Dyadic Psychosocial eHealth Interventions: Systematic Scoping Review.
Dyadic psychosocial interventions have been found beneficial both for people coping with mental or physical health conditions as well as their family members and friends who provide them with support. Delivering these interventions via electronic health (eHealth) may help increase their scalability. This scoping review aimed to provide the first comprehensive overview of dyadic eHealth interventions for individuals of all ages affected by mental or physical illness and their family members or friends who support them. The goal was to understand how dyadic eHealth interventions have been used and to highlight areas of research needed to advance dyadic eHealth intervention development and dissemination. A comprehensive electronic literature search of PubMed, EMBASE, Cochrane, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO was conducted for articles published in the English language through March 2019. Eligible records described a psychosocial eHealth intervention that intervened with both care recipients and their support person. A total of 7113 records were reviewed of which 101 met eligibility criteria. There were 52 unique dyadic eHealth interventions identified, which were tested across 73 different trials. Of the unique interventions, 33 were conducted among dyads of children and their supporting parent, 1 was conducted with an adolescent-young adult care recipient population, and the remaining 18 were conducted among adult dyads. Interventions targeting pediatric dyads most commonly addressed a mental health condition (n=10); interventions targeting adult dyads most commonly addressed cancer (n=9). More than three-fourths of interventions (n=40) required some human support from research staff or clinicians. Most studies (n=64) specified one or more primary outcomes for care recipients, whereas less than one-fourth (n=22) specified primary outcomes for support persons. Where specified, primary outcomes were most commonly self-reported psychosocial or health factors for both care recipients (n=43) and support persons (n=18). Results of the dyadic eHealth intervention tended to be positive for care recipients, but evidence of effects for support persons was limited because of few studies specifying primary outcomes for supporters. Trials of dyadic eHealth interventions were most commonly randomized controlled trials (RCTs; n=44), and RCTs most commonly compared the dyadic eHealth intervention to usual care alone (n=22). This first comprehensive review of dyadic eHealth interventions demonstrates that there is substantial, diverse, and growing literature supporting this interventional approach. However, several significant gaps were identified. Few studies were designed to evaluate the unique effects of dyadic interventions relative to individual interventions. There was also limited assessment and reporting of outcomes for support persons, and there were no interventions meeting our eligibility criteria specifically targeting the needs of older adult dyads. Findings highlight areas of research opportunities for developing dyadic eHealth interventions for novel populations and for increasing access to dyadic care.


Precision in imaging multivariate optical computing.
Multivariate optical computing (MOC) is a method of performing chemical analysis using a multilayer thin-film structure known as a multivariate optical element (MOE). Recently we have been advancing MOC for imaging problems by using an imaging MOE (IMOE) in a normal-incidence geometry and employing normalization by the 1-norm. There are several important differences between the previously described 45 degree and the normal-incidence imaging, one of which is the measurement precision due to photon counting. We compare this precision to 45 degree MOC. We also discuss how MOE models with similar values of standard errors of calibration and prediction and similar gain values may vary in precision because of the sign or offset of the regression vector encoded in the IMOE spectrum. Experimental verification of a key result is provided by near-infrared imaging of slides coated with a dye-doped polymer film.


Larvae of Ixodes ricinus transmit Borrelia afzelii and B. miyamotoi to vertebrate hosts.
Lyme borreliosis is the most common tick-borne human disease and is caused by Borrelia burgdorferi sensu lato (s.l.). Borrelia miyamotoi, a relapsing fever spirochaete, is transmitted transovarially, whereas this has not been shown for B. burgdorferi (s.l). Therefore, B. burgdorferi (s.l) is considered to cycle from nymphs to larvae through vertebrates. Larvae of Ixodes ricinus are occasionally B. burgdorferi (s.l) infected, but their vector competence has never been studied. We challenged 20 laboratory mice with field-collected larvae of I. ricinus. A subset of these larvae was analysed for infections with B. burgdorferi (s.l) and B. miyamotoi. After three to four challenges, mice were sacrificed and skin and spleen samples were analysed for infection by PCR and culture. Field-collected larvae were naturally infected with B. burgdorferi (s.l) (0.62%) and B. miyamotoi (2.0%). Two mice acquired a B. afzelii infection and four mice acquired a B. miyamotoi infection during the larval challenges. We showed that larvae of I. ricinus transmit B. afzelii and B. miyamotoi to rodents and calculated that rodents have a considerable chance of acquiring infections from larvae compared to nymphs. As a result, B. afzelii can cycle between larvae through rodents. Our findings further imply that larval bites on humans, which easily go unnoticed, can cause Lyme borreliosis and Borrelia miyamotoi disease.


[Tularemia vaccine strain is a potential vector].
The immunological and genetic properties of Francisella tularensis vaccine strain are discussion with regard to its use to produce recombinant vaccines. This bacterium-based vector is supposed to be an excellent object for investigating the role of protective antigens in the development of immunity against intracellular bacteria.


Bustling argon: biological effect.
Argon is a noble gas in group 18 of the periodic table. Certificated to exist in air atmosphere merely one century ago, discovery of argon shows interesting stories of researching and exploring. It was assumed to have no chemical activity. However, argon indeed present its biological effect on mammals. Narcotic effect of argon in diving operation and neur-protective function of argon in cerebral injury demonstrate that argon has crucial effect and be concentrated on is necessary. Furthermore, consider to be harmless to human, argon clinical application in therapy would be another option.


Host cell invasion by pathogenic Neisseriae.
As outlined in this review, various experimental techniques have been employed in an attempt to understand neisserial pathogenesis. In vitro genetic analysis has been used to study the genetic basis for the structural variability of cell surface components. Transformed or primary epithelial cell cultures have provided the simplest model to analyze bacterial adherence and invasion, while the infection of polarized epithelial monolayers, fallopian tube and nasopharyngeal organ cultures, and ureteral tissue have each been used to more closely represent the events which occur in vivo. Finally, the in vivo infection of human volunteers with N. gonorrhoeae has provided a powerful means to confirm and expand the results obtained in vitro. By these various approaches, a number of neisserial adhesins (i.e. pilli, Opa, Opc and P36) and additional putative virulence determinants which affect bacterial adherence and invasion into host cells (i.e. LOS, capsule, PorB) have been identified. Clearly, neisserial surface variation serves as an adaptive mechanism which can modulate tissue tropism, immune evasion and survival in the changing host environment. Important progress has been made in recent years with respect to the host cellular receptors and subsequent signal transduction processes which are involved in neisserial adherence, invasion and transcytosis. This has led to the identification of (i) CD46 as a receptor for pilus which allows adherence to epithelial and endothelial cells, (ii) HSPGs, in cooperation with vitronectin and fibronectin, as receptors for a particular subset of Opa proteins and Opc, which may both mediate invasion into most epithelial and endothelial cells, and (iii) CD66 as the receptors for most Opa variants, potentially being involved in cellular interactions including adherence, invasion and transcytosis with epithelial, endothelial and phagocytic cells. As most of these data have been obtained using transformed cell lines growing in vitro, attempts must be made to translate these basic observations into a more natural situation. It can be expected that the successful ongoing integration of laboratory findings from the various infection models with human volunteer studies will further increase our understanding of the biology of neisserial infection. Perhaps the most difficult but also most rewarding challenge for the future will be to use volunteer studies to identify and understand the role of host factors which are important for the infectious process. Hopefully, insights gained from each of these studies will reveal new and useful strategies for the preventive and/or therapeutic intervention into infection and disease by these fascinating microbes.


