GOLPH3 is essential for contractile ring formation and Rab11 localization to the cleavage site during cytokinesis in Drosophila melanogaster.
The highly conserved Golgi phosphoprotein 3 (GOLPH3) protein has been described as a Phosphatidylinositol 4-phosphate [PI(4)P] effector at the Golgi. GOLPH3 is also known as a potent oncogene, commonly amplified in several human tumors. However, the molecular pathways through which the oncoprotein GOLPH3 acts in malignant transformation are largely unknown. GOLPH3 has never been involved in cytokinesis. Here, we characterize the Drosophila melanogaster homologue of human GOLPH3 during cell division. We show that GOLPH3 accumulates at the cleavage furrow and is required for successful cytokinesis in Drosophila spermatocytes and larval neuroblasts. In premeiotic spermatocytes GOLPH3 protein is required for maintaining the organization of Golgi stacks. In dividing spermatocytes GOLPH3 is essential for both contractile ring and central spindle formation during cytokinesis. Wild type function of GOLPH3 enables maintenance of centralspindlin and Rho1 at cell equator and stabilization of Myosin II and Septin rings. We demonstrate that the molecular mechanism underlying GOLPH3 function in cytokinesis is strictly dependent on the ability of this protein to interact with PI(4)P. Mutations that abolish PI(4)P binding impair recruitment of GOLPH3 to both the Golgi and the cleavage furrow. Moreover telophase cells from mutants with defective GOLPH3-PI(4)P interaction fail to accumulate PI(4)P-and Rab11-associated secretory organelles at the cleavage site. Finally, we show that GOLPH3 protein interacts with components of both cytokinesis and membrane trafficking machineries in Drosophila cells. Based on these results we propose that GOLPH3 acts as a key molecule to coordinate phosphoinositide signaling with actomyosin dynamics and vesicle trafficking during cytokinesis. Because cytokinesis failures have been associated with premalignant disease and cancer, our studies suggest novel insight into molecular circuits involving the oncogene GOLPH3 in cytokinesis.


A communitywide intervention to improve outcomes and reduce disability among injured workers in Washington State.
One pressing challenge facing the U.S. health care system is the development of effective policies and clinical management strategies to address deficiencies in health care quality. In collaboration with researchers at the University of Washington, the Washington State Department of Labor and Industries has created a communitywide delivery system intervention to improve health outcomes and reduce disability among injured workers. This intervention is currently being tested in two sites in western and eastern Washington. So far, it appears to be possible to engage physicians and health care institutions in quality improvement initiatives and to form effective public-private partnerships for this purpose. Furthermore, collaborating with university researchers may help enhance the scientific rigor of the quality improvement initiative and create more opportunities for a successful evaluation.


Intimate Partner Violence and Work: A Scoping Review of Published Research.
Increasingly, intimate partner violence (IPV) is recognized as having important impacts on work. The purpose of this scoping review is to describe the nature and extent of research on IPV and workers, the workplace, and/or employment. Using multiple search strategies, including searches conducted by a professional librarian from database inception to May 2018, 2,306 unique articles were retrieved and independently screened for eligibility by two team members. A total of 235 articles met predefined inclusion criteria, which were that articles must: (1) report findings of a research study, (2) be published in a peer-reviewed journal, and (3) be focused on IPV and the workplace, workers, and/or employment. The most common topics examined were the relationship between IPV and employment, IPV- and work-related factors, and the impacts of IPV on work. Most articles were quantitative and cross-sectional and focused on the abuse of women by men. Major research gaps include evaluations of interventions to address IPV and work and research focused on the experiences and needs of perpetrators and gender and sexual minorities. Further evidence synthesis is recommended in several areas and implications for policy and practice are discussed.


Molecular subtyping of human T-cell lymphotropic virus type 2 by single-strand conformation polymorphism analysis. Retrovirus Epidemiology Donor Study Group.
Molecular subtyping of human T-cell lymphotropic virus type 2 (HTLV-2) by the currently used method of restriction fragment length polymorphism analysis may not be sufficiently discriminatory for transmission studies because of the predominance of single restriction types in various HTLV-2-infected populations. The utility of single-strand conformations polymorphism (SSCP) analysis was evaluated as a tool to improve the sensitivity of the subtyping of HTLV-2. The assay was designed to target a highly variable region in the long terminal repeat and was shown to be able to detect single nucleotide changes in cloned HTLV-2 sequences. Analysis of 52 HTLV-2 samples, of which 32 were from 16 sex partner pairs (16 males, 16 females), showed nine different SSCP patterns. Identical SSCP results were obtained for each of the 16 couples, suggesting the presence of similar viral genotypes and, therefore, supporting the likelihood of sexual transmission of HTLV-2 in each of these couples. Furthermore, SSCP analysis of seven HTLV-2 samples of the same restriction type (b5) showed five different SSCP patterns. Nucleotide sequencing of two samples with distinct SSCP patterns confirmed the sequence differences. SSCP provides a facile and discriminatory tool for the differentiation of HTLV-2 strains, including those previously indistinguishable by restriction fragment length polymorphism.


Everyday functioning in young children with cerebral palsy: functional skills, caregiver assistance, and modifications of the environment.
Everyday functioning is described in 95 children with cerebral palsy (CP; 55 males and 40 females; mean age 58 months, SD 18 months, range 25 to 87 months) using the three scales of the Pediatric Evaluation of Disability Inventory (PEDI): Functional Skills, Caregiver Assistance, and Modifications of the Environment. Types of CP in the children were hemiplegia, (n=19), spastic/ataxic diplegia, (n=44), spastic quadriplegia, (n=16), dyskinetic, (n=9), and mixed (n=7). Symptoms were grouped by severity according to the Gross Motor Function Classification System (GMFCS): 23% were classified at level I, 21% at level II, 10% at level III, 23% at level IV, and 23% level V. A large variability in functioning in mobility, self-care, and social function was seen because of the heterogeneity of children with CP. Limitations in achievement of activities, need for assistance, and use of assistive devices increased progressively with GMFCS level. Furthermore, these children differed to a great extent from the normative sample of the PEDI. Stepwise regression analysis showed that the GMFCS was a good predictor of everyday functioning with age and learning problems as significantly contributing factors, particularly in self-care and social function. In conclusion, the three scales of the PEDI represent different but strongly related aspects of everyday functioning in young children with CP.


Multichannel hydrogel based on a chitosan-poly(vinyl alcohol) composition for directed growth of animal cells.
In this study, a new method for production of hydrogels with oriented multichannel structure based on chitosan-poly(vinyl alcohol) compositions was developed. Microscopic and biological studies of the obtained hydrogels were conducted to determine the optimal composition, which would ensure that structure of the material mimics that of the epineurium and perineurium in a nerve. Structure of the hydrogels was adjusted by variation of the initial concentration of the precipitant, poly(vinyl alcohol), and acid in the chitosan compositions. A single cycle of freezing and thawing of the produced hydrogels resulted in lower structural heterogeneity, which is promising for the production of a scaffold that simulates the structure of the native peripheral nerve. in vitro cytotoxic assays showed biocompatibility of the manufactured hydrogels.


Rate-distortion analysis of motion-compensated rate scalable video.
Generally speaking, rate scalable video systems today are evaluated operationally, meaning that the algorithm is implemented and the rate-distortion performance is evaluated for an example set of inputs. However, in these cases it is difficult to separate the artifacts caused by the compression algorithm and data set with general trends associated with scalability. In this paper, we derive and evaluate theoretical rate-distortion performance bounds for both layered and continuously rate scalable video compression algorithms which use a single motion-compensated prediction (MCP) loop. These bounds are derived using rate-distortion theory based on an optimum mean-square error (MSE) quantizer, and are thus applicable to all methods of intraframe encoding which use MSE as a distortion measure. By specifying translatory motion and using an approximation of the predicted error frame power spectral density, it is possible to derive parametric versions of the rate-distortion functions which are based solely on the input power spectral density and the accuracy of the motion-compensated prediction. The theory is applicable to systems which allow prediction drift, such as the data-partitioning and SNR-scalability schemes in MPEG-2, as well as those with zero prediction drift such as fine granularity scalability MPEG-4. For systems which allow prediction drift we show that optimum motion compensation is a sufficient condition for stability of the decoding system.


Influence of long-distance climate teleconnection on seasonality of water temperature in the world's largest lake--Lake Baikal, Siberia.
Large-scale climate change is superimposed on interacting patterns of climate variability that fluctuate on numerous temporal and spatial scales--elements of which, such as seasonal timing, may have important impacts on local and regional ecosystem forcing. Lake Baikal in Siberia is not only the world's largest and most biologically diverse lake, but it has exceptionally strong seasonal structure in ecosystem dynamics that may be dramatically affected by fluctuations in seasonal timing. We applied time-frequency analysis to a near-continuous, 58-year record of water temperature from Lake Baikal to examine how seasonality in the lake has fluctuated over the past half century and to infer underlying mechanisms. On decadal scales, the timing of seasonal onset strongly corresponds with deviation in the zonal wind intensity as described by length of day (LOD); on shorter scales, these temperature patterns shift in concert with the El Nino-Southern Oscillation (ENSO). Importantly, the connection between ENSO and Lake Baikal is gated by the cool and warm periods of the Pacific Decadal Oscillation (PDO). Large-scale climatic phenomena affecting Siberia are apparent in Lake Baikal surface water temperature data, dynamics resulting from jet stream and storm track variability in central Asia and across the Northern Hemisphere.


Rho Chi lecture. Pharmaceutical sciences in the next millennium.
Even a cursory survey of this article suggests that the pharmaceutical sciences are being rapidly transformed under the influence of both the new technologies and sciences and the economic imperatives. Of particular importance are scientific and technological advances that may greatly accelerate the critical process of discovery. The possibility of a drug discovery process built around the principles of directed diversity, self-reproduction, evolution, and self-targeting suggests a new paradigm of lead discovery, one based quite directly on the paradigms of molecular biology. Coupled with the principles of nanotechnology, we may contemplate miniature molecular machines containing directed drug factories, circulating the body and capable of self-targeting against defective cells and pathways -- the ultimate "drug delivery machine." However, science and technology are not the only factors that will transform the pharmaceutical sciences in the next century. The necessary reductions in the costs of drug discovery brought about by the rapidly increasing costs of the current drug discovery paradigms means that efforts to decrease the discovery phase and to make drug development part of drug discovery will become increasingly important. This is likely to involve increasing numbers of "alliances," as well as the creation of pharmaceutical research cells -- highly mobile and entrepreneurial groups within or outside of a pharmaceutical company that are formed to carry out specific discovery processes. Some of these will be in the biotechnology industry, but an increasing number will be in universities. The linear process from basic science to applied technology that has been the Western model since Vannevar Bush's Science: The Endless Frontier has probably never been particularly linear and, in any event, is likely to be rapidly supplanted by models where science, scientific development, and technology are more intimately linked. The pharmaceutical sciences have always been an example of use-directed basic research, but the relationships between the pharmaceutical industry, small and large, and the universities seems likely to become increasingly developed in the next century. This may serve as a significant catalyst for the continued transformation of universities into the "knowledge factories" of the 21st century. Regardless, we may expect to see major changes in the research organizational structure in the pharmaceutical sciences even as pharmaceutical companies enjoy record prosperity. And this is in anticipation of tough times to come.


