningococcal polysaccharide mimics a unique epitope on group B Neisseria meningitidis.
Antibodies induced in mice by the N-propionyl (N-Pr)-group B meningococcal polysaccharide (GBMP)-tetanus toxoid (TT) conjugate were bactericidal for GBM organisms independent of protein serotype. The antisera contained two populations of N-Pr-GBMP-specific antibodies, only one of which crossreacted with the GBMP. Particularly significant was the fact that the bactericidal activity was mainly associated with the population of antibodies that did not crossreact with the GBMP. Therefore it can be inferred from the above evidence that the N-Pr-GBMP mimics a unique epitope on the surface of GBM organisms that is not present on the exogenous GBMP.


Tobramycin and nebramine as pseudo-oligosaccharide scaffolds for the development of antimicrobial cationic amphiphiles.
Antimicrobial cationic amphiphiles derived from aminoglycoside pseudo-oligosaccharide antibiotics interfere with the structure and function of bacterial membranes and offer a promising direction for the development of novel antibiotics. Herein, we report the design and synthesis of cationic amphiphiles derived from the pseudo-trisaccharide aminoglycoside tobramycin and its pseudo-disaccharide segment nebramine. Antimicrobial activity, membrane selectivity, mode of action, and structure-activity relationships were studied. Several cationic amphiphiles showed marked antimicrobial activity, and one amphiphilic nebramine derivative proved effective against all of the tested strains of bacteria; furthermore, against several of the tested strains, this compound was well over an order of magnitude more potent than the parent antibiotic tobramycin, the membrane-targeting antimicrobial peptide mixture gramicidin D, and the cationic lipopeptide polymyxin B, which are in clinical use.


Mechanisms of human motion perception revealed by a new cyclopean illusion.
A new cyclopean illusion of motion may bear on neural mechanisms of direction selectivity. Stationary flickering patterns were presented to each eye, and the resulting fused pattern was perceived to be moving. To determine direction of motion, the visual system seems to integrate image components differing by 90 degrees in spatial and temporal phase. On the other hand, image speed seems to be derived from displacement of features over time. A model of neural direction selectivity is discussed in light of these results.


Physiological mechanisms of imprinting and homing migration in Pacific salmon Oncorhynchus spp.
After several years of feeding at sea, salmonids have an amazing ability to migrate long distances from the open ocean to their natal stream to spawn. Three different research approaches from behavioural to molecular biological studies have been used to elucidate the physiological mechanisms underpinning salmonid imprinting and homing migration. The study was based on four anadromous Pacific salmon Oncorhynchus spp., pink salmon Oncorhynchus gorbuscha, chum salmon Oncorhynchus keta, sockeye salmon Oncorhynchus nerka and masu salmon Oncorhynchus masou, migrating from the North Pacific Ocean to the coast of Hokkaido, Japan, as well as lacustrine O. nerka and O. masou in Lake Toya, Hokkaido, where the lake serves as the model oceanic system. Behavioural studies using biotelemetry techniques showed swimming profiles from the Bering Sea to the coast of Hokkaido in O. keta as well as homing behaviours of lacustrine O. nerka and O. masou in Lake Toya. Endocrinological studies on hormone profiles in the brain-pituitary-gonad axis of O. keta, and lacustrine O. nerka identified the hormonal changes during homing migration. Neurophysiological studies revealed crucial roles of olfactory functions on imprinting and homing during downstream and upstream migration, respectively. These findings are discussed in relation to the physiological mechanisms of imprinting and homing migration in anadromous and lacustrine salmonids.


Teaching and promoting testicular self-examination.
Testicular cancer is the commonest malignancy of young men, but it also has a high cure rate. This article discusses the teaching and promotion of testicular self-examination as a technique for early detection of the disease.


[Diagnosis and therapy of cerebral angiomas].
Cerebral angiomas are rare, congenital malformations of the cerebral blood vessels. Approximately 60 new cases are diagnosed in Switzerland each year. These malformations become symptomatic most often with cerebral hemorrhage, epilepsy or intractable headache. Total excision is the only curative therapy. Alternative treatments are embolization with isobutyl-cyanoacrylate or high energy radiotherapy, although these latter procedures rarely achieve complete obliteration. Indications for the different therapeutic modalities are discussed.