The Temporal Ordering of Motivation and Self-Control: A Cross-Lagged Effects Model.
Mechanisms leading to cognitive energy depletion in performance settings such as high-level sports highlight likely associations between individuals' self-control capacity and their motivation. Investigating the temporal ordering of these concepts combining self-determination theory and psychosocial self-control theories, the authors hypothesized that athletes' self-control capacity would be more influenced by their motivation than vice versa and that autonomous and controlled types of motivation would predict self-control capacity positively and negatively, respectively. High-level winter-sport athletes from Norwegian elite sport colleges (N = 321; 16-20 years) consented to participate. Using Bayesian structural equation modeling and 3-wave analyses, findings revealed credible self-control → motivation → self-control cross-lagged effects. Athletes' trait self-control especially initiated the temporal ordering of the least controlled types of motivation (i.e., intrinsic, integrated, and amotivation). Findings indicate that practicing self-control competencies and promoting athletes' autonomous types of motivation are important components in the development toward the elite level. These components will help athletes maintain their persistent goal striving by increasing the value and inherent satisfaction of the development process, avoiding the debilitating effects of self-control depletion and exhaustion.


Transcription of the pcbAB, pcbC and penDE genes of Penicillium chrysogenum AS-P-78 is repressed by glucose and the repression is not reversed by alkaline pHs.
Glucose repressed transcription of the penicillin biosynthesis genes pcbAB, pcbC and penDE when added at inoculation time to cultures of Penicillium chrysogenum AS-P-78 but it had little repressive effect when added at 12 h and no effect when added at 24 or 36 h. A slight increase in the expression of pcbC and penDE (and to a smaller extent of pcbAB) was observed in glucose-grown cultures at pH 6.8, 7.4 and 8.0 as compared with pH 6.2, but alkaline pHs did not override the strong repression exerted by glucose. Transcription of the actin gene used as control was not significantly affected by glucose or alkaline pHs. Repression by glucose of the three penicillin biosynthetic genes was also observed using the lacZ reporter gene coupled to each of the three promoters in monocopy transformants with the constructions integrated at the pyrG locus. Glucose repression of the three genes encoding enzymes of penicillin biosynthesis therefore appears to be exerted by a regulatory mechanism independent from pH regulation.


Beta-alanyl-L-tyrosine. Chemical synthesis, properties and occurrence in larvae of the fleshfly Sarcophaga bullata Parker.
1. A naturally occurring peptide, termed sarcophagine, has been isolated from larvae of the fleshfly Sarcophaga bullata. 2. The physicochemical properties of the natural peptide are identical with those of synthetic beta-alanyl-l-tyrosine. 3. During larval growth the concentration of the dipeptide increases continuously; in the fully grown larva it is the predominant non-protein ninhydrin-positive material. 4. Sarcophagine is rapidly and extensively utilized at the time of hardening and darkening of the insect puparium. 5. By virtue of its much higher solubility than that of free tyrosine, the peptide may serve as a reservoir to provide large amounts of readily available tyrosine for subsequent puparium formation.


Top-down mass analysis of protein tyrosine nitration: comparison of electron capture dissociation with "slow-heating" tandem mass spectrometry methods.
Tyrosine nitration in proteins is an important post-translational modification (PTM) linked to various pathological conditions. When multiple potential sites of nitration exist, tandem mass spectrometry (MS/MS) methods provide unique tools to locate the nitro-tyrosine(s) precisely. Electron capture dissociation (ECD) is a powerful MS/MS method, different in its mechanisms to the "slow-heating" threshold fragmentation methods, such as collision-induced dissociation (CID) and infrared multiphoton dissociation (IRMPD). Generally, ECD provides more homogeneous cleavage of the protein backbone and preserves labile PTMs. However recent studies in our laboratory demonstrated that ECD of doubly charged nitrated peptides is inhibited by the large electron affinity of the nitro group, while CID efficiency remains unaffected by nitration. Here, we have investigated the efficiency of ECD versus CID and IRMPD for top-down MS/MS analysis of multiply charged intact nitrated protein ions of myoglobin, lysozyme, and cytochrome c in a commercial Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. CID and IRMPD produced more cleavages in the vicinity of the sites of nitration than ECD. However the total number of ECD fragments was greater than those from CID or IRMPD, and many ECD fragments contained the site(s) of nitration. We conclude that ECD can be used in the top-down analysis of nitrated proteins, but precise localization of the sites of nitration may require either of the "slow-heating" methods.


Simulation Study of the Conformational Properties of Diblock Polyelectrolytes in Salt Solutions.
Coarse-grained molecular dynamics simulations are performed to understand the behavior of diblock polyelectrolytes in solutions of divalent salt by studying the conformations of chains over a wide range of salt concentrations. The polymer molecules are modeled as bead spring chains with different charged fractions and the counterions and salt ions are incorporated explicitly. Upon addition of a divalent salt, the salt cations replace the monovalent counterions, and the condensation of divalent salt cations onto the polyelectrolyte increases, and the chains favor to collapse. The condensation of ions changes with the salt concentration and depends on the charged fraction. Also, the degree of collapse at a given salt concentration changes with the increasing valency of the counterion due to the bridging effect. As a quantitative measure of the distribution of counterions around the polyelectrolyte chain, we study the radial distribution function between monomers on different polyelectrolytes and the counterions inside the counterion worm surrounding a polymer chain at different concentrations of the divalent salt. Our simulation results show a strong dependence of salt concentration on the conformational properties of diblock copolymers and indicate that it can tune the self-assembly behaviors of such charged polyelectrolyte block copolymers.


[The effect of physical activity on dementia].
Τhe rate of patients suffering from mild cognitive impairment or any type of dementia has been constantly on the rise. Considering that no effective treatment of dementia has been discovered to date and that drug use can have numerous side effects, there is an urgent need for the application of alternative, non-pharmacological interventions. To this end, the aim of this study was to investigate the effects of physical activity on the cognitive impairment of the elderly, and its use as a form of non-pharmacological intervention for the treatment of dementia. Taking a review of the relevant literature, as its data collection method, this study examined peer-reviewed papers published between 2010 and 2018 that met the criteria for their inclusion. The articles were drawn from three electronic databases (PubMed, ScienceDirect and Web of Science), and were examined with regard to the populations under consideration, research design, type of intervention programs and assessment tools applied. The vast majority of these research papers tend to support that physical activity offers significant benefits to people suffering from Alzheimer's disease or other dementias. Specifically, it helps stabilize and improve cognitive function as well as reduce and delay the onset of severe neuropsychiatric symptoms such as depression, confusion, apathy, etc. In addition, physical exercise plays an important role in improving the executive functioning of patients with dementia, increasing autonomy in their everyday activities and reducing the risk of falls. In conclusion, recent research shows physical activity to be a promising intervention for the prevention and non-pharmacological treatment of dementia in that it contributes to the improvement of patients' quality of life. However, results vary according to the particularly characteristics of the exercise under review, such as type, intensity, frequency, and duration. It is therefore important to gain both awareness and understanding of the specific factors that give physical activity its therapeutic potential leading to the development of exercise programs designed specially to treat dementia.