Electroencephalographic Study on Sensory Integration in Visually Induced Postural Sway.
A periodically reversing optic flow animation, experienced while standing, induces an involuntary sway termed visually induced postural sway (VIPS). Interestingly, VIPS is suppressed during light finger touch to a stationary object. Here, we explored whether VIPS is mediated by parietal field activity in the dorsal visual stream as well as by activity in early visual areas, as has been suggested. We performed a mobile brain/body imaging study using high-density electroencephalographic recording from human participants (11 men and 3 women) standing during exposure to periodically reversing optic flow with and without light finger touch to a stable surface. We also performed recording their visuo-postural tracking movements as a typical visually guided movement to explore differences of cortical process of VIPS from the voluntary visuomotor process involving the dorsal stream. In the visuo-postural tracking condition, the participants moved their center of pressure in time with a slowly oscillating (expanding, shrinking) target rectangle. Source-resolved results showed that alpha band (8-13 Hz) activity in the medial and right occipital cortex during VIPS was modulated by the direction and velocity of optic flow and increased significantly during light finger touch. However, source-resolved potentials from the parietal association cortex showed no such modulation. During voluntary postural sway with feedback (but no visual flow) in which the dorsal stream is involved, sensorimotor areas produced more theta band (4-7 Hz) and less beta band (14-35 Hz) activity than during involuntary VIPS. These results suggest that VIPS involves cortical field dynamic changes in the early visual cortex rather than in the posterior parietal cortex of the visual dorsal stream.


The role of Borrelia burgdorferi in interstitial cystitis.
Borrelia burgdorferi spirochete has been found both in bladder biopsies and the urine of patients with Lyme disease (LD) as well as in experimental animals. The urological symptoms in borreliosis resemble those of interstitial cystitis (IC): frequency, urgency and nocturia. The aim of this studies is to find the role of B. burgdorferi in interstitial cystitis. We studied antibodies against B. burgdorferi from serum samples of 50 IC patients with two separate EIA tests. Patients with positive serology in both tests underwent cystoscopy and a bladder biopsy was taken. The presence of borrelia DNA was studied with borrelia-specific polymerase chain reaction (PCR), and with universal bacterial PCR. IgM class antibodies to B. burgdorferi were not found, but IgG antibodies were found in four samples (8%). This was higher than in the control material (2%). One patient's sample was strongly positive, whereas three samples were weakly positive. Bladder biopsies taken from the 4 patients were negative for borrelia DNA in both PCR tests. None of the seropositive patients had any symptoms consistent with LD. These results indicate that persistent infection of B. burgdorferi has no role in the etiology of IC. On the other hand a connection with a past borrelia infection and IC is not excluded.


Magnetization curves of haemoproteins measured by low-temperature magnetic-circular-dichroism spectroscopy.
The magnetic-circular-dichroism (m.c.d.) spectra of methymyoglobin cyanide and oxidized horse heart cytochrome c were measured in the region of the Soret band over a range of temperatures from 1.5 to 50 K and in fields from 0 to 5T. A similar study has been made with reduced bovine heart cytochrome c oxidase, which contains one high-spin ferrous haem, namely a3. M.c.d. magnetization curves characteristic of an isolated Kramer's ground state with spin S = 1/2. These curves contrast with the magnetization curve of the high-spin ferrous haem with spin S = 2. The electronic ground state of the latter compound contains zero-field components that are thermally accessible over the temperature range of the experiment. Hence the magnetization curves are a complex nested set. The magnetization curves of the S = 1/2 proteins were analysed and it is shown that it is possible to make estimates of the ground-state g-factors even in the presence of rhombic anisotropy, provided that some knowledge of the polarizations of the electronic transitions is available. The striking difference between the m.c.d. magnetization curves of a simple S = 1/2 paramagnet and magnetically complex ground state should prove extremely useful when m.c.d. spectroscopy is sued to probe the magentic properties of metal centres in proteins, and should have wide application beyond the field of haemoproteins.


Application of the Person-Environment-Occupation Model: a practical tool.
Occupational therapy focuses on complex dynamic relationships between people, occupations and environments. Therapists must clearly communicate their practices and how their practice influences outcomes. This paper explores applications of the Person-Environment-Occupation Model (Law et al., 1996) in occupational therapy practice, and delineates how this particular model helps therapists to conceptualize, plan, communicate and evaluate occupational performance interventions. Three case studies illustrate how the model can be used by occupational therapists to systematically approach analysis of occupational performance issues while considering the complexities of human functioning and experience. The ways in which the model facilitates communication within and outside occupational therapy are explained. The Person-Environment-Occupation Model is offered as a tool for therapists to use in client(s)-therapist alliances to enable clients to successfully engage in meaningful occupations in chosen environments.


Tubulin tyrosine nitration regulates microtubule organization in plant cells.
During last years, selective tyrosine nitration of plant proteins gains importance as well-recognized pathway of direct nitric oxide (NO) signal transduction. Plant microtubules are one of the intracellular signaling targets for NO, however, the molecular mechanisms of NO signal transduction with the involvement of cytoskeletal proteins remain to be elucidated. Since biochemical evidence of plant α-tubulin tyrosine nitration has been obtained recently, potential role of this posttranslational modification in regulation of microtubules organization in plant cell is estimated in current paper. It was shown that 3-nitrotyrosine (3-NO2-Tyr) induced partially reversible Arabidopsis primary root growth inhibition, alterations of root hairs morphology and organization of microtubules in root cells. It was also revealed that 3-NO2-Tyr intensively decorates such highly dynamic microtubular arrays as preprophase bands, mitotic spindles and phragmoplasts of Nicotiana tabacum Bright Yellow-2 (BY-2) cells under physiological conditions. Moreover, 3D models of the mitotic kinesin-8 complexes with the tail of detyrosinated, tyrosinated and tyrosine nitrated α-tubulin (on C-terminal Tyr 450 residue) from Arabidopsis were reconstructed in silico to investigate the potential influence of tubulin nitrotyrosination on the molecular dynamics of α-tubulin and kinesin-8 interaction. Generally, presented data suggest that plant α-tubulin tyrosine nitration can be considered as its common posttranslational modification, the direct mechanism of NO signal transduction with the participation of microtubules under physiological conditions and one of the hallmarks of the increased microtubule dynamics.


"Gating" effects of simultaneous peripheral electrical stimulations on human secondary somatosensory cortex: a whole-head MEG study.
The secondary somatosensory cortex (SII) is strongly involved in the processing of somatosensory tactile and nociceptive sensations. We investigated the effect on SII responses of simultaneous painful and nonpainful electrical stimulations delivered to the thumb and little finger. According to the "bimodal" (i.e., nociceptive, tactile) organization of SII, it was expected that simultaneous painful and nonpainful stimulations would lead to modality interference with a marked reduction ("gating") of somatosensory evoked fields (SEFs) generated in SII. Eight different stimulus conditions were studied. Two conditions were simultaneous "unimodal" (thumb and little finger nonpainful; thumb and little finger painful) and two conditions were simultaneous "bimodal" (thumb nonpainful and little finger painful; thumb painful and little finger nonpainful). As a reference, four conditions included stimulations at single sites (thumb nonpainful, little finger nonpainful, thumb painful, little finger painful). The gating phenomenon was defined as the percentage of difference between the intensities of SII activation after simultaneous compared to the sum of the separate stimulations. Results showed that simultaneous stimulations induced gating effects on SEFs generated by SII. No significant gating differences were observed after the two unimodal stimulations, suggesting a negligible effect of global energy on gating. Instead, the gating effects on bilateral SII activity were stronger after simultaneous bimodal when compared to unimodal stimulations. Our findings hint that there could be a greater level of integration/convergence of painful and nonpainful stimuli in SII with respect to SI. Future studies should explore if it could have an important role in exploring pain relief.


Alcoholism: clinical implications of recent research.
The alcoholism field has traditionally been marked by strong divisions between research and clinical practice. The most common modes of clinical practice, rooted in a strong self-help tradition, have not seemed to gain much from biological or behavioral research. Indeed, the most famous (and controversial) behavioral research study of the 1970s appeared to undermine the efforts of clinicians to encourage abstinence as the only reasonable treatment goal for alcoholics. Another study conducted in England in the 1970s appeared to show that simple one-time advice worked as well as more intensive, traditional treatment interventions in persuading alcoholic individuals to modify their behavior. In the 1980s, studies on DSM-III-defined co-morbid psychopathology have served to redefine the heterogeneity of alcoholic patients in treatment, while describing the impact of co-morbidity on clinical course and treatment response. Measures of severity of alcohol dependence in clinical populations led directly to the development of the DSM-III-R criteria for this disorder. Indeed, these measures of severity may have predictive validity relative to treatment response. Finally, newer pharmacological strategies have been suggested, based upon animal and preliminary human studies, which may reduce risk of relapse in some patients. Reviews of the current state of clinically significant research in the alcohol field, with implications for clinicians and clinical investigators are presented.


Reduced mitochondrial DNA content associates with poor prognosis of prostate cancer in African American men.
Reduction or depletion of mitochondrial DNA (mtDNA) has been associated with cancer progression. Although imbalanced mtDNA content is known to occur in prostate cancer, differences in mtDNA content between African American (AA) and Caucasian American (CA) men are not defined. We provide the first evidence that tumors in AA men possess reduced level of mtDNA compared to CA men. The median tumor mtDNA content was reduced in AA men. mtDNA content was also reduced in normal prostate tissues of AA men compared to CA men, suggesting a possible predisposition to cancer in AA men. mtDNA content was also reduced in benign prostatic hyperplasia (BPH) tissue from AA men. Tumor and BPH tissues from patients ≥ 60 years of age possess reduced mtDNA content compared to patients <60 years of age. In addition, mtDNA content was higher in normal tissues from patients with malignant T3 stage disease compared to patients with T2 stage disease. mtDNA levels in matched normal prostate tissues were nearly doubled in Gleason grade of >7 compared to ≤ 7, whereas reduced mtDNA content was observed in tumors of Gleason grade >7 compared to ≤ 7. Together, our data suggest that AA men possess lower mtDNA levels in normal and tumor tissues compared to CA men, which could contribute to higher risk and more aggressive prostate cancer in AA men.