Double Trouble: A Case Series on Concomitant Genetic Aberrations in NSCLC.
Several oncogenic drivers have been identified in non-small cell lung cancer. Targeted therapies for these aberrations have already been successfully developed and implemented in clinical practice. Owing to improved sensitivity in genetic testing, more and more tumors with multiple driver mutations are identified, resulting in dilemmas for treating physicians whether and which targeted therapy to use. In this case series, we provide an overview of patients with intrinsic double mutations in oncogenic drivers and their reported response to targeted therapies, with a focus on epidermal growth factor receptor, anaplastic lymphoma kinase, cMET, and Kirsten rat sarcoma viral oncogene. We also include an unpublished case report on a patient with an epidermal growth factor receptor L858R and cMET exon 14 skipping.


Motor ability and working memory in Omani and German primary school-aged children.
This study investigated the motor ability and working memory performance of Omani and German primary school-aged children. One hundred eighty-five children from public schools participated in a gross motor test that integrated whole body coordination, three different ball tasks, and a 20-meter run. Furthermore, they completed four working memory tests (the Digit-Span Test forward and backwards and the Corsi Block-Tapping Test forward and backwards). Two MANOVAS with the different motor and working memory tests and one univariate analysis of the general motor ability with the between-subject factors group and gender were conducted. Additionally, correlations between motor ability and working memory scores were executed. German children outperformed Omani children in the overall measurement of motor ability, (p = .01) and all aspects of working memory, (all p< .015). There were no correlations between motor and cognitive variables, when analyzing the results for the Omani and German children separately. These findings may be a result of different educational styles or socioeconomic status and must be investigated in more detail.


Long non-coding RNA LINC01503 promotes colorectal cancer cell proliferation and invasion by regulating miR-4492/FOXK1 signaling.
Increasing evidence indicates that long non-coding RNAs (lncRNAs) are closely associated with the progression of human cancer, including colorectal cancer (CRC). A previous study suggested that lncRNA LINC01503 promotes squamous cell carcinoma progression. However, the function of LINC01503 in CRC has remained elusive. The present study indicated that LINC01503 was significantly upregulated in CRC tissues compared with that in adjacent normal tissues as detected by reverse transcription-quantitative polymerase chain reaction. It was demonstrated that knockdown of long intergenic non-protein coding RNA (LINC)01503 markedly inhibited the proliferation and invasion of CRC cells, whereas overexpression of LINC01503 had the opposite effects, as indicated by Cell Counting kit-8 and Transwell assays. Mechanistically, it was revealed that LINC01503 serves as a sponge for microRNA (miR)-4492, which targets forkhead box K1 (FOXK1) in CRC cells. In addition, luciferase reporter assays demonstrated the direct binding of miR-4492 mimics to LINC01503 and to a sequence in the 3'-untranslated region of FOXK1. Furthermore, it was demonstrated that overexpression of LINC01503 reduced the availability of miR-4492 in CRC cells. Furthermore, miR-4492 mimics inhibited FOXK1 expression, while simultaneous overexpression of LINC01503 abolished this effect. Finally, it was demonstrated that restoration of FOXK1 abolished the inhibitory effect of LINC01503 knockdown on CRC cell proliferation and invasion. Taken together, the present results suggested that LINC01503 promotes CRC progression via acting as a competing endogenous RNA for miR-4492/FOXK1.


Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis.
Complete interferon-gamma receptor 1 (IFNgammaR1) deficiency has been identified previously as a cause of fatal bacillus Calmette-Guérin (BCG) infection with lepromatoid granulomas, and of disseminated nontuberculous mycobacterial (NTM) infection in children who had not been inoculated with BCG. We report here a kindred with partial IFNgammaR1 deficiency: one child afflicted by disseminated BCG infection with tuberculoid granulomas, and a sibling, who had not been inoculated previously with BCG, with clinical tuberculosis. Both responded to antimicrobials and are currently well without prophylactic therapy. Impaired response to IFN-gamma was documented in B cells by signal transducer and activator of transcription 1 nuclear translocation, in fibroblasts by cell surface HLA class II induction, and in monocytes by cell surface CD64 induction and TNF-alpha secretion. Whereas cells from healthy children responded to even low IFN-gamma concentrations (10 IU/ml), and cells from a child with complete IFNgammaR1 deficiency did not respond to even high IFN-gamma concentrations (10,000 IU/ml), cells from the two siblings did not respond to low or intermediate concentrations, yet responded to high IFN-gamma concentrations. A homozygous missense IFNgR1 mutation was identified, and its pathogenic role was ascertained by molecular complementation. Thus, whereas complete IFNgammaR1 deficiency in previously identified kindreds caused fatal lepromatoid BCG infection and disseminated NTM infection, partial IFNgammaR1 deficiency in this kindred caused curable tuberculoid BCG infection and clinical tuberculosis.