Halo and reverse halo signs in canine pulmonary computed tomography.
The halo sign (HS) and reverse halo sign (RHS) are radiologic signs identified on pulmonary computed tomography (CT) in people. The HS is described as a circular area of ground-glass attenuation surrounding a pulmonary nodule or mass. The RHS is defined as a focal, rounded area of ground-glass attenuation surrounded by a more or less complete ring of consolidation. These signs have been identified in a variety of diseases in people. The purpose of this retrospective study was to determine if the HS and RHS occur in dogs with pulmonary disease and to determine if they are associated with a particular disease process. In addition, the appearance of the HS and RHS was correlated with the histopathologic changes. Our results indicate that the HS and RHS are not common signs identified in dogs with pulmonary disease with an HS noted in five cases and an RHS in 4 of the 33 dogs that met the inclusion criteria. An association between the HS (P-value 0.8163) or RHS (P-value 0.5988) and neoplasia, infectious/inflammatory, and other disease processes was not identified using a Fisher's exact test. The HS was identified in neoplastic, infectious, and inflammatory conditions, with the RHS identified in neoplastic and infectious diseases and a lung lobe torsion. Histologically, the HS and RHS were caused by tumor extension, necrosis, and/or hemorrhage of the pulmonary parenchyma.


Recent declines in cancer incidence: related to the Great Recession?
In recent years, cancer case counts in the U.S. underwent a large, rapid decline-an unexpected change given population growth for older persons at highest cancer risk. As these declines coincided with the Great Recession, we examined whether they were related to economic conditions. Using California Cancer Registry data from California's 30 most populous counties, we analyzed trends in cancer incidence during pre-recession (1996-2007) and recession/recovery (2008-2012) periods for all cancers combined and the ten most common sites. We evaluated the recession's association with rates using a multifactorial index that measured recession impact, and modeled associations between case counts and county-level unemployment rates using Poisson regression. Yearly cancer incidence rate declines were greater during the recession/recovery (3.3% among males, 1.4% among females) than before (0.7 and 0.5%, respectively), particularly for prostate, lung, and colorectal cancers. Lower case counts, especially for prostate and liver cancer among males and breast cancer, melanoma, and ovarian cancer among females, were associated with higher unemployment rates, irrespective of time period, but independent of secular effects. The associations for melanoma translated up to a 3.6% decrease in cases with each 1% increase in unemployment. Incidence declines were not greater in counties with higher recession impact index. Although recent declines in incidence of certain cancers are not differentially impacted by economic conditions related to the Great Recession relative to pre-recession conditions, the large recent absolute declines in the case counts of some cancer may be attributable to the large declines in unemployment in the recessionary period. This may occur through decreased engagement in preventive health behaviors, particularly for clinically less urgent cancers. Continued monitoring of trends is important to detect any rises in incidence rates as deferred diagnoses come to clinical attention.


Ki-67 and MCM-2 in dental follicle and odontogenic cysts: the effects of inflammation on proliferative markers.
The aim of this study was to investigate whether there is any association between inflammation and the expression of markers of cell cycle entry (Ki-67 and MCM-2) in dental follicle (DF) of asymptomatic impacted teeth and odontogenic cysts. The study consisted of 70 DFs and 20 odontogenic cysts (radicular cyst (RC), dentigerous cyst (DC) and keratocytic odontogenic tumor (KCOT) located at posterior mandibular region. Histological findings of inflammation for all specimen and mucous cell prosoplasia, squamous metaplasia, glandular epithelium for all DFs were stained with hematoxyline and eosin, periodic acid schiff, alcian blue, and mucin. Epithelial cell proliferation was determined by using immunohistochemical labeling for Ki-67 and MCM-2. The histologic examinations showed 16% mucous cell prosoplasia, 54% squamous metaplasia, 20% glandular epithelium, 37% inflammation. Inflammation was detected in all RCs and %62 in DF, %43 in DC and KCOT. Positive correlation was found between the inflammation of DF and odontogenic cysts (P < 0.01). The mean Ki-67 and MCM-2 expressions were found 9, 64 ± 5, 99 and 6, 34 ± 3, 81 in DF, 11, 85 ± 9, 01 and 13, 6 ± 9, 94 in odontogenic cysts, respectively. While the mean Ki-67 expressions were statistically significant in DF and KCOT (P < 0.01), MCM-2 were significant in RC and KCOT (P < 0.01). MCM-2 expresion in RCs were statistically significant than KCOT (P < 0.01). The results of this study indicated that the higher MCM-2 expressions in RC than the KCOT might be related to the inflammation and this protein might be more sensitive to inflammation.


A wet dressing for male genital surgery: A phase II clinical trial.
This study was to confirm the safety and efficacy of BC dressing when used in surgical male wound healing at the urogenital area. Open, non-controlled clinical study of phase II. A total of 141 patients, among those children, adolescents and adults with hypospadias (112), epispadias (04), phymosis (13) and Peyronie's disease (12) that had a BC dressing applied over the operated area after surgery. A written informed consent was obtained from all participants. Study exclusion criteria were patients with other alternative treatment indications due to the severity, extent of the injury or the underlying disease. The outcomes evaluated were efficacy, safe and complete healing. The costs were discussed. In 68% patients, the BC dressing fell off spontaneously. The BC was removed without complications in 13% of patients at the outpatient clinic during the follow-up visit and 17% not reported the time of removal. In 3% of the cases, the dressing fell off early. Complete healing was observed between 8th and 10th days after surgery. The BC dressings have shown a good tolerance by all the patients and there were no reports of serious adverse events. The bacterial cellulose dressings have shown efficacy, safety and that can be considered as a satisfactory alternative for postoperative wound healing in urogenital area and with low cost.


Patterns of cell division, DNA base compositions, and fine structures of some radiation-resistant vegetative bacteria found in food.
Representative highly radiation-resistant Moraxella-Acinetobacter (M-A), Pseudomonas radiora, Micrococcus radiodurans, and Micrococcus radiophilus exhibited a wide variety of division systems and cell wall characteristics. However, the most resistant M-A possessed unusually thick cell walls, indicating a possible role of the cell wall in radiation resistance in the M-A. Thick septation was present in most of the bacteria studied, but was absent in P. radiora, thus excluding this as a necessity for high resistance. Reliable determination of the number of division planes of the M-A for use as a taxonomic criterion was achieved by the direct observation of dividing cells. The highly resistant M-A were found to divide in multiple planes and had base compositions of 54.0 to 57.5%, unlike typical Moraxella and/or Acinetobacter species. The taxonomic position of most highly resistant bacteria remains unclear.