Stability of the synaptic structure in the hippocampus of BALB/c mice with allergic rhinitis.
The aim of this study was to determine whether allergic rhinitis can induce structural changes in the synapse formation in the hippocampus of BALB/c mice immunocytochemically. Allergic rhinitis was induced in mice by two intra-peritoneal injections of ovalbumin administered with a one-week interval. After two weeks, the sensitised mice were challenged with an intra-nasal injection of ovalbumin for two weeks. To analyse the hippocampal synaptic structures, sections were immunostained with antibodies against glutamic acid decarboxylase 65 and glutamic acid decarboxylase 67 (for γ-aminobutyric acid-ergic terminals), synaptophysin (for glutamatergic and γ-aminobutyric acid-ergic terminals) and spinophilin (for dendritic spines). The number of nasal rubbing movements was significantly greater in the allergic rhinitis mice than in the control mice. However, the expression patterns of the four above-mentioned synaptic markers in the hippocampus showed no detectable difference between the allergic rhinitis and control mice. These data indicate that the synaptic structure in the hippocampus might remain unaltered in allergic rhinitis patients.


Targeted overexpression of leukemia inhibitory factor to preserve myocardium in a rat model of postinfarction heart failure.
Myocardial infarction leads to cardiomyocyte loss. The cytokine leukemia inhibitory factor regulates the differentiation and growth of embryonic and adult heart tissue. This study examined the effects of gene transfer of leukemia inhibitory factor in infarcted rat hearts. Lewis rats underwent ligation of the left anterior descending coronary artery and direct injection of adenovirus encoding leukemia inhibitory factor (n = 10) or null transgene as control (n = 10) into the myocardium bordering the ischemic area. A sham operation group (n = 10) underwent thoracotomy without ligation. After 6 weeks, the following parameters were evaluated: cardiac function with a pressure-volume conductance catheter, left ventricular geometry and architecture by histologic methods; myocardial fibrosis by Masson trichrome staining, apoptosis by terminal deoxynucleotidal transferase-mediated deoxyuridine triphosphate nick-end labeling assay, and cardiomyocyte size by immunofluorescence. Rats with overexpression of leukemia inhibitory factor had more preserved myocardium and less fibrosis in both the infarct and its border zone. The border zone in leukemia inhibitory factor-treated animals contained fewer apoptotic nuclei (1.6% +/- 0.1% vs 3.3% +/- 0.2%, P < .05) than that in control animals and demonstrated cardiomyocytes with larger cross-sectional areas (910 +/- 60 microm 2 vs 480 +/- 30 microm 2 , P < .05). Leukemia inhibitory factor-treated animals had increased left ventricular wall thickness (2.1 +/- 0.1 mm vs 1.8 +/- 0.1 mm, P < .05) and less dilation of the left ventricular cavity (237 +/- 22 microL vs 301 +/- 16 microL, P < .05). They also had improved cardiac function, as measured by maximum change in pressure over time (3950 +/- 360 mm Hg/s vs 2750 +/- 230 mm Hg/s, P < .05) and the slopes of the maximum change in pressure over time-end-diastolic volume relationship (68 +/- 5 mm Hg/[s . microL] vs 46 +/- 6 mm Hg/[s . microL], P < .05) and the preload recruitable stroke work relationship (89 +/- 10 mm Hg vs 44 +/- 4 mm Hg, P < .05). Myocardial gene transfer of leukemia inhibitory factor preserved cardiac tissue, geometry, and function after myocardial infarction in rats.


Driving and neurodegenerative diseases.
The proportion of elderly people in the general population is rising, resulting in greater numbers of drivers with neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. These neurodegenerative disorders impair cognition, visual perception, and motor function, leading to reduced driver fitness and greater crash risk. Yet neither medical diagnosis nor age alone is reliable enough to predict driver safety or crashes or to revoke the driving privileges of these individuals. Driving research utilizes tools such as questionnaires about driving habits and history, driving simulators, standardized road tests utilizing instrumented vehicles, and state driving records. Research challenges include outlining the evolution of driving safety, understanding the mechanisms of driving impairment, and developing a reliable and efficient standardized test battery for prediction of driver safety in neurodegenerative disorders. This information will enable healthcare providers to advise their patients with neurodegenerative disorders with more certainty, affect policy, and help develop rehabilitative measures for driving.


Label-free detection of Staphylococcus aureus captured on immutable ligand arrays.
The rapid capture and label-free detection of Staphylococcus aureus , an opportunistic bacterium that can infect upon contact, can be performed using periodic microarrays of ligand-protein conjugates created by noncontact (inkjet) printing, darkfield imaging conditions, and a FFT-based readout method. Ink solutes were prepared using bovine serum albumin (BSA) conjugated to a glycan with high affinity for bacterial adhesins and printed as dot-matrix arrays with periodicities of 80-120 μm using a thermal injection method. Upon exposing the glycan-BSA microarrays to live strains of S. aureus , patterns emerge that can be detected under optical darkfield conditions. These patterns can be decoded by fast Fourier transform (FFT) analysis to generate fault-tolerant readout signals that correspond to the capture of S. aureus, with a limit of detection between 10(2) and 10(3) cfu/mL. Inkjet printing provides independent control over array periodicity, enabling FFT signals to be assigned to specific frequencies in reciprocal k-space.


Infant hyperacuity for radial deformation.
Poor response rates and/or the confounding of motion and offset responses make it difficult to interpret results of previous studies of infant hyperacuity. The aim of the present study was to design a protocol that overcomes these limitations and to investigate the normal maturation of hyperacuity. Hyperacuity of 31 healthy term infants aged 4 to 12 months was measured using radial deformation of static circular D4 patterns with a two-alternative, forced-choice, preferential-looking (FPL) protocol and maximum likelihood threshold estimation. FPL grating resolution acuity was assessed on the same visit. Both hyperacuity and resolution acuity were 1.1 to 1.2 logMAR (12-16 minutes arc) at 4 months of age. Hyperacuity improved rapidly to approximately 0.3 logMAR (2.0 minutes arc) by 9 to 12 months of age. This 0.9 log unit improvement in the hyperacuity still leaves the 12-month-old infant at a level 0.4 log unit poorer than adults' thresholds. Resolution acuity improved more gradually to approximately 0.7 logMAR (5 minutes arc) by 9 to 12 months of age. This 0.4 log unit improvement leaves the 12-month-old infant at a level 0.6 log unit poorer than adults' resolution acuity. Hyperacuity measured via radial deformation thresholds matures very rapidly between 4 and 6 months of age and continues to mature more slowly throughout infancy and into early childhood. The radial deformation protocol may provide a sensitive index for detecting and monitoring abnormalities in spatial vision in cases of infantile esotropia.


Efficacy of the use of a colorimetric pupil light reflex device in the diagnosis of fundus disease or optic pathway disease in dogs.
The aim of this study was to determine the efficacy of a colorimetric pupil light reflex (PLR) device (Melan-100(®), U.S.A.) in dogs with sudden acquired retinal degeneration syndrome (SARDS; 16 cases), progressive retinal atrophy (PRA; 10 cases) and optic pathway disease (6 cases). The colorimetric device detected PLR abnormality in 32, 16 and 9 eyes with SARDS, PRA and optic pathway disease, respectively, whereas white light detected PLR abnormality in 18, 11 and 9 eyes with SARDS, PRA and optic pathway disease, respectively. SARDS dogs displayed miosis, while optic pathway disease dogs displayed mydriasis in a blue light examination. Thus, colorimetric PLR may be a useful method for determining whether electroretinography (ERG) or magnetic resonance imaging (MRI) should be performed for dogs with acute blindness.


[Forensic medical diagnostics of chronic alcoholic intoxication based on histological changes in the soft tissues of oral cavity and salivary glands].
Histological studies of oral cavity mucosa and salivary glands in subjects with chronic alcoholic intoxication revealed changes at the surface of the tongue and in the glandular tissues. Specific features of chronic alcoholic intoxication include acinar and ductal hyperplasia, reduction of the adipose tissue mass in salivary gland stroma, predominance of T-lymphocytes in hard palate minor salivary glands and B-lymphocytes in the stroma of labial minor salivary gland, the absence of plasma cells in the stroma of hard palate minor salivary glands and labial mucosa. Leukoplakia, dysplasia, and hyperplasia of the basal epithelial layer of oral cavity mucosa are considered to be the signs of long-term (over 12 months) alcohol consumption.


Intrinsic positional memory guides target-specific axon regeneration in the zebrafish vagus nerve.
Regeneration after peripheral nerve damage requires that axons re-grow to the correct target tissues in a process called target-specific regeneration. Although much is known about the mechanisms that promote axon re-growth, re-growing axons often fail to reach the correct targets, resulting in impaired nerve function. We know very little about how axons achieve target-specific regeneration, particularly in branched nerves that require distinct targeting decisions at branch points. The zebrafish vagus motor nerve is a branched nerve with a well-defined topographic organization. Here, we track regeneration of individual vagus axons after whole-nerve laser severing and find a robust capacity for target-specific, functional re-growth. We then develop a new single-cell chimera injury model for precise manipulation of axon-environment interactions and find that (1) the guidance mechanism used during regeneration is distinct from the nerve's developmental guidance mechanism, (2) target selection is specified by neurons' intrinsic memory of their position within the brain, and (3) targeting to a branch requires its pre-existing innervation. This work establishes the zebrafish vagus nerve as a tractable regeneration model and reveals the mechanistic basis of target-specific regeneration.