RNA binding strategies of ribosomal proteins.
Structures of a number of ribosomal proteins have now been determined by crystallography and NMR, though the complete structure of a ribosomal protein-rRNA complex has yet to be solved. However, some ribosomal protein structures show strong similarity to well-known families of DNA or RNA binding proteins for which structures in complex with cognate nucleic acids are available. Comparison of the known nucleic acid binding mechanisms of these non-ribosomal proteins with the most highly conserved surfaces of similar ribosomal proteins suggests ways in which the ribosomal proteins may be binding RNA. Three binding motifs, found in four ribosomal proteins so far, are considered here: homeodomain-like alpha-helical proteins (L11), OB fold proteins (S1 and S17) and RNP consensus proteins (S6). These comparisons suggest that ribosomal proteins combine a small number of fundamental strategies to develop highly specific RNA recognition sites.


Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC.
Head and neck squamous cell carcinomas (HNSCC) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials, and identification of predictive biomarkers remains challenging. To investigate mTORC-specific inhibition, we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors ± cetuximab in a panel of HNSCC cell lines and patient-derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single-agent mTORC inhibition inhibited growth of one PIK3CA-mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA-mutant model. In all models, the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway's role in driving proliferation. Although single-agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence, suggesting that approaches that attempt to match biomarkers to the optimal therapy in HNSCC remain complex and challenging. Mol Cancer Ther; 16(7); 1257-68. ©2017 AACR.


An alternatively spliced isoform of PSD-93/chapsyn 110 binds to the inwardly rectifying potassium channel, Kir2.1.
Inwardly rectifying potassium (Kir) channels are prime determinants of resting membrane potential in neurons. Their subcellular distribution and surface density thus help shape neuronal excitability, yet mechanisms governing the membrane targeting and localization of Kir channels are poorly understood. Here we report a direct interaction between the strong inward rectifier, Kir2.1, and a recently identified splice variant of postsynaptic density-93 (PSD-93), a protein involved the subcellular targeting of ion channels and glutamate receptors at excitatory synapses. Yeast two-hybrid screening of a human brain cDNA library using the carboxyl terminus of Kir2.1 as bait yielded cDNA encoding the first two PDZ domains of PSD-93, but with an extended N-terminal region that diverged from other PSD-93 isoforms. This clone represented the human homologue of the mouse PSD-93 splice variant, PSD-93delta. Reverse transcription-polymerase chain reaction analysis showed diffuse low level PSD-93delta expression throughout the brain, with significantly higher levels in spinal cord. In vitro binding studies revealed that a type I PDZ recognition motif at the extreme C terminus of the Kir2.1 mediates interaction with all three PDZ domains of PSD-93delta, and association between Kir2 channels and PSD-93delta was confirmed further by the ability of anti-Kir2.1 antibodies to coimmunoprecipitate PSD-93delta from rat spinal cord lysates. Functionally, coexpression of Kir2.1 and PSD-93delta had no discernible effect upon channel kinetics but resulted in cell surface Kir2.1 clustering and suppression of channel internalization. We conclude that PSD-93delta is potentially an important regulator of the spatial and temporal distribution of Kir2 channels within neuronal membranes of the central nervous system.