Efferent neurotransmission of circadian rhythms in Limulus lateral eye. I. Octopamine-induced increases in retinal sensitivity.
Octopamine increases the sensitivity of the Limulus lateral eye in situ when injected beneath the cornea during the day. The effect of octopamine is dose-dependent with a threshold concentration of about 0.1 microM injected at 1 microliter/min for 15 min. Injection of 40 microM octopamine increases lateral eye sensitivity to approximately 70% of the nighttime level normally caused by the efferent output of a circadian clock. Injections of octopamine analogues and other candidate neurotransmitters indicate that the postsynaptic receptor mediating the increase of retinal sensitivity is relatively specific for the structure of octopamine. The postsynaptic receptor is tentatively classified as a type 2B octopamine receptor (Evans, P. D. (1981) J. Physiol. (Lond.) 318: 99-122). Clozapine suppresses the effects of both exogenous octopamine and the endogenous efferent neurotransmitter. Together with the results from Barlow et al. (Barlow, R. B., Jr., S. J. Bolanowski, Jr., and M. L. Brachman (1977) Science 197: 86-89) and Battelle et al. (Batelle, B. -A., J. A. Evans, and S. C. Chamberlain (1982) Science 216: 1250-1252) our study leads to the following conclusion: retinal efferents, driven by a circadian clock in Limulus brain, release octopamine that increases visual sensitivity.


Antigen-specific memory NK cell responses against HIV and influenza use the NKG2/HLA-E axis.
Multiple studies have broadened the roles of natural killer (NK) cells functioning as purely innate lymphocytes by demonstrating that they are capable of putative antigen-specific immunological memory against multiple infectious agents including HIV-1 and influenza. However, the mechanisms underlying antigen specificity remain unknown. Here, we demonstrate that antigen-specific human NK cell memory develops upon exposure to both HIV and influenza, unified by a conserved and epitope-specific targetable mechanism largely dependent on the activating CD94/NKG2C receptor and its ligand HLA-E. We validated the permanent acquisition of antigen specificity by individual memory NK cells by single-cell cloning. We identified elevated expression of KLRG1, α4β7, and NKG2C as biomarkers of antigen-specific NK cell memory through complex immunophenotyping. Last, we uncovered individual HLA-E-restricted peptides that may constitute the dominant NK cell response in HIV-1- and influenza-infected persons in vivo. Our findings clarify the mechanisms contributing to antigen-specific memory NK cell responses and suggest that they could be potentially targeted therapeutically for vaccines or other therapeutic interventions.


A self-improved water-oxidation catalyst: is one site really enough?
The homogeneous catalysis of water oxidation by transition-metal complexes has experienced spectacular development over the last five years. Practical energy-conversion schemes, however, require robust catalysts with large turnover frequencies. Herein we introduce a new oxidatively rugged and powerful dinuclear water-oxidation catalyst that is generated by self-assembly from a mononuclear catalyst during the catalytic process. Our kinetic and DFT computational analysis shows that two interconnected catalytic cycles coexist while the mononuclear system is slowly and irreversibly converted into the more stable dinuclear system: an extremely robust water-oxidation catalyst that does not decompose over extended periods of time.


Deleting Rac1 improves vertebral bone quality and resistance to fracture in a murine ovariectomy model.
The roles of Rac1 and Rac2 in regulating osteoclast-mediated bone quality in postmenopausal osteoporosis were evaluated using an ovariectomized murine model. Animals' bone composition and architecture were evaluated. Our results demonstrate that the deletion of Rac1 increases vertebral bone quality compared to wild-type bones in an ovariectomized model. To determine the roles of the Rho family small GTPases Rac1 and Rac2 in regulating osteoclast-mediated bone quality in a model of postmenopausal osteoporosis. Twelve-month-old female mice from three genotypes-wild type (WT), Rac1 null (LysM.Rac1 KO), and Rac2 null (Rac2KO)--were studied in control and ovariectomized groups (mice previously ovariectomized at 4 months of age). Animals were sacrificed at 12 months of age, and the femora and vertebrae were harvested for mechanical testing, bone densitometry, micro-computed tomography, and histomorphometric analyses to evaluate bone mineralization and architecture. The results were compared between groups using ANOVA and LSD post-hoc tests. We observed that LysM.Rac1 KO mice showed higher vertebral bone mineral density compared to WT in both control and ovariectomized groups. Consistent with this finding, LysM.Rac1 KO vertebrae showed increased resistance to fracture and increased trabecular connectivity compared to WT in both groups. Micro-CT analysis revealed that Rac2KO ovariectomized vertebrae have more trabecular bone compared to WT and LysM.Rac1 KO, but this did not translate into increased fracture resistance. Our results demonstrate that the deletion of Rac1 increases vertebral bone quality compared to WT bones in a postmenopausal osteoporosis model.


Progressive multifocal leukoencephalopathy: what's new?
Progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease that is caused by human JC polyomavirus, was first described as a complication of immune suppression 50 years ago and emerged as a major complication of HIV infection in the 1980s. The prognosis has remained dismal since then, with discouraging results from clinical trials of various therapeutic approaches, including immunomodulation and/or inhibition of viral replication. PML is caused by reactivation of latent JC virus, and serotonergic 5-HT(2a) receptors have been identified as being critical for viral infection of glial cells. In recent years, immunosuppressive therapeutic antibodies have been associated with an increased incidence rate of PML. Here, the authors review findings on the pathogenesis of PML and the encouraging case reports of novel treatments.


Postoperative Pulmonary Complications After Cardiac Surgery: The VENICE International Cohort Study.
Postoperative pulmonary complications (PPC) remain a main issue after cardiac surgery. The objective was to report the incidence and identify risk factors of PPC after cardiac surgery. An international multicenter prospective study (42 international centers in 9 countries). A total of 707 adult patients who underwent cardiac surgery under cardiopulmonary bypass. None MEASUREMENTS AND MAIN RESULTS: During a study period of 2 weeks, the investigators included all patients in their respective centers and screened for PPCs. PPC was defined as the occurrence of at least 1 pulmonary complication among the following: atelectasis, pleural effusion, respiratory failure, respiratory infection, pneumothorax, bronchospasm, or aspiration pneumonitis. Among 676 analyzed patients, 373 patients presented with a PPC (55%). The presence of PPC was significantly associated with a longer intensive care length of stay and hospital length of stay. One hundred ninety (64%) patients were not intraoperatively ventilated during cardiopulmonary bypass. Ventilation settings were similar regarding tidal volume, respiratory rate, inspired oxygen. In the regression model, age, the Euroscore II, chronic obstructive pulmonary disease, preoxygenation modality, intraoperative positive end-expiratory pressure, the absence of pre- cardiopulmonary bypass ventilation, the absence of lung recruitment, and the neuromuscular blockade were associated with PPC occurrence. Both individual risk factors and ventilatory settings were shown to explain the high level of PPCs. These findings require further investigations to assess a bundle strategy for optimal ventilation strategy to decrease PPC incidence.