Impact of antimicrobial ingredients and irradiation on the survival of Listeria monocytogenes and the quality of ready-to-eat turkey ham.
Irradiation is an effective technology in eliminating Listeria monocytogenes, but it induces quality changes in meat products at or above specific radiation doses. To minimize irradiation-induced quality changes, only low irradiation doses are recommended. However, low-dose irradiation provides a chance for some pathogens to survive and proliferate during prolonged storage. To solve this problem, antimicrobial ingredients [2% sodium lactate (SL), 0.1% sodium diacetate (SDA), 0.1% potassium benzoate (PB)] and low-dose irradiation were combined and tested for their effects on the growth of L. monocytogenes and meat quality. The log10 reductions of L. monocytogenes in hams following exposure to 1.0 to 2.5 kGy of irradiation ranged from 2.0 to 5.0. The D10 values were 0.52 kGy for control ham or ham with PB, SL, or PB + SL; 0.49 kGy for ham with SL+SDA; and 0.48 kGy for ham with PB + SL + SDA (PSS). Addition of SL + SDA or PB + SL in combination with 1.0 kGy of irradiation was effective in suppressing the growth of L. monocytogenes for about 6 wk when stored at 4 degrees C, whereas 2.0 kGy of irradiation was listeriostatic. Ham irradiated with 1 kGy in combination with PSS was listeriostatic throughout storage. SL increased firmness of turkey hams, and sensory panelists noted that the saltiness was a little higher in products containing SL, but its overall impact on quality was minimal. Amounts of benzene were detected in irradiated hams with PB, showing PB was not fit as an antimicrobial ingredient for irradiated foods. In conclusion, 2% SL and 0.1% SDA in combination with low-dose irradiation were effective in ensuring the safety of ready-to-eat meat products against L. monocytogenes.


Antidiabetic antihyperlipidemic and hepato-protective effect of Gluconorm-5: A polyherbal formulation in steptozotocin induced hyperglycemic rats.
The antidiabetic, antihyperlipidemic, and hepato-protective effect of Gluconorm-5, was studied in steptozotocin (STZ) induced hyperglycemic rats. The hypoglycemic effect of single dose of Gluconorm-5 (150, 300 and 600 mg/kg body weight) made up of five plants namely Camellia sinensis, Punica granatum, Macrotyloma uniflorum, Foeniculum vulgare and Trigonella foenum-graecum was studied in normal, glucose loaded normal and diabetes-induced rats. The extent of antihyperlipidemic and liver-protective effect was studied by estimating the lipid profile, and the liver marker enzymes. Histopathological studies of the pancreatic tissue were also carried out with glibenclamide as standard antihyperglycemic agent. Fifteen days of oral feeding of the Gluconorm-5 (300 and 600 mg/kg) to diabetic rats resulted in a significant (P < 0.01) reduction of blood glucose, lipid profile, liver weight and marker enzymes as compared to those rats in whom STZ induced toxicity was untreated. The diabetic rats treated with the drug showed expanded islets as compared to the untreated diabetic rats, which showed the shrunken islets. The animals that received 300 mg/kg of Gluconorm-5 showed pronounced antidiabetic, antihyperlipidemic and hepato-protective effect in the present study, which was comparable with glibenclamide, a standard drug. Gluconorm-5 exerts potent antidiabetic antihyperlipidemic and hepato-protective effect, which can be used as adjuvant in the treatment of diabetes mellitus.


Extracellular signal-regulated kinase activation delays hyperoxia-induced epithelial cell death in conditions of Akt downregulation.
Hyperoxia (fraction of inspired oxygen = 95%) induces death of lung epithelial cells. The duration of cell survival in the setting of hyperoxia depends on hyperoxia-induced activation of intracellular survival pathways. Two survival pathways with known effects on lung epithelial cells are the propidium iodide 3-kinase/Akt and extracellular signal-regulated kinase (ERK)/mitogen-activated protein (MAP) kinase pathways. We investigated the effect of hyperoxia on activity of both the Akt and ERK pathways in the A549 lung epithelial cell line. Hyperoxia-exposed cells show progressive loss of Akt activation and total Akt protein. Hyperoxia decreases Akt mRNA, consistent with the loss of total Akt. In addition, hyperoxia induces ERK activation. Inhibition of ERK with the MAP kinase kinase 1/2 inhibitor, U0126, shortens the survival time of cells in hyperoxia, suggesting that increased ERK activity partially compensates for the hyperoxia-induced Akt downregulation. Our findings show, for the first time, that hyperoxia has divergent effects on two survival pathways (Akt and ERK), and that ERK activity compensates for the loss of the Akt survival effects, delaying the death of hyperoxia-exposed lung epithelial cells.


A ten gene-containing genomic island determines flagellin glycosylation: implication for its regulatory role in motility and virulence of Xanthomonas oryzae pv. oryzae.
Flagellin glycosylation plays a crucial role in flagellar assembly, motility and virulence in several pathogenic bacteria. However, little is known about the genetic determinants and biological functions of flagellin glycosylation in Xanthomonas oryzae pv. oryzae (Xoo), the causal pathogen of bacterial blight of rice. Here, the structure, regulation and functions of a ten-gene cluster gigX (glycosylation island genes of Xoo), which was embedded in a flagellar regulon, were characterized. gigX1 to gigX10 encoded putative enzymes or proteins involved in glycan biosynthesis and transfer, including a nucleotide sugar transaminase, an acyl-carrier protein (ACP), a 3-oxoacyl-ACP synthase, a 3-oxoacyl-ACP reductase, a dehydrogenase, an acetyltransferase, a ring hydroxylating dioxygenase, a hypothetical protein, a methyltransferanse and a glycosyltransferase, respectively. The gigX genes were co-transcribed in an operon and up-regulated by the upstream σ54 factor RpoN2 and transcriptional activator FleQ. In-frame deletion of each gigX gene affected flagellin glycosylation modification, meaning that the unglycosylated flagellin of the mutants was smaller than the glycosylated flagellin of the wild-type. No significant changes in flagellar filament and motility were observed in the ΔgigX mutants, among which only ΔgigX6 displayed increased swimming ability. Importantly, all mutants, except ΔgigX9, showed significantly increased virulence and bacterial growth in the susceptible rice cultivar IR24, and ΔgigX1 and ΔgigX10 showed enhanced type III secretion system (T3SS)-related gene expression. Moreover, the glycosylated flagellin of the wild-type induced higher H2 O2 levels in rice leaves than did the unglycosylated flagellins of ΔgigX1 or ΔgigX10. Taken together, this study reveals that the gigX cluster determines flagellin glycosylation, and implicates the regulatory role of post-translational modification with the glycosylation, acetylation and methylation of flagellin in the regulation of motility and virulence of Xoo.


Receptor-specific targeting mediated by the coexpression of a targeted murine leukemia virus envelope protein and a binding-defective influenza hemagglutinin protein.
The entry of retroviral vectors into cells requires two events: binding to a cell surface receptor and the subsequent fusion of viral and cellular membranes. The host range of a vector is therefore determined largely by the receptor specificity of the fusion protein contained in the outer viral envelope. Previous attempts to generate targeted retroviral vectors have included the addition of targeting ligands to the murine leukemia virus envelope protein (MuLV Env). Although such proteins frequently display modified cell-binding characteristics, the interaction with the targeted receptors fails to trigger virus-cell fusion. Here, we report the use of a binding-defective but fusion-competent hemagglutinin (HA) protein to complement the fusion defect in a chimeric MuLV Env targeted to the Flt-3 receptor. Retroviral vectors containing both proteins showed enhanced transduction of cells expressing Flt-3, which was abrogated by preincubating the target cells with soluble Flt-3 ligand. Furthermore, the fusion function of HA was absolutely required. These data demonstrate that it is possible to separate the binding and fusion events of retroviral entry, using two separate proteins, and suggest that varying the binding protein component in this scheme may allow a general strategy for targeting retroviral vectors.


[Antidepressant guidelines poorly adhered to in young people].
To examine if Dutch physicians adhere to the national guidelines on the treatment of depression in children and adolescents. Retrospective database research. Data on children and adolescents aged between 6 and 17 years were selected from the IADB, a Dutch database of filled prescriptions. We examined whether children and adolescents were prescribed fluoxetine as recommended by the guideline, and whether the starting dose was in accordance with the guideline. Of 2942 children and adolescents in whom antidepressant treatment was initiated, the proportion prescribed fluoxetine increased from 10.1% in 1994-2003 to 19.7% in 2010-2014. However, paroxetine (1994-2003) and citalopram (2004-2014) were the most frequently prescribed antidepressants. Starting doses were guideline-concordant in 58% of children, 31% of preadolescents and 16% of adolescents. Sixty percent of all adolescents were prescribed an adult starting dose. Guideline adherence was poor. In contrast to the guidelines, physicians preferred citalopram to fluoxetine in children and adolescents with depression. Furthermore, adolescents often received an adult starting dose. These results suggest that dedicated effort is necessary to improve guideline adherence.


Early B cell factor promotes B lymphopoiesis with reduced interleukin 7 responsiveness in the absence of E2A.
The basic helix-loop-helix transcription factors encoded by the E2A gene function at the apex of a transcriptional hierarchy involving E2A, early B cell factor (EBF), and Pax5, which is essential for B lymphopoiesis. In committed B lineage progenitors, E2A proteins have also been shown to regulate many lineage-associated genes. Herein, we demonstrate that the block in B lymphopoiesis imposed by the absence of E2A can be overcome by expression of EBF, but not Pax5, indicating that EBF is the essential target of E2A required for development of B lineage progenitors. Our data demonstrate that EBF, in synergy with low levels of alternative E2A-related proteins (E proteins), is sufficient to promote expression of most B lineage genes. Remarkably, however, we find that E2A proteins are required for interleukin 7-dependent proliferation due, in part, to a role for E2A in optimal expression of N-myc. Therefore, high levels of E protein activity are essential for the activation of EBF and N-myc, whereas lower levels of E protein activity, in synergy with other B lineage transcription factors, are sufficient for expression of most B lineage genes.


Selenoprotein DIO2 Is a Regulator of Mitochondrial Function, Morphology and UPRmt in Human Cardiomyocytes.
Members of the fetal-gene-program may act as regulatory components to impede deleterious events occurring with cardiac remodeling, and constitute potential novel therapeutic heart failure (HF) targets. Mitochondrial energy derangements occur both during early fetal development and in patients with HF. Here we aim to elucidate the role of DIO2, a member of the fetal-gene-program, in pluripotent stem cell (PSC)-derived human cardiomyocytes and on mitochondrial dynamics and energetics, specifically. RNA sequencing and pathway enrichment analysis was performed on mouse cardiac tissue at different time points during development, adult age, and ischemia-induced HF. To determine the function of DIO2 in cardiomyocytes, a stable human hPSC-line with a DIO2 knockdown was made using a short harpin sequence. Firstly, we showed the selenoprotein, type II deiodinase (DIO2): the enzyme responsible for the tissue-specific conversion of inactive (T4) into active thyroid hormone (T3), to be a member of the fetal-gene-program. Secondly, silencing DIO2 resulted in an increased reactive oxygen species, impaired activation of the mitochondrial unfolded protein response, severely impaired mitochondrial respiration and reduced cellular viability. Microscopical 3D reconstruction of the mitochondrial network displayed substantial mitochondrial fragmentation. Summarizing, we identified DIO2 to be a member of the fetal-gene-program and as a key regulator of mitochondrial performance in human cardiomyocytes. Our results suggest a key position of human DIO2 as a regulator of mitochondrial function in human cardiomyocytes.