Plasma membrane H(+)-HCO3- transport in rat hepatocytes: a principal role for Na(+)-coupled HCO3- transport.
Na(+)-coupled HCO3- transport has been demonstrated in the basolateral membrane of hepatocytes, but there is uncertainty regarding its stoichiometry or capacity compared with other mechanisms of H(+)-HCO3- transport. After preincubation in medium free of Na+, either in the presence or absence of HCO3(-)-CO2, rat hepatocytes in primary culture were reexposed to Na+ or HCO3(-)-CO2 alone or in combination. Transporter electrogenicity was assessed by measuring membrane potential difference (PD), and the relative capacities of Na(+)-coupled HCO3- transport, Cl(-)-HCO3- exchange, and Na(+)-H+ exchange were assessed by measuring the magnitude and rate of change of intracellular pH (pHi) using BCECF. In the absence of Na+, exposure to HCO3- alone had no consistent effect on PD or pHi. In the absence of HCO3-, reexposure to Na+ depolarized cells by 3 +/- 1 mV and caused an amiloride-inhibitable increase in pHi of 0.031 +/- 0.02 units/min. In the presence of HCO3-, reexposure to Na+ hyperpolarized cells by -14 +/- 5 mV and increased pHi at a rate of 0.133 +/- 0.11 units/min; both the hyperpolarization and alkalinization were inhibited by SITS but unaffected by amiloride. These changes in PD indicate that Na(+)-coupled HCO3- transport is electrogenic, consistent with coupling of more than one HCO3- to each Na+. Furthermore, SITS-inhibitable Na(+)-dependent alkalinization exceeds amiloride-inhibitable Na(+)-dependent alkalinization by an order of magnitude, suggesting that the transport capacity of Na(+)-coupled HCO3- transport exceeds that of Na(+)-H+ exchange.(ABSTRACT TRUNCATED AT 250 WORDS)


Long-term outcomes of pars plana Ahmed valve implant and vitrectomy in eyes with refractory glaucoma.
Pars plana vitrectomy with implantation of an Ahmed glaucoma valve in the vitreous cavity has been reported with a success rate in the management of refractory and neovascular glaucoma. This study aimed to present the outcomes of pars plana Ahmed glaucoma valve (PPAV) surgical implantation in cases with refractory glaucoma. In this single-center, retrospective, comparative study, 87 consecutive patients diagnosed with refractory glaucoma who underwent PPAV surgical implantation between October 2015 and October 2019 were evaluated. A successful postoperative outcome was defined as intraocular pressure (IOP) ≤ 21 mmHg upon examination and a reduction in the number of anti-glaucoma agents used at the latest follow-up. Finally, 81 eyes of 78 patients with refractory glaucoma were included; 54 (66.66%) of the eyes had neovascular glaucoma. The mean follow-up was 20.65 ± 12.17 months (range: 2-52 months). The mean preoperative IOP was 40.01 ± 1.19 mmHg and reduced significantly to 16.73 ± 0.82 mmHg at the latest follow-up (P < 0.001); a successful IOP outcome was achieved in 88.89% of eyes. The mean number of anti-glaucoma agents decreased significantly from 2.86 ± 0.09 preoperatively to 1.46 ± 0.11 at the latest follow-up (P < 0.001); while 61 (75.31%) of eyes had a reduction in the number of IOP lowering eye drops, and 14 (17.28%) had no need for IOP lowering eye drops. PPAV surgery is a successful procedure for IOP reduction in patients with refractory glaucoma. Our study demonstrated either reduction or elimination of IOP lowering eye drops postoperatively. Large scale studies with a comparison group, a longer follow-up, and having various subtypes of glaucoma are required as future research to confirm these outcomes.


Severe air pollution events not avoided by reduced anthropogenic activities during COVID-19 outbreak.
Due to the pandemic of coronavirus disease 2019 in China, almost all avoidable activities in China are prohibited since Wuhan announced lockdown on January 23, 2020. With reduced activities, severe air pollution events still occurred in the North China Plain, causing discussions regarding why severe air pollution was not avoided. The Community Multi-scale Air Quality model was applied during January 01 to February 12, 2020 to study PM2.5 changes under emission reduction scenarios. The estimated emission reduction case (Case 3) better reproduced PM2.5. Compared with the case without emission change (Case 1), Case 3 predicted that PM2.5 concentrations decreased by up to 20% with absolute decreases of 5.35, 6.37, 9.23, 10.25, 10.30, 12.14, 12.75, 14.41, 18.00 and 30.79 μg/m3 in Guangzhou, Shanghai, Beijing, Shijiazhuang, Tianjin, Jinan, Taiyuan, Xi'an, Zhengzhou, Wuhan, respectively. In high-pollution days with PM2.5 greater than 75 μg/m3, the reductions of PM2.5 in Case 3 were 7.78, 9.51, 11.38, 13.42, 13.64, 14.15, 14.42, 16.95 and 22.08 μg/m3 in Shanghai, Jinan, Shijiazhuang, Beijing, Taiyuan, Xi'an, Tianjin, Zhengzhou and Wuhan, respectively. The reductions in emissions of PM2.5 precursors were ~2 times of that in concentrations, indicating that meteorology was unfavorable during simulation episode. A further analysis shows that benefits of emission reductions were overwhelmed by adverse meteorology and severe air pollution events were not avoided. This study highlights that large emissions reduction in transportation and slight reduction in industrial would not help avoid severe air pollution in China, especially when meteorology is unfavorable. More efforts should be made to completely avoid severe air pollution.