Development and testing of the ethical reasoning tool (ERT): an instrument to measure the ethical reasoning of nurses.
Ascertaining the thinking of professionals as they are confronted with ethical practice issues is a prerequisite to understanding ethical decision making. Before researchers or educators can examine the effectiveness of various approaches to ethics teaching and learning, there is a need for reliable and valid tools to assess practitioners' cognition. A potential problem with the few measuring instruments currently available is the fact that they ask subjects to rank order existing lists of issues. This says little about an individuals' own thinking about ethical issues and may prompt thinking or responses which would not otherwise have occurred. This paper reports the results of a study to test the psychometric properties of a new instrument, the Ethical Reasoning Tool (ERT) that measures ethical reasoning of nurses. The ERT demonstrates a promising way to reveal unprompted ethical thinking about a practice dilemma, thereby clarifying 'real' versus 'assumed' professional reasoning. The tool allows nurse educators to identify areas of student learning/reasoning deficiency that can be addressed by educational interventions. The ERT also allows nurse educators to evaluate the effectiveness of nursing ethics study units in a trustworthy way.


Diabetic ulcers--a clinical and bacteriological study.
One hundred consecutive patients with diabetic ulcers were studied in an 8-month-period. There were 58 females. The mean age was 59.9 years. Eighty three patients had non-insulin dependent diabetes mellitus. The mean duration of diabetes mellitus was 11.6 years. The mean duration of the ulcer was 8.5 months. Sixty nine of the ulcers were gangrenous. Over 50% of the ulcers involved the big toes. Neuropathic ulcers were found mainly in the sole of the feet. Roentgenograms showed evidence of osteomyelitis in 44 patients. There were 356 bacterial isolates (340 aerobes and 16 anaerobes) from the ulcers. There were 3.6 infecting organisms per ulcer in gangrenous ulcers, while in neuropathic ulcers, there were 3.4 infecting organisms per ulcer. In both types of ulcer Staphylococcus aureus and Escherichia coli were the commonest infecting organisms each being isolated in 88 of the 100 ulcers studied. In repeat bacterial cultures at 4 weeks there were 116 bacterial isolates. Staphylococcus aureus persisted in 63 ulcers despite therapy, while Escherichia coli persisted in 35. There were no new organisms isolated at repeat cultures and no ulcer was completely sterile. The Staphylococcus aureus was 100% sensitive to Augmentin (Amoxicillin plus clavulinic acid), Clindamycin, Novobiocin, and Amikacin while the gram negative bacilli were sensitive to Cefotaxime, Piperacillin, Amikacin and augmentin, Clindamycin, Chloramphenicol and Lincomycin inhibited the growth of anaerobes to a varying degree.


Connective tissue arrangement in respiratory airways.
Connective tissue provides dynamic stability to the architecture and mechanical function of the lungs. This study examines the parenchymal connective tissue components of the alveolar ducts, their associated respiratory bronchioles and respective alveoli. Thick sections 100 mu and 200 mu, and serial sections at 8 mu of lungs of different ages were examined histologically after fixation in distention. The varying proportions and spatial architecture of the collagen and elastic fibers and the packing and spatial interrelationships of alveoli were studied using graphic serial reconstruction. Alveolar mouth typically have a polygonal configuration as they arise from the airways. Denser connective tissue passes through the polygonal array and forms a helix encircling the airway. Polygonal packing of alveolar mouths provides a mechanically stable ductular structure with conservation of materials. A helical modification of the polygonal arrangement permits reversible changes in linear and circumferential airway dimensions.


Ephrins negatively regulate cell proliferation in the epidermis and hair follicle.
Ephrins and their Eph tyrosine kinase receptors control many processes during embryonic development. They have more recently also been identified as important regulators of proliferation of stem/progenitor cells in the adult brain and intestine and have been implicated in tumorigenesis in a large number of tissues. We here describe the expression of a large number of ephrins and Eph receptors in the adult mouse skin. Disruption of the ephrin-Eph interaction in vivo with antagonists against the A or B class resulted in an approximate doubling of cell proliferation in the hair follicle and epidermis of adult mice. We conclude that ephrins are negative regulators of proliferation in the skin and that blocking the ephrin-Eph interaction may be an attractive strategy for regenerative therapies.


Reported barriers to mental health care in three samples of U.S. Army National Guard soldiers at three time points.
The military community and its partners have made vigorous efforts to address treatment barriers and increase appropriate mental health services use among returning National Guard soldiers. We assessed whether there were differences in reports of treatment barriers in 3 categories (stigma, logistics, or negative beliefs about treatment) in sequential cross-sectional samples of U.S. soldiers from a Midwestern Army National Guard Organization who were returning from overseas deployments. Data were collected during 3 time periods: September 2007-August 2008 (n = 333), March 2009-March 2010 (n = 884), and August 2011-August 2012 (n = 737). In analyses using discretized time periods and in trend analyses, the percentages of soldiers endorsing negative beliefs about treatment declined significantly across the 3 sequential samples (19.1%, 13.9%, and 11.1%). The percentages endorsing stigma barriers (37.8%, 35.2%, 31.8%) decreased significantly only in trend analyses. Within the stigma category, endorsement of individual barriers regarding negative reactions to a soldier seeking treatment declined, but barriers related to concerns about career advancement did not. Negative treatment beliefs were associated with reduced services use (OR = 0.57; 95% CI [0.33, 0.97]).


Directed motion of C60 on a graphene sheet subjected to a temperature gradient.
Nonequilibrium molecular dynamics simulations are used to study the motion of a C(60) molecule on a graphene sheet subjected to a temperature gradient. The C(60) molecule is actuated and moves along the system while it just randomly dances along the perpendicular direction. Increasing the temperature gradient increases the directed velocity of C(60). It is found that the free energy decreases as the C(60) molecule moves toward the cold end. The driving mechanism based on the temperature gradient suggests the construction of nanoscale graphene-based motors.


Role of FDG PET-CT in asymptomatic epithelial ovarian cancer with rising serum CA-125: a pilot study.
We evaluated the role of ¹⁸F-fluorodeoxy glucose (FDG) PET-CT scan in the diagnosis of early relapse in patients with epithelial ovarian cancer (EOC) who were asymptomatic but had a rising serum CA-125 level. Between May 2006 and July 2008, 16 patients with advanced EOC (stages III and IV) who had achieved complete response after cytoreductive surgery and platinum-based chemotherapy were included. These patients were asymptomatic but had a rising serum CA-125 level with normal physical examination and contrast-enhanced CT scan of the abdomen and pelvis. Patients were evaluated with (18)F-FDG PET-CT scan. Written informed consent was taken. Patients with a positive PET-CT scan were advised ultrasound-guided fine-needle aspiration cytology (FNAC) from the area showing increased uptake. Patients in whom FNAC was negative or inconclusive or those with negative PET-CT scan were followed up closely for the next 6 months with repeat clinical evaluation and CT scan. Fifteen patients (15/16) had a positive PET-CT scan. In 9 patients the positive PET lesion was confirmed on FNAC, while in 5 patients this was confirmed on follow-up CT scan after 6 months. One patient who had a single positive lesion in the pelvis on PET-CT was initially considered false-positive because a follow-up CT scan at 6 months did not show the lesion. However, on regular follow-up after 2 years, she was detected to have an isolated lesion in the PET-positive area which was confirmed on secondary cytoreduction. This patient was considered as true-positive in the current analysis. One patient, who had a negative PET-CT scan and a negative CT scan at 6 months' follow-up was considered true-negative. The sensitivity and specificity of PET-CT scan was 100%. We could confirm positivity on histopathology/FNAC in 10 of the 15 (66.7%) true-positive cases. ¹⁸F-FDG PET-CT scan is a sensitive and specific technique for early diagnosis of relapse in asymptomatic EOC patients with rising CA-125. However, its role in the management of recurrent ovarian cancers needs further evaluation.