Biomarker combination and SOFA score for the prediction of mortality in sepsis and septic shock: A prospective observational study according to the Sepsis-3 definitions.
Biomarkers are valuable tools for the prediction of mortality in patients with sepsis. However, the use of a single biomarker to predict patient outcomes is challenging owing to the complexity and redundancy of the immune response to infections.We aimed to conduct a prospective observational analysis to investigate the prognostic value of pentraxin 3, interleukin 6, procalcitonin, and lactate combined in predicting the 28-day mortality rate in patients with sepsis or septic shock (n = 160; sepsis, 78; sepsis shock, 82). Two methods (the frequency sum of values above the cutoff, and the multivariate logistic regression model) were used to assess the prognostic value of the biomarker combination.In the receiver operating characteristic curve analyses, the combination of the 4 biomarkers was better than the Sequential Organ Failure Assessment (SOFA) score in predicting the 28-day mortality rate, regardless of whether the frequency sum of values above the cutoff or the multivariate logistic model was used for the analysis. The addition of the SOFA score to the biomarker combination did not result in a better performance for the prediction of mortality.The combined biomarker approach showed good performance in predicting 28-day all-cause mortality among patients diagnosed with either sepsis or septic shock according to the Sepsis-3 definitions. Furthermore, it was superior to the SOFA score in predicting mortality.


Development and Validation of an Arterial Pressure-Based Cardiac Output Algorithm Using a Convolutional Neural Network: Retrospective Study Based on Prospective Registry Data.
Arterial pressure-based cardiac output (APCO) is a less invasive method for estimating cardiac output without concerns about complications from the pulmonary artery catheter (PAC). However, inaccuracies of currently available APCO devices have been reported. Improvements to the algorithm by researchers are impossible, as only a subset of the algorithm has been released. In this study, an open-source algorithm was developed and validated using a convolutional neural network and a transfer learning technique. A retrospective study was performed using data from a prospective cohort registry of intraoperative bio-signal data from a university hospital. The convolutional neural network model was trained using the arterial pressure waveform as input and the stroke volume (SV) value as the output. The model parameters were pretrained using the SV values from a commercial APCO device (Vigileo or EV1000 with the FloTrac algorithm) and adjusted with a transfer learning technique using SV values from the PAC. The performance of the model was evaluated using absolute error for the PAC on the testing dataset from separate periods. Finally, we compared the performance of the deep learning model and the FloTrac with the SV values from the PAC. A total of 2057 surgical cases (1958 training and 99 testing cases) were used in the registry. In the deep learning model, the absolute errors of SV were 14.5 (SD 13.4) mL (10.2 [SD 8.4] mL in cardiac surgery and 17.4 [SD 15.3] mL in liver transplantation). Compared with FloTrac, the absolute errors of the deep learning model were significantly smaller (16.5 [SD 15.4] and 18.3 [SD 15.1], P<.001). The deep learning-based APCO algorithm showed better performance than the commercial APCO device. Further improvement of the algorithm developed in this study may be helpful for estimating cardiac output accurately in clinical practice and optimizing high-risk patient care.


Do Patients with Obstructive Sleep Apnea have an Increased Risk of Desaturation During Induction of Anesthesia for Weight Loss Surgery?
Obstructive sleep apnea (OSA) is an independent risk factor to develop perioperative complications during weight loss surgery, but the mechanisms are unclear. It is possible, that patients with OSA have a higher incidence of desaturation during induction of anesthesia. We enrolled 100 morbidly obese (body mass index: 53+/-10) adult patients undergoing open bariatric surgery in a prospective study. At least 1 h before induction of anesthesia, peripheral oxygen saturation (SpO(2)) was measured by an oximetry finger probe in the sitting and supine positions, and Mallampati score was taken. Oxygen saturation was recorded also during induction of anesthesia, and nadir values were analyzed, and the STOP-BANG questionnaire was applied. Thirty-six patients presented with clinical suspicion of OSA. Body weight predicted oxygen saturation in the supine and sitting position, prior to induction of anesthesia. Nadir oxygen saturation during induction of anesthesia was considerably higher in patients with clinical suspicion of OSA, a significant finding that persisted as a trend after correction for age, gender and BMI. The Mallampati score was an independent predictor of OSA, even in morbidly obese patients scheduled for weight loss surgery. Morbidly obese patients presenting for weight loss surgery have a significant risk to desaturate during induction of anesthesia. A history of OSA does not independently increase the risk of desaturation during induction of anesthesia, if the appropriate precautions are being taken.


Thioctic acid for patients with symptomatic diabetic polyneuropathy: a critical review.
Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life. Near-normoglycemia is now generally accepted as the primary approach to prevention of diabetic neuropathy, but is not achievable in a considerable number of patients. A growing body of evidence suggests that oxidative stress resulting from enhanced free-radical formation and/or defects in antioxidant defense is implicated in the pathogenesis of diabetic neuropathy. Markers of oxidative stress such as superoxide anion and peroxynitrite production are increased in diabetic patients in relation to the severity of polyneuropathy. In experimental diabetic neuropathy, oxygen free-radical activity in the sciatic nerve is increased, and treatment with thioctic acid, a potent lipophilic antioxidant, results in prevention or improvement of the diabetes-induced neurovascular and metabolic abnormalities in various organ systems. Pharmacodynamic studies have shown that thioctic acid favorably influences the vascular abnormalities of diabetic polyneuropathy such as impaired microcirculation, increased indices of oxidative stress, and increased levels of markers for vascular dysfunction, such as thrombomodulin, albuminuria, and nuclear factor-kappaB. Thus far, seven controlled randomized clinical trials of thioctic acid in patients with diabetic neuropathy have been completed (Alpha-Lipoic Acid in Diabetic Neuropathy [ALADIN I-III], Deutsche Kardiale Autonome Neuropathie [DEKAN], Oral Pilot [ORPIL], Symptomatic Diabetic Neuropathy [SYDNEY], Neurological Assessment of Thioctic Acid in Neuropathy [NATHAN] II) using different study designs, durations of treatment, doses, sample sizes, and patient populations. Recently, a comprehensive analysis was undertaken of trials with comparable designs that met specific eligibility criteria for a meta-analysis to obtain a more precise estimate of the efficacy and safety of thioctic acid (600mg intravenously for 3 weeks) in diabetic patients with symptomatic polyneuropathy. This meta-analysis included the largest sample of diabetic patients (n = 1258) ever to have been treated with a single drug or class of drugs to reduce neuropathic symptoms, and confirmed the favorable effects of thioctic acid based on the highest level of evidence (Class Ia: evidence from meta-analyses of randomized, controlled trials). The following conclusions can be drawn from these trials: (i) short-term treatment for 3 weeks using intravenous thioctic acid 600 mg/day reduces the chief symptoms of diabetic polyneuropathy to a clinically meaningful degree; (ii) this effect on neuropathic symptoms is accompanied by an improvement of neuropathic deficits, suggesting potential for the drug to favorably influence underlying neuropathy; (iii) oral treatment for 4-7 months tends to reduce neuropathic deficits and improve cardiac autonomic neuropathy; and (iv) clinical and postmarketing surveillance studies have revealed a highly favorable safety profile of the drug. Based on these findings, a pivotal long-term multicenter trial of oral treatment with thioctic acid (NATHAN I) is being conducted in North America and Europe to investigate effects on progression of diabetic polyneuropathy, using a clinically meaningful and reliable primary outcome measure that combines clinical and neurophysiological assessment.


[Prevalence of suicidal ideation, suicide plans, and attempted suicide: a population-based survey in Campinas, São Paulo State, Brazil].
This study aimed to estimate the lifetime prevalence rates for suicidal ideation, suicide plans, and attempted suicide, based on a cluster sample of 515 residents of Campinas, São Paulo State, Brazil. The Multisite Intervention Study on Suicidal Behavior interview was performed, and lifetime prevalence rates and 95% confidence intervals (95%CI) were calculated. Lifetime prevalence rates were 17.1% (95%CI: 12.9-21.2) for suicidal ideation, 4.8% (95%CI: 2.8-6.8) for suicide plans, and 2.8% (95%CI: 0.09-4.6) for attempted suicide. Suicidal behavior was more frequent among women and young adults. The suicide plan/attempt ratio was approximately 5:3. Only one-third of those who attempted suicide contacted a health service following the attempt. Prevalence rates for suicidal behavior were similar to most studies from other countries. Suicide prevention strategies should take data from community-based studies into account.


Local cerebral PO2, PCO2, and blood flow measurements by mass spectrometry.
Partial pressures of intracerebral tissue gases (PO2, PCO2) and local cerebral blood flow (local CBF) were determined simultaneously by means of a single cannula implanted stereotaxically in a given structure. Minute quantities of the gases (O2, CO2, and tracer gas) were withdrawn continuously. After a short period of tracer (He) inhalation, CBF was measured by determination of the clearance rate (T1/2). The measurements of PO2 and PCO2 were continuous and quantitative, whereas the measurements of local CBF were sequential and quantitative. The results obtained for local CBF were compared with those found with two other methods (H2 clearance by polarography, thermoclearance) in the same structure of the same animal.


Study of CP violating effects in time dependent B0(B0)-->D(*)-/+pi+/- decays.
We report measurements of time dependent decay rates for B0(B(0))-->D((*)-/+)pi(+/-) decays and extraction of CP violation parameters containing phi(3). Using fully reconstructed D((*))pi events from a 140 fb(-1) data sample collected at the Upsilon(4S) resonance, we obtain the CP violation parameters for D(*)pi and Dpi decays, 2R(D((*))pi)sin((2phi(1)+phi(3)+/-delta(D((*))pi)), where R(D((*))pi) is the ratio of the magnitudes of the doubly Cabibbo-suppressed and Cabibbo-favored amplitudes, and delta(D((*))pi) is the strong phase difference between them. Under the assumption of delta(D((*))pi) being close to either 0 degrees or 180 degrees, we obtain |2R(D(*)pi)sin((2phi(1)+phi(3))|=0.060+/-0.040(stat)+/-0.019(syst) and |2R(Dpi)sin((2phi(1)+phi(3))|=0.061+/-0.037(stat)+/-0.018(syst).