Risk and Protective Factors in the Lives of Transgender/Gender Nonconforming Adolescents.
Research suggests that transgender and gender nonconforming (TGNC) youth may be at greatly increased risk of high-risk health behaviors compared with cisgender youth, but existing studies are limited by convenience samples and small numbers. This study uses a large school-based sample of adolescents to describe the prevalence of TGNC identity, associations with health risk behaviors and protective factors, and differences across birth-assigned sex. This study analyzes existing surveillance data provided by 9th and 11th grade students in Minnesota in 2016 (N = 81,885). Students who were transgender, genderqueer, genderfluid, or unsure about their gender identity (TGNC) were compared with those who were not, using χ2 and t-tests. Outcome measures included four domains of high-risk behaviors and experiences and four protective factors. The prevalence of TGNC identity was 2.7% (n = 2,168) and varied significantly across gender, race/ethnicity, and economic indicators. Involvement in all types of risk behaviors and experiences was significantly higher, and reports of four protective factors were significantly lower among TGNC than cisgender youth. For example, almost two-thirds (61.3%) of TGNC youth reported suicidal ideation, which is over three times higher than cisgender youth (20.0%, χ2 = 1959.9, p < .001). Among TGNC youth, emotional distress and bullying experience were significantly more common among birth-assigned females than males. This research presents the first large-scale, population-based evidence of substantial health disparities for TGNC adolescents in the United States, highlighting numerous multilevel points of intervention through established protective factors. Health care providers are advised to act as allies by creating a safe space for young people, bolstering protective factors, and supporting their healthy development.


Measuring effectiveness of drugs in observational databanks: promises and perils.
Observational databanks have inherent strengths and shortcomings. As in randomized controlled trials, poor design of these databanks can either exaggerate or reduce estimates of drug effectiveness and can limit generalizability. This commentary highlights selected aspects of study design, data collection and statistical analysis that can help overcome many of these inadequacies. An international metaRegister and a formal mechanism for standardizing and sharing drug data could help improve the utility of databanks. Medical journals have a vital role in enforcing a quality checklist that improves reporting.


Management of the Hindfoot and Ankle in Charcot Arthropathy.
Neuropathic destabilization of the hindfoot and/or ankle is a significant complication for the patient with diabetes/neuropathy. The loss of ligamentous integrity and bony destruction results in a limb that is not stable for weight bearing. This loss of independence adds significant health risks to the patient. Management of this disease process is both time consuming and technically demanding for both the practitioner and the patient. Attention to detail and aggressive decision making is often necessary to salvage the limb. The goal for treatment is to produce a stable, weight-bearing limb that is shoeable and free from soft-tissue ulceration.


Piracetam in elderly motorists.
101 elderly motorists with reduced reaction capacity were examined under real traffic conditions with regard to their driving ability. They were given a daily dose of 4.8 g piracetam or placebo over a six-week period in a randomised double-blind study. The percentage of correctly solved sign-observance items, which reflects orientation and perception in real traffic conditions, increased in the placebo-treated test-group from 79.86% in the pretest to 80.07% in the retest, whereas the test subjects of the piracetam-treated group improved their performance from 77.08% to 84.16%. After being treated with piracetam for 6 weeks, the drivers showed a significantly better performance than the placebo-group. Of particular interest is the finding that the test-subjects who had scored less than 80% in the pretest improved without exception in the retest after treatment with piracetam.