Real-world outcomes of adjuvant immunotherapy candidates with upper tract urothelial carcinoma: results of a multicenter cohort study.
Recent clinical trials have reported improved disease-free survival rates of patients with stage pT3-4/ypT2-4 or pN + upper tract urothelial carcinoma (UTUC) on adjuvant nivolumab therapy. However, the appropriateness of the patient selection criteria used in clinical practice remains uncertain. We retrospectively analyzed 895 patients who underwent nephroureterectomy to treat UTUC. The patients were divided into two groups: grade pT3-4 and/or pN + without neoadjuvant chemotherapy (NAC) or grade ypT2-4 and/or ypN + on NAC (adjuvant immunotherapy candidates) and others (not candidates for adjuvant immunotherapy). Kaplan-Meier curves were drawn to assess the oncological outcomes, including recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Cox proportional hazards models were used to identify significant prognostic factors for oncological outcomes. The Kaplan-Meier curves revealed notably inferior RFS, CSS, and OS of patients who were candidates for adjuvant immunotherapy. Multivariate analysis revealed that pathological T and N grade and lymphovascular invasion (LVI) status were independent risk factors for poor RFS, CSS, and OS. In total, 44.8% of patients were candidates for adjuvant immunotherapy. In addition to pathological T and N status, LVI was a significant predictor of survival, and may thus play a pivotal role in the selection of patients eligible for adjuvant immunotherapy.


The expression of select genes necessary for membrane-associated estrogen receptor signaling differ by sex in adult rat hippocampus.
17β-estradiol can rapidly modulate neuron function via membrane estrogen receptors (ERs) in a sex-specific manner. For example, female rat hippocampal neurons express palmitoylated versions of ERα and ERβ that associate with the plasma membrane. These membrane-associated ERs are organized by caveolin proteins into functional signaling microdomains with metabotropic glutamate receptors (mGluRs). ER/mGluR signaling mediates several sex-specific estradiol actions on hippocampal neuron function. An important unanswered question regards the mechanism by which sex-specific membrane-associated ER signaling is generated, especially since it has been previously demonstrated that mGluR action is not sex-specific. One possibility is that the genes necessary for the ER membrane complex are differentially expressed between males and females, including genes that encode ERα and β, caveolin 1 and 3, and/or the palmitoylacyltransferases DHHC-7 and -21. Thus we used qPCR to test the hypothesis that these genes show sex differences in expression in neonatal and adult rat hippocampus. As an additional control we tested the expression of the 20 other DHHC palmitoylacyltransferases with no known connections to ER. In neonatal hippocampus, no sex differences were detected in gene expression. In adult hippocampus, the genes that encode caveolin 1 and DHHC-7 showed decreased expression in females compared to males. Thus, select genes differ by sex at specific developmental stages, arguing for a more nuanced model than simple widespread perinatal emergence of sex differences in all genes enabling sex-specific estradiol action. These findings enable the generation of new hypotheses regarding the mechanisms by which sex differences in membrane-associated ER signaling are programmed.


On-line Sequencing of CRISPR Guide RNAs and Their Impurities via the Use of Immobilized Ribonuclease Cartridges Attached to a 2D/3D-LC-MS System.
In this study, for the first time, the automated digestion and sequencing of an RNA molecule via the use of immobilized RNase cartridges attached to a multidimensional liquid chromatography (LC)-mass spectrometry (MS) system are presented. We first developed an on-line digestion-HILIC two-dimensional (2D)-LC-MS method in order to sequence CRISPR guide RNAs for gene editing. Three RNases (T1, A, and U2) were immobilized on polyetheretherketone cartridges, and their performance was evaluated. Ultrafast digestions were performed within 2.3 min with the on-line approach versus 30 min via the conventional off-line approach. The higher sequence coverage was achieved by the RNase T1 (71%), which is the same as the off-line mode. A 20-fold reduction in the gRNA sample amount was achieved with the on-line digestion approach (6.5 μg) in comparison to that with the off-line approach (130 μg). In the second step, a three-dimensional (3D)-LC-MS method was developed for the sequencing of fractions collected on-line across the main peak and the partially separated tail by the reference ion-pairing RPLC method. Additional insights were gained in order to better understand the cause of the main peak tailing.


Unlocking the potential of natural products in drug discovery.
The natural product specialized metabolites produced by microbes and plants are the backbone of our current drugs. Despite their historical importance, few pharmaceutical companies currently emphasize their exploitation in new drug discovery and instead favour synthetic compounds as more tractable alternatives. Ironically, we are in a Golden Age of understanding of natural product biosynthesis, biochemistry and engineering. These advances have the potential to usher in a new era of natural product exploration and development taking full advantage of the unique and favourable properties of natural products compounds in drug discovery.


Short report: improved diagnosis and follow-up of canine leishmaniasis using amastigote-based indirect immunofluorescence.
A comparison of an indirect immunofluorescence test using promastigotes (IFATp) or cultured amastigotes (IFATa) in the diagnosis and follow-up of canine leishmaniasis caused by Leishmania infantum was carried out. Results obtained with both diagnostic methods were in good agreement although the IFATa titration was more sensitive than the currently used IFATp without losing specificity. The higher sensitivity of the amastigote-based IFAT resulted in an earlier diagnosis in the absence of clinical signs. Both methods showed comparable results for monitoring the clinical evolution of naturally infected and treated (meglumine antimoniate plus allopurinol) dogs.


Evidence for retrotransposition of the I factor, a LINE element of Drosophila melanogaster.
LINEs are transposable elements found in various eukaryotes such as plants, protists, insects, and mammals. Their transposition is usually difficult to study, particularly in humans, where some diseases have been shown to result from LINE insertion mutations. This is due to the fact that most copies of any particular family of elements are defective and that their transposition frequency is low. By contrast, the I factor of Drosophila melanogaster transposes at high frequency during I-R hybrid dysgenesis and is a good model for studying the LINE element superfamily. LINEs encode putative polypeptides showing similarities with viral reverse transcriptases but, unlike viral retrotransposons, they do not have terminal repeats and their ability to transpose by reverse transcription has previously only been inferred from structural analysis. Here we present direct evidence for LINE retrotransposition. Transposition of an I factor marked by an intron resulted in accurate removal of the intron.