A comprehensive review of clinical nurse specialist-led peripherally inserted central catheter placement in Korea: 4101 cases in a tertiary hospital.
Peripherally inserted central catheters (PICCs) are expected to be convenient and reliable venous access devices. The purpose of this study was to analyze clinical nurse specialist (CNS)-led PICC placement and to describe its growth in a tertiary hospital. A computerized database identified 3508 patients who had PICCs placed between November 2001 and June 2010. One thousand, eight hundred ninety-eight of the 4101 PICCs were available for complete follow-up, and 791 of 1898 PICCs were still in place. The mean dwell time of 1898 PICCs was 27.4 days (1∼422 days). Most PICCs were removed after the completion of infusion therapy; the remainder were removed following death, occlusion, suspected infection, or phlebitis, or were removed by the patient. The study found that CNS-led PICC placement for infusion therapies was effective and safe with relatively low complication rates and that CNSs played important roles in the increased use of PICCs.


Clinical inquiries: what drugs are best for bipolar depression?
Antidepressants and lamotrigine are effective. Atypical antipsychotics, lithium, and anticonvulsants also may help. Antidepressants, including tricyclics and selective serotonin reuptake inhibitors (SSRIs), are useful adjuncts in short-term treatment of bipolar depression and have low rates of inducing mania (strength of recommendation [SOR]: 1 systematic review and randomized controlled trials [RCTs]). Lamotrigine is beneficial for both acute treatment of bipolar depression and prevention of recurrent episodes (SOR: 1 systematic review and 1 RCT). Some atypical antipsychotics alone (SOR: 2 RCTs) or in combination with antidepressants (SOR: 1 multicenter RCT) effectively treat acute bipolar depression. Lithium and anticonvulsants such as valproate also may be useful (SOR: limited number of studies with small sample sizes).


The protective effect of fermented milk kefir on radiation-induced apoptosis in colonic crypt cells of rats.
To evaluate the effect of fermented milk kefir on X-ray-induced apoptosis in the colon of rats, we examined the apoptotic index, the mean number of apoptotic cells detected by H&E staining per crypt in the colon, in control rats and kefir-pretreated rats drinking kefir for 12 days before irradiation. Apoptotic cells were confirmed by TUNEL staining, and active caspase-3 expression was studied by immunohistochemistry. The cell position of apoptotic cells and active caspase-3 positive cells were examined. The apoptotic index of kefir-treated rats was significantly (p < 0.05) decreased 2 h after 1 Gy irradiation in comparison with control rats at crypt cell positions 1-3, 5-7, 13, and 15. Active caspase-3 expression in the kefir-treated rats was also significantly (p < 0.05) reduced in comparison with control rats 2 h after 1 Gy irradiation at crypt cell positions 1-4, 13, and 15. This study indicated that kefir protects colonic crypt cells against radiation-induced apoptosis, which was most pronounced in the stem cell region of the crypt. The antiapoptotic effect of fermented milk kefir was due to the inhibition of caspase-3 activation.


Heart failure in patients with sick sinus syndrome treated with single lead atrial or dual-chamber pacing: no association with pacing mode or right ventricular pacing site.
Previous studies indicate that ventricular pacing may precipitate heart failure (HF). We investigated occurrence of HF during long-term follow-up among patients with sick sinus syndrome (SSS) randomized to AAIR or DDDR pacing. Furthermore, we investigated effects of percentage of ventricular pacing (%VP) and pacing site in the ventricle. We analysed data from 1415 patients randomized to AAIR (n = 707) or DDDR pacing (n = 708). Ventricular pacing leads were recorded as located in either an apical or a non-apical position. The %VP and HF hospitalizations were recorded during follow-up. Patients were classified with new HF, if in New York Heart Association (NYHA) functional class IV or if presence of ≥2 of: oedema; dyspnoea; NYHA functional class III. Mean follow-up was 5.4 ± 2.4 years. Heart failure hospitalizations did not differ between groups. In the AAIR group, 170 of the 707 (26%) patients developed HF vs. 169 of the 708 (26%) patients in the DDDR group, hazard rate ratio (HR) 1.00, 95% confidence interval (CI) 0.79-1.22, P = 0.87. In DDDR patients, 146 of the 512 patients (29%) with ventricular leads in an apical position developed HF vs. 28 of the 161 patients (17%) with the leads in a non-apical position, HR 0.67, CI 0.45-1.00, P = 0.05. After adjustments this difference was non-significant. The incidence of HF was not associated with %VP (P = 0.57). In patients with SSS, HF was not associated with pacing mode, %VP, or ventricular lead localization. This suggests that DDDR pacing is safe in patients with SSS without precipitating HF.


Photocatalytic Redox-Neutral Alkoxyacylation of Alkenes.
β-Alkoxyketones are important building blocks in organic synthesis. By utilizing CBZ6, with an oxidative potential of -2.16 V (vs the saturated calomel electrode), as a redox-neutral photocatalyst, alkoxyacylation of olefins was accomplished under the irradiation of visible light via a cationic intermediate. It involves the addition of an acyl radical to olefin to form a radical intermediate and the following oxidation of the radical intermediate to the benzyl cationic intermediate that is captured by alkoxy anions. This process provides concise and practical access to the β-functionalized ketones.


Electromyographic response to displacement of different forelimb joints in the squirrel monkey.
The electromyographic (EMG) reflex response evoked in muscles stretched by imposed angular joint displacement has previously been studied in a variety of muscles and species. In most muscles studied, the EMG response consists of an initial burst of activity at latencies comparable to tendon tap responses followed by one or more bursts of EMG activity occurring at latencies less than somatosensory reaction time. The longer latency bursts or peaks of activity have often been assumed to be of similar origin in functionally diverse muscles. The present experiments were performed to examine the EMG response to imposed joint displacement in several different muscles of the squirrel monkey forelimb. The EMG was studied in muscles stretched by elbow, wrist, and metacarpophalangeal joint extension. Early (M1) and long (M2) latency peaks of activity could be observed in the EMG responses of short head of biceps (SHB), flexor carpi ulnaris (FCU), and flexor digitorum profundus (FDP), at latencies which are similar to those reported in other primate species allowing for differences in the size of the animals. The intervals between these peaks did not correspond to the period of oscillations in tension which occurred after the onset of the joint extension. The M2 peak consistently occurred later in SHB than in FCU and FDP. The M1 peak was smaller in distal than in proximal muscles and was frequently absent in FDP at resting levels of EMG activity. The ratio of M1 to M1 + M2 activity for different muscles revealed that proximal muscles had prominent early with less prominent long latency activity, whereas distal muscles had minimal early latency activity with prominent long latency activity. The onset of EMG activity approached tendon tap latencies in FCU at high base line EMG levels but in most cases occurred at approximately twice tendon tap latencies in FDP at high base line EMG levels. The results demonstrate the presence of significant differences between the EMG response to joint displacement in the proximal-distal series of forelimb flexors. Differences in the reflex response to joint displacement are discussed in view of twitch times and motor unit composition of the muscles studied.


A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V.
A boy with recurrent pyrexial episodes from early life sustained a painless ankle injury and was found to have a calcaneus fracture and, later, neuropathic joint degeneration of the tarsus. Examination revealed distal loss of pain and temperature sensation and widespread anhidrosis. Sural nerve biopsy demonstrated severe reduction in small-caliber myelinated fiber density but only modest reduction in unmyelinated axons, the pattern of type V hereditary sensory and autonomic neuropathy (HSAN V). DNA analysis showed that he was homozygous for a mutation in the NTRK1/high-affinity nerve growth factor (TrkA) gene, his parents being heterozygous. Mutations in this gene are known to be responsible for HSAN IV (congenital insensitivity to pain with anhidrosis). The two disorders are therefore likely to be allelic.


Antiinflammatory effects in THP-1 cells treated with verbascoside.
Verbascum thapsus commonly known as 'mullein' is part of a large family of Scrophulariaceae consisting of more than 360 species. From antiquity Verbascum thapsus has been used as a medicinal herb, it contains diverse polysaccharides, iroid glycosides, flavonoids, saponins, volatile oils and phenylentanoids. Inducible nitric oxide synthase (iNOS) represents one of the three isoforms that produce nitric oxide using L-arginine as a substrate in response to an increase in superoxide anion activated by NF-kB. It is implicated in different pathophysiological events and its expression increases greatly during an inflammatory process, due to oxidative stress and the activation of the enzymes of the antioxidant network such as SOD, CAT and GPx.In this study an inflammatory state was reproduced by treating THP-1 cells (human myelomonocytic leukaemia) with pro-inflammatory stimuli, such as LPS and IFN-gamma, obtaining an up-regulation both in the expression and in the activity of iNOS. The aim of the work was to investigate the antiinflammatory action of verbascoside using a concentration of 100 mum. The results show a significant decrease of the expression and activity of iNOS, extracellular O(2) (-) production, SOD, CAT and GPx activity when the cells were treated with verbascoside. Based on these results it is hypothesized that verbascoside has antiinflammatory properties since it reduces the production of superoxide radicals and consequently reduces the activity of iNOS.


Calpain inhibition promotes the rescue of F(508)del-CFTR in PBMC from cystic fibrosis patients.
A basal calpain activity promotes the limited proteolysis of wild type (WT) cystic fibrosis conductance regulator (CFTR), inducing the internalization of the split channel. This process contributes to the regulation in the level of the active CFTR at the plasma membranes. In peripheral blood mononuclear cells (PBMC) from 16 healthy donors, the inhibition of calpain activity induces a 3-fold increase in the amount of active WT CFTR at the plasma membranes. Instead, in PBMC from cystic fibrosis (CF) patients, calpain activity is expressed at aberrant levels causing the massive removal of F(508)del-CFTR from the cell surface. In these patients, the inhibition of such abnormal proteolysis rescues physiological amounts of active mutated CFTR in 90% of the patients (25 over 28). The recovery of functional F(508)del-CFTR at the physiological location, in cells treated with a synthetic calpain inhibitor, indicates that F(508)del-CFTR folding, maturation, and trafficking operate in CF-PBMC at significant rate. Thus, an increase in the basal calpain activity seems primarily involved in the CFTR defect observed in various CF cells. Furthermore, in CF-PBMC the recovery of the scaffolding protein Na(+)/H(+) exchanger regulatory factor 1 (NHERF-1), occurring following inhibition of the aberrant calpain activity, can contribute to rescue CFTR-functional clusters.