Conventional versus molecular diagnostic tests.
In this session, emphasis was placed on the diagnosis of various mycoses through the identification of antibodies and antigens in sera, as well as on new techniques to properly identify medically important fungi through molecular biological procedures. The use of restriction fragment length polymorphism (RFLP) on fungal mitochondrial DNA (mtDNA) has enabled the identification of different strains of Sporothrix schenkii, several dermatophytes, Candida spp. and black fungi according to their species-specific mtDNA-RFLP patterns. In some species, distinct specific types where found in relation to the geographic origin of the patients. These particular molecular diagnostic tests are useful in the identification of strains and in epidemiological studies. An account of the applications of serological methods in the diagnosis of paracoccidioidomycosis was presented. Serology has been used in the identification of paracoccidioidomycosis using a specific, sensitive and rapid antibody-based immunodiagnosis method. Using the gp43 antigen, the diagnostic coverage of inmunodifussion has been improved from the 93-95% achieved with crude antigens, to 100% in an enzyme-linked immunodiffusion assay capture test. Cross-reactions were eliminated by treatment of the antigen with sodium metaperiodate. Antibody detection is useful, especially in paracoccidioidomycosis and histoplasmosis.


Persistent cytokine expression in trigeminal ganglion latently infected with herpes simplex virus type 1.
Following ocular infection, herpes simplex virus type 1 (HSV-1) establishes latency in trigeminal ganglion (TG) neurons. Using reverse transcription-PCR, cytokine gene expression was analyzed in the TGs of mice infected with HSV-1. IL-2, TNF-alpha, IFN-gamma, IL-10, and RANTES mRNAs were readily detected in TGs taken from mice 7 days postinoculation (PI). Likewise, IL-2, IL-6, IL-10, and IFN-gamma protein were detected by ELISA of TG homogenates. Between 5 and 45 days PI, IL-10, IFN-gamma, TNF-alpha, and RANTES mRNAs were detected in nearly 100% of latently infected TGs (latent infection was confirmed by reverse transcription-PCR detection of HSV-1 latency-associated transcripts). T cell-associated cytokine and chemokine mRNAs (IL-2, IL-10, IFN-gamma, and RANTES) were still detected in the majority of latently infected TG samples taken between 60 and 135 days PI. In contrast, these cytokine mRNA species were rarely detected in uninfected TGs. Measurement of serum Abs to HSV-1 at different times revealed that anti-HSV-1 Ab concentrations approached a plateau in mice by 30 days PI but remained at high levels 67 and 125 days PI. Although there was molecular evidence of an ongoing immune response to HSV-1 in latently infected TG, histologic analysis indicated that very few mononuclear cells remained in the ganglion 60 days PI. Collectively, the results suggest that residual lymphocytes encounter viral Ag during HSV-1 latency with sufficient frequency to remain activated. The paradox of a persistent immune response against a latent infection is discussed.


Contribution of inhibition to stimulus selectivity in primary auditory cortex of awake primates.
Recent studies have demonstrated the high selectivity of neurons in primary auditory cortex (A1) and a highly sparse representation of sounds by the population of A1 neurons in awake animals. However, the underlying receptive field structures that confer high selectivity on A1 neurons are poorly understood. The sharp tuning of A1 neurons' excitatory receptive fields (RFs) provides a partial explanation of the above properties. However, it remains unclear how inhibitory components of RFs contribute to the selectivity of A1 neurons observed in awake animals. To examine the role of the inhibition in sharpening stimulus selectivity, we have quantitatively analyzed stimulus-induced suppressive effects over populations of single neurons in frequency, amplitude, and time in A1 of awake marmosets. In addition to the well documented short-latency side-band suppression elicited by masking tones around the best frequency (BF) of a neuron, we uncovered long-latency suppressions caused by single-tone stimulation. Such long-latency suppressions also included monotonically increasing suppression with sound level both on-BF and off-BF, and persistent suppression lasting up to 100 ms after stimulus offset in a substantial proportion of A1 neurons. The extent of the suppression depended on the shape of a neuron's frequency-response area ("O" or "V" shaped). These findings suggest that the excitatory RF of A1 neurons is cocooned by wide-ranging inhibition that contributes to the high selectivity in A1 neurons' responses to complex stimuli. Population sparseness of the tone-responsive A1 neuron population may also be a consequence of this pervasive inhibition.


[Achalasia in circumscribed scleroderma].
A 38-year-old man had been suffering from circumscribed scleroderma for 12 years. Dysphagia had been diagnosed 5 years ago and for the last 2 years he had retrosternal dysphagia for solid and liquid food. His symptoms had increased markedly 6 months before presenting at our hospital and the patient had lost 15 kg of weight. 2 months ago, a percutaneous endoscopic gastrostomy (PEG) had been inserted at another hospital. The patient presented in a reduced general and nutritional state. The routine laboratory tests and tumor markers were within normal range. Endoscopy showed a moderately dilated esophagus with food remnants. It was not possible to pass the cardia without exerting pressure. Esophageal manometry and barium upper gastrointestinal series revealed the classical findings of achalasia. An extramucosal Heller myotomy with anterior semifundoplication (Dor's procedure) was performed. The postoperative course was uneventful and the patient was able to take solid and liquid food without any dysphagia. The association of achalasia and circumscribed scleroderma has not been described in medical publications yet. The entity could possibly be based on common autoimmune mechanisms and an analogous pathogenesis with resulting fibrosis.


Prevalence and risk factors of latent tuberculosis infection in Africa: a systematic review and meta-analysis protocol.
Latent tuberculosis infection (LTBI) remains a major public health problem and one of the major contributors to the pool of active tuberculosis cases. The true burden of LTBI in Africa is not known. Early modelling studies estimate that over 33% of the world's population is infected with latent tuberculosis. We propose conducting a systematic review and a meta-analysis to evaluate the burden and risk factors of LTBI in Africa reported in studies from 2000 to 2017. We will include cross-sectional studies, cohort studies and case-control studies estimating either tuberculin skin test (TST) or interferon-gamma release assay (IGRA) confirmed prevalence of LTBI and associated risk factors among people in African countries. A comprehensive search of relevant literature will be conducted on electronic databases using common and medical subject heading (MeSH) terms for LTBI, and an African search filter. Risk of bias will be evaluated by assessing all qualifying full-text articles for quality and eligibility using a quality score assessment tool. Standardised data extraction will be carried out after which prevalence estimates will be pooled using random-effects models in Stata V.13. Where there is sufficient data , subgroup meta-analyses will be conducted by risk factors including participant's age group, occupation, location and HIV status. This systematic review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocols 2015 Statement. No ethical issues were foreseen given that this was a protocol for a systematic review of published studies. The results of this study will be published in a peer-reviewed journal and presented at conferences. Systematic review registration: PROSPERO CRD42016037997.


DeepSEED: 3D Squeeze-and-Excitation Encoder-Decoder Convolutional Neural Networks for Pulmonary Nodule Detection.
Pulmonary nodule detection plays an important role in lung cancer screening with low-dose computed tomography (CT) scans. It remains challenging to build nodule detection deep learning models with good generalization performance due to unbalanced positive and negative samples. In order to overcome this problem and further improve state-of-the-art nodule detection methods, we develop a novel deep 3D convolutional neural network with an Encoder-Decoder structure in conjunction with a region proposal network. Particularly, we utilize a dynamically scaled cross entropy loss to reduce the false positive rate and combat the sample imbalance problem associated with nodule detection. We adopt the squeeze-and-excitation structure to learn effective image features and utilize inter-dependency information of different feature maps. We have validated our method based on publicly available CT scans with manually labelled ground-truth obtained from LIDC/IDRI dataset and its subset LUNA16 with thinner slices. Ablation studies and experimental results have demonstrated that our method could outperform state-of-the-art nodule detection methods by a large margin.