Health care provider preferences for, and barriers to, cannabis use in cancer care.
Limited research has been conducted about the perspectives of oncology health care providers (hcps) concerning the use of cannabis in cancer care and their potential role in advising patients. We sought to determine the barriers encountered by hcps with respect to medical cannabis and their preferred practices in this area. An anonymous survey about cannabis was distributed to oncology hcps at the Tom Baker Cancer Centre in Calgary, Alberta. The 45-question survey measured the opinions of hcps about cannabis use and authorization in oncology. Of 103 oncology hcps who participated in the study, 75% were women. By hcp type, the most commonly reported professional groups were oncology nurse (40%), radiation therapist (9%), and pharmacist (6%). Of respondents, 75% reported providing direct care to cancer patients. More than half (69%) had spoken to a patient about cannabis in the preceding month, and 84% believed that they lacked sufficient knowledge about cannabis to make recommendations. Barriers such as monitoring the patient's use of cannabis (54%), prescribing an accurate dose (61%) or strain (53%), and having insufficient research (50%) were most commonly reported. More than half of hcps (53%) would be interested in receiving more information or training about the use of cannabis in oncology. The survey indicated that this group of oncology hcps believed that they lacked sufficient knowledge about cannabis to make recommendations to patients. In addition to that lack of knowledge, a number of notable barriers were reported, and more than half the hcps indicated interest in learning more about cannabis in the future.


Whole-body PET/MRI: the effect of bone attenuation during MR-based attenuation correction in oncology imaging.
In combined PET/MRI standard PET attenuation correction (AC) is based on tissue segmentation following dedicated MR sequencing and, typically, bone tissue is not represented. We evaluate PET quantification in whole-body (WB)-PET/MRI following MR-AC without considering bone attenuation and then investigate different strategies to account for bone tissue in clinical PET/MR imaging. To this purpose, bone tissue representation was extracted from separate CT images, and different bone representations were simulated from hypothetically derived MR-based bone classifications. Twenty oncology patients referred for a PET/CT were injected with either [18F]-FDG or [18F]-NaF and imaged on PET/CT (Biograph TruePoint/mCT, Siemens) and PET/MRI (mMR, Siemens) following a standard single-injection, dual-imaging clinical WB-protocol. Routine MR-AC was based on in-/opposed-phase MR imaging (orgMR-AC). PET(/MRI) images were reconstructed (AW-OSEM, 3 iterations, 21 subsets, 4mm Gaussian) following routine MR-AC and MR-AC based on four modified attenuation maps. These modified attenuation maps were created for each patient by non-linear co-registration of the CT images to the orgMR-AC images, and adding CT bone mask values representing cortical bone: 1200HU (cortCT), spongiosa bone: 350HU (spongCT), average CT value (meanCT) and original CT values (orgCT). Relative difference images of the PET following AC using the modified attenuation maps were compared. SUVmean was calculated in anatomical reference regions and for PET-positive lesions. The relative differences in SUVmean across patients following orgMR-AC and orgCT in soft tissue lesions and in bone lesions were similar (range: 0.0% to -22.5%), with an average underestimation of SUVmean of 7.2% and 10.0%, respectively when using orgMR-AC. In bone lesions, spongCT values were closest to orgCT (median bias of 1.3%, range: -9.0% to 13.5%) while the overestimation of SUVmean with respect to orgCT was highest for cortCT (40.8%, range: 1.5% to 110.8%). For soft tissue lesions the bias was highest using cortCT (13.4%, range: -2.3% to 17.3%) and lowest for spongCT (-2.2%, range: 0.0% to -13.7%). In PET/MR imaging using standard MR-AC PET uptake values in soft lesions and bone lesions are underestimated by about 10%. In individual patients this bias can be as high as 22%, which is significant during clinical follow-up exams. If bone segmentation is available, then assigning a fixed attenuation value of spongious bone to all bone structures appears reasonable and results in only a minor bias of 5%, or less in uptake values of soft tissue and bone lesions.


Zeta potential of motile spores of the green alga Ulva linza and the influence of electrostatic interactions on spore settlement and adhesion strength.
The zeta potential of the motile spores of the green alga (seaweed) Ulva linza was quantified by video microscopy in combination with optical tweezers and determined to be -19.3+/-1.1 mV. The electrostatic component involved in the settlement and adhesion of spores was studied using electret surfaces consisting of PTFE and bearing different net charges. As the surface chemistry remains the same for differently charged surfaces, the experimental results isolate the influence of surface charge and thus electrostatic interactions. Ulva spores were demonstrated to have a reduced tendency to settle on negatively charged surfaces and when they did settle the adhesion strength of settled spores was lower than with neutral or positively charged surfaces. These observations can be ascribed to electrostatic interactions.


Assessing risk of bias: a proposal for a unified framework for observational studies and randomized trials.
Evidence based medicine aims to integrate scientific evidence, clinical experience, and patient values and preferences. Individual health care professionals need to appraise the evidence from randomized trials and observational studies when guidelines are not yet available. To date, tools for assessment of bias and terminologies for bias are specific for each study design. Moreover, most tools appeal only to methodological knowledge to detect bias, not to subject matter knowledge, i.e. in-depth medical knowledge about a topic. We propose a unified framework that enables the coherent assessment of bias across designs. Epidemiologists traditionally distinguish between three types of bias in observational studies: confounding, information bias, and selection bias. These biases result from a common cause, systematic error in the measurement or common effect of the intervention and outcome respectively. We applied this conceptual framework to randomized trials and show how it can be used to identify bias. The three sources of bias were illustrated with graphs that visually represent researchers' assumptions about the relationships between the investigated variables (causal diagrams). Critical appraisal of evidence started with the definition of the research question in terms of the population of interest, the compared interventions and the main outcome. Next, we used causal diagrams to illustrate how each source of bias can lead to over- or underestimated treatment effects. Then, we discussed how randomization, blinded outcome measurement and intention-to-treat analysis minimize bias in trials. Finally, we identified study aspects that can only be appraised with subject matter knowledge, irrespective of study design. The unified framework encompassed the three main sources of bias for the effect of an assigned intervention on an outcome. It facilitated the integration of methodological and subject matter knowledge in the assessment of bias. We hope that graphical diagrams will help clarify debate among professionals by reducing misunderstandings based on different terminology for bias.


Chronic inflammatory demyelinating polyneuropathy and pregnancy: systematic review.
Pregnancy largely affects disease activity and clinical course in women with immune-mediated neurological disorders. Chronic inflammatory demyelinating polyneuropathy (CIDP) is rare but the most common chronic immune-mediated neuropathy; however, the effects of pregnancy on CIDP have never been investigated except case reports or series. We here provide a systematic review of the literature from 1 January 1969 to 30 June 2020 that revealed 24 women with CIDP, who had onset or relapse during pregnancy. Of these, 17 (71%) developed CIDP during the first pregnancy, and 8 (47%) had a relapse during subsequent pregnancies. Of the 17 patients, in whom the CIDP subtypes were determined, all of them had typical CIDP. First-line treatments for CIDP, such as corticosteroids, immunoglobulin and plasma exchange were efficacious and safe. We suggest that pregnancy can trigger typical CIDP in some women, and women with CIDP have a higher risk of relapse during pregnancy. The onset or relapse of CIDP during pregnancy is a rare but challenging constellation for physicians.


Inactivation of poly (ADP-ribose) polymerase by hypochlorous acid.
The effects of the phagocyte-derived reactive oxidants hydrogen peroxide (H2O2) and hypochlorous acid (HOC1) on the activity of poly(ADP-ribose) polymerase (pADP RP), an enzyme involved in DNA repair, and on the induction and repair of DNA strand breaks in human mononuclear leukocytes (MNL) have been investigated in vitro. Exposure of MNL to reagent H2O2 was accompanied by DNA damage and activation of pADP RP. Addition of reagent HOCl (25 microM) was not associated with DNA strand breaks. However, when combined with 150 microM H2O2, HOCl potentiated H2O2-mediated DNA damage, and compromised the repair process. Furthermore, HOCl caused a dose-related decrease in the activity of pADP RP in both control and H2O2-exposed MNL. Interactions between the phagocyte-derived reactive oxidants H2O2 and HOCl are probably involved in the etiology of inflammation-related cancer.


Dual-wavelength responsive CuS@COF nanosheets for high-performance photothermal/photodynamic combination treatments.
Photothermal therapy (PTT) makes it difficult to achieve good performance on tumor treatments due to insufficient photothermal conversion efficiency, etc. Combining PTT with photodynamic therapy (PDT) and other therapeutic tools can significantly enhance the tumor-killing ability and has been widely used in the development of therapeutic platforms. Copper sulfide nanoparticle (CuS NP) photothermal reagents have the advantages of low toxicity and simple synthesis; therefore, combining CuS NPs with PDT photosensitizers is an effective strategy to construct a PTT/PDT combination therapeutic platform. However, PDT photosensitizers and photothermal agents generally assembled through hydrophobic interaction, suffer from low coating efficiency or the risk of drug leakage, thus seriously restricting their applications. To address these challenges, CuS NPs with excellent photothermal conversion performance were selected as the core material to prepare CuS@COF nanosheets through a dual-ligand assistant strategy with 4,7-bis(4-aminophenyl)-2,1,3-benzothiadiazole (BTD) and 2,4,6-trihydroxybenzene-1,3,5-tricarbaldehyde (TP). As a PTT/PDT combination therapeutic platform, CuS@COF nanosheets possess a porous TP-BDT-based COF shell, and it can sufficiently contact oxygen to provide high singlet oxygen (1O2) yield under 505 nm laser irradiation. Upon illumination with a 1064 nm laser, CuS@COF nanosheets can effectively convert the photon energy into thermal energy with a photothermal conversion efficiency of 63.4%. The results of the CCK8 experiment showed that the phototoxicity of the PTT/PDT combination treatment reached 85.1%, which was much higher than the effect of a single treatment. It was also confirmed in vivo that the tumor inhibition effect of the PDT/PTT combination treatment group was much greater than that of the single treatment group.


Cloning, characterisation and comparative analysis of a starch synthase IV gene in wheat: functional and evolutionary implications.
Starch is of great importance to humans as a food and biomaterial, and the amount and structure of starch made in plants is determined in part by starch synthase (SS) activity. Five SS isoforms, SSI, II, III, IV and Granule Bound SSI, have been identified, each with a unique catalytic role in starch synthesis. The basic mode of action of SSs is known; however our knowledge of several aspects of SS enzymology at the structural and mechanistic level is incomplete. To gain a better understanding of the differences in SS sequences that underscore their specificity, the previously uncharacterised SSIVb from wheat was cloned and extensive bioinformatics analyses of this and other SSs sequences were done. The wheat SSIV cDNA is most similar to rice SSIVb with which it shows synteny and shares a similar exon-intron arrangement. The wheat SSIVb gene was preferentially expressed in leaf and was not regulated by a circadian clock. Phylogenetic analysis showed that in plants, SSIV is closely related to SSIII, while SSI, SSII and Granule Bound SSI clustered together and distinctions between the two groups can be made at the genetic level and included chromosomal location and intron conservation. Further, identified differences at the amino acid level in their glycosyltransferase domains, predicted secondary structures, global conformations and conserved residues might be indicative of intragroup functional associations. Based on bioinformatics analysis of the catalytic region of 36 SSs and 3 glycogen synthases (GSs), it is suggested that the valine residue in the highly conserved K-X-G-G-L motif in SSIII and SSIV may be a determining feature of primer specificity of these SSs as compared to GBSSI, SSI and SSII. In GBSSI, the Ile485 residue may partially explain that enzyme's unique catalytic features. The flexible 380s Loop in the starch catalytic domain may be important in defining the specificity of action for each different SS and the G-X-G in motif VI could define SSIV and SSIII action particularly.


Characterization of Candida isolates from pediatric burn patients.
To provide more detailed information about Candida epidemiology and pathogenesis in pediatric burn patients, Candida isolates from 113 patients collected over 3 years were identified at the species level and the serotypes and biotypes of the C. albicans isolates were determined. A total of 85% of the patients were colonized or infected by C. albicans, 18% by C. tropicalis, and 11% by C. parapsilosis. Although colonization or infection often was found at multiple sites and times, 87% of the patients were colonized or infected by only one Candida species or strain; the other 13% showed multiple colonizations or infections, some of which occurred simultaneously at the same site. C. albicans biotyping determined the tolerance of the isolates to pH (pH 1.4) and salt; flucytosine, borate, and safranine resistance; and ability to produce proteinase and assimilate urea, sorbose, and citrate; results are expressed as three-digit numbers. For isolates from three different anatomical sites, the distribution of the nine biotype characteristics was similar in all cases but one. Significantly more fecal than wound or throat isolates were resistant to safranine. Sixty-four different serotype-biotype combinations were found in the 96 patients with C. albicans infections or colonizations. Twenty-nine percent of all C. albicans isolates had the partial biotype -57, while 20 of the 96 patients had specifically serotype B, biotype 557 colonizations or infections. Eleven patients had the B557 infection when admitted; nine patients acquired the yeast in-house. Thirty percent of the C. albicans isolated from 23 adult patients at a nearby hospital also showed the -57 biotype pattern, suggesting that C. albicans isolates expressing this biotype are either extremely prevalent in nature or are more virulent than other C. albicans isolates.


Precision standardization of radial keratotomy.
Radial keratotomy is an experimental surgical procedure being performed in increasingly large numbers, often without carefully designed protocols which meet accepted methodology for clinical research. This paper presents an instrumentation system which makes it possible to have precise control of the length, depth, and spacing of radial keratotomy incisions. This is not a paper in favor of radial keratotomy. It raises the need for rigid standardization of the technique with evaluation of the results according to carefully controlled and accepted clinical trial methodology.


Inhibition of syngeneic fibrosarcoma growth by lymphocytes sensitized on tumor-cell monolayers in the presence of the thymic humoral factor.
The present experiments were performed to investigate the possibility of inhibiting tumor growth in vivo with syngeneic lymphocytes sensitized in vitro on monolayers of the tumor under test, and to study the effect of a thymic humoral factor (THF) in this sensitization process. Monolayers of fibrosarcoma cells were used to sensitize spleen cells from syngeneic donors against the tumor. Such sensitized lymphocytes manifested cytotoxic activity against cells fo the fibrosarcoma in a microassay measuring tumor-cell detachment. However, when the sensitized lymphocytes were mixed with the fibrosarcoma cells and injected into syngeneic mice, enhanced tumor growth was observed in vivo. Addition of thymic humoral factor to the cultures during sensitization resulted in increased cytotoxic activity by the lymphocytes in vitro and a reduction in the tumor enhancement caused by these cells when injected in vivo. Enhanced tumor growth occured when activated lymphocytes of allogeneic as well as syngeneic origin were injected together with the fibrosarcoma cells. Enhancement, which was already apparent when the spleen cells had been sensitized for 24 h, could be circumvented by separate administration of lymphocytes and tumor cells. Syngeneic lymphocytes injected systemically after sensitization for 5 days exerted anti-tumor reactivity against the fibrosarcoma grafted in the foot-pad of syngeneic mice. Tumor growth was further inhibited by systemic injection of lymphocytes which had been sensitized in the presence of the thymic humoral factor.


A bright future for glucagon and alpha cell biology.
Long lagging behind insulin, glucagon research has caught up in large part, thanks to technological breakthroughs. Here we review how the field was propelled by the development of novel techniques and approaches. The glucagon radioimmunoassay and islet isolation are methods that now seem trivial, but for decades they were crucial in defining the biology of the pancreatic alpha cell and the role of glucagon in glucose homeostasis. More recently, mouse models have become the main workhorse of this research effort, if not of biomedical research in general. The mouse model allowed detailed mechanistic studies that are revealing alpha cell functions beyond its canonical glucoregulatory role. A recent profusion of gene expression and transcription regulation studies is providing new vistas into what constitutes alpha cell identity. In particular, the combination of transcriptomic techniques with functional recordings promises to move molecular guesswork into real-time physiology. The challenge right now is not to get enamored with these powerful techniques and to make sure that the research continues to be transformative and paradigm shifting. We should imagine a future in which the biology of the alpha cell will be studied at single-cell resolution, non-invasively, and in real time in the human body.


Estimation of serum V kappa IIIb light chains in rheumatoid arthritis and correlation with CD5-positive B-cells.
The presence of V kappa IIIb light chains in the sera of rheumatoid arthritis (RA) patients has been evaluated by an enzyme-linked immunosorbent assay (ELISA). V kappa IIIb light chains have been confirmed to be largely restricted to IgM, and were rarely detected in the IgG fraction of sera. The concentration of total serum V kappa IIIb did not significantly vary with age, nor did it correlate with IgM-rheumatoid factor (RF) titre. Although total serum V kappa IIIb was not significantly increased in RA patients compared with matched controls, IgM-RFs frequently contained V kappa IIIb. Using flow cytometry, CD5-positive B-cells were not increased in these RA patients compared with healthy laboratory control personnel. Furthermore, there was no direct correlation between total serum IgM V kappa IIIb content and CD5-positive B-cell numbers in peripheral blood.


HIV-1/AIDS and the control of other infectious diseases in Africa.
The effect of HIV-1 on other infectious diseases in Africa is an increasing public health concern. In this review, we describe the role that three major infectious diseases--malaria, sexually transmitted diseases (STDs), and tuberculosis--have had in the HIV-1 epidemic. The high prevalence of untreated STD infections has been a major factor facilitating the spread of HIV-1 in Africa; with the synergistic interaction between HIV-1 transmission and genital herpes being of special concern for control of both diseases. Increased susceptibility to tuberculosis after infection with HIV-1 has led to a rising incidence and threat of increased transmission of tuberculosis. Clinical malaria occurs with an increased frequency and severity in HIV-1-infected individuals, especially during pregnancy. As with tuberculosis, STDs, and other communicable HIV-1-associated diseases, the net effect of HIV-1 might include increased rates of malaria transmission across communities. In addition to enhancing access to HIV-1 prevention and care, public health surveillance and control programmes should be greatly intensified to cope with the new realities of infectious disease control in Africa.


Genome characteristics reveal the impact of lichenization on lichen-forming fungus Endocarpon pusillum Hedwig (Verrucariales, Ascomycota).
Lichen is a classic mutualistic organism and the lichenization is one of the fungal symbioses. The lichen-forming fungus Endocarpon pusillum is living in symbiosis with the green alga Diplosphaera chodatii Bialsuknia as a lichen in the arid regions. 454 and Illumina technologies were used to sequence the genome of E. pusillum. A total of 9,285 genes were annotated in the 37.5 Mb genome of E. pusillum. Analyses of the genes provided direct molecular evidence for certain natural characteristics, such as homothallic reproduction and drought-tolerance. Comparative genomics analysis indicated that the expansion and contraction of some protein families in the E. pusillum genome reflect the specific relationship with its photosynthetic partner (D. chodatii). Co-culture experiments using the lichen-forming fungus E. pusillum and its algal partner allowed the functional identification of genes involved in the nitrogen and carbon transfer between both symbionts, and three lectins without signal peptide domains were found to be essential for the symbiotic recognition in the lichen; interestingly, the ratio of the biomass of both lichen-forming fungus and its photosynthetic partner and their contact time were found to be important for the interaction between these two symbionts. The present study lays a genomic analysis of the lichen-forming fungus E. pusillum for demonstrating its general biological features and the traits of the interaction between this fungus and its photosynthetic partner D. chodatii, and will provide research basis for investigating the nature of its drought resistance and symbiosis.


Genetic diversity in Fusarium graminearum from a major wheat-producing region of Argentina.
The Fusarium graminearum species complex (FGSC) is a group of mycotoxigenic fungi that are the primary cause of Fusarium head blight (FHB) of wheat worldwide. The distribution, frequency of occurrence, and genetic diversity of FGSC species in cereal crops in South America is not well understood compared to some regions of Asia, Europe and North America. Therefore, we examined the frequency and genetic diversity of a collection of 183 FGSC isolates recovered from wheat grown during multiple growing seasons and across a large area of eastern Argentina, a major wheat producing region in South America. Sequence analysis of the translation elongation factor 1-α and β-tubulin genes as well as Amplified Fragment Length Polymorphism (AFLP) analyses indicated that all isolates were the FGSC species F. graminearum sensu stricto. AFLP analysis resolved at least 11 subgroups, and all the isolates represented different AFLP haplotypes. AFLP profile and geographic origin were not correlated. Previously obtained trichothecene production profiles of the isolates revealed that the 15-acetyldeoxynivalenol chemotype was slightly more frequent than the 3-acetyldeoxynivalenol chemotype among the isolates. These data extend the current understanding of FGSC diversity and provide further evidence that F. graminearum sensu stricto is the predominant cause of FHB in the temperate main wheat-growing area of Argentina. Moreover, two isolates of F. crookwellense and four of F. pseudograminearum were also recovered from wheat samples and sequenced. The results also suggest that, although F. graminearum sensu stricto was the only FGSC species recovered in this study, the high level of genetic diversity within this species should be considered in plant breeding efforts and development of other disease management strategies aimed at reducing FHB.