The genetic and phenotypic spectra of adult genetic leukoencephalopathies in a cohort of 309 patients.
Genetic leukoencephalopathies (gLEs) are a highly heterogeneous group of rare genetic disorders. The spectrum of gLEs varies among patients of different ages. Distinct from the relatively more abundant studies of gLEs in children, only a few studies that explore the spectrum of adult gLEs have been published, and it should be noted that the majority of these excluded certain gLEs. Thus, to date, no large study has been designed and conducted to characterize the genetic and phenotypic spectra of gLEs in adult patients. We recruited a consecutive series of 309 adult patients clinically suspected of gLEs from Beijing Tiantan Hospital between January 2014 and December 2021. Whole-exome sequencing, mitochondrial DNA sequencing and repeat analysis of NOTCH2NLC, FMR1, DMPK and ZNF9 were performed for patients. We describe the genetic and phenotypic spectra of the set of patients with a genetically confirmed diagnosis and summarize their clinical and radiological characteristics. A total of 201 patients (65%) were genetically diagnosed, while 108 patients (35%) remained undiagnosed. The most frequent diseases were leukoencephalopathies related to NOTCH3 (25%), NOTCH2NLC (19%), ABCD1 (9%), CSF1R (7%) and HTRA1 (5%). Based on a previously proposed pathological classification, the gLEs in our cohort were divided into leukovasculopathies (35%), leuko-axonopathies (31%), myelin disorders (21%), microgliopathies (7%) and astrocytopathies (6%). Patients with NOTCH3 mutations accounted for 70% of the leukovasculopathies, followed by HTRA1 (13%) and COL4A1/2 (9%). The leuko-axonopathies contained the richest variety of associated genes, of which NOTCH2NLC comprised 62%. Among myelin disorders, demyelinating leukoencephalopathies (61%)-mainly adrenoleukodystrophy and Krabbe disease-accounted for the majority, while hypomyelinating leukoencephalopathies (2%) were rare. CSF1R was the only mutated gene detected in microgliopathy patients. Leukoencephalopathy with vanishing white matter disease due to mutations in EIF2B2-5 accounted for half of the astrocytopathies. We characterized the genetic and phenotypic spectra of adult gLEs in a large Chinese cohort. The most frequently mutated genes were NOTCH3, NOTCH2NLC, ABCD1, CSF1R and HTRA1.


Remediation of language processing in aphasia: Improving activation and maintenance of linguistic representations in (verbal) short-term memory.
BACKGROUND: Verbal short-term memory (STM) impairments are invariably present in aphasia. Word processing involves a minimal form of verbal STM, i.e., the time course over which semantic and phonological representations are activated and maintained until they are comprehended, produced, or repeated. Thus it is reasonable that impairments of word processing and verbal STM may co-occur. The co-occurrence of language and STM impairments in aphasia has motivated an active area of research that has revealed much about the relationship of these two systems and the effect of their impairment on language function and verbal learning (Freedman & Martin, 2001; Martin & Saffran, 1999; Trojano & Grossi, 1995). In keeping with this view a number of researchers have developed treatment protocols to improve verbal STM in order to improve language function (e.g., Koenig-Bruhin & Studer-Eichenberger, 2007). This account of aphasia predicts that treatment of a fundamental ability, such as STM, which supports language function, should lead to improvements that generalise to content and tasks beyond those implemented in treatment. AIMS: We investigated the efficacy of a treatment for language impairment that targets two language support processes: verbal short-term memory (STM) and executive processing, in the context of a language task (repetition). We hypothesised that treatment of these abilities would improve repetition abilities and performance on other language tasks that require STM. METHOD: A single-participant, multiple-baseline, multiple-probe design across behaviours was used with a participant with conduction aphasia. The treatment involved repetition of words and nonwords under three "interval" conditions, which varied the time between hearing and repeating the stimulus. Measures of treatment effects included acquisition, maintenance, and follow-up data, effect sizes, and pre- and post-treatment performance on a test battery that varies the STM and executive function demands of language tasks. OUTCOMES #ENTITYSTARTX00026; RESULTS: Improvement of repetition was mostly specific to treated stimuli. Post-treatment measures of language ability indicated improvements in single and multiple word processing tasks, verbal working memory tasks, and verbal span. CONCLUSIONS: Treatment of STM and executive processes in the context of a word repetition task resulted in improvements in other non-treated language tasks. The approach used in this study can be incorporated into other language-processing tasks typically used in treatment of language disorders (e.g., sentence processing).


Differential gene expression in bacterial symbionts from loliginid squids demonstrates variation between mutualistic and environmental niches.
Luminescent bacteria (gamma-Proteobacteria: Vibrionaceae) are found in complex bilobed light organs of both sepiolid and loliginid squids (Mollusca: Cephalopoda). Despite the existence of multiple strain colonization between Vibrio bacteria and loliginid squids, specificity at the genus level still exists and may influence interactions between symbiotic and free-living stages of the symbiont. The environmentally transmitted behaviour of Vibrio symbionts bestows a certain degree of recognition that exists prior and subsequent to the colonization process. Therefore, we identified bacterial genes required for successful colonization of loliginid light organs by examining transcripts solely expressed in either the light organ or free-living stages. Selective capture of transcribed sequences (SCOTS) was used to differentiate genes expressed by the same bacterium when thriving in two different environments (i.e. loliginid light organs and seawater). Genes specific for squid light organs included vulnibactin synthetase, outer membrane protein W and dihydroxy dehydratase, which have been associated with the maintenance of bacterial host associations in other systems. In contrast, genes that were solely expressed in the free-living condition consisted of transcripts recognized as important factors for bacterial survival in the environment. These transcripts included genes for methyl accepting chemotaxis proteins, arginine decarboxylase and chitinase. These results provide valuable information regarding mechanisms determining specificity, establishment, and maintenance of bacteria-squid associations.


Bone marrow chimeras reveal non-H-2 hematopoietic control of susceptibility to Theiler's virus persistent infection.
The DA strain of Theiler's murine encephalomyelitis virus persists in the white matter of the spinal cords of susceptible mice. Previous results showed that the difference in susceptibility to viral persistence between the susceptible SJL/J strain and the resistant B10.S strain was due to multiple non-H-2 loci. The respective roles of hematopoietic and nonhematopoietic cells in this difference have been evaluated with bone marrow chimeras. The results show that non-H-2 loci with a major effect on susceptibility are expressed in hematopoietic cells. However, the study of the SJL.B10-D10Mit180-D10Mit74 congenic line suggests that other loci expressed in nonhematopoietic cells also play a role.


Benchmarking specialty hospitals, a scoping review on theory and practice.
Although benchmarking may improve hospital processes, research on this subject is limited. The aim of this study was to provide an overview of publications on benchmarking in specialty hospitals and a description of study characteristics. We searched PubMed and EMBASE for articles published in English in the last 10 years. Eligible articles described a project stating benchmarking as its objective and involving a specialty hospital or specific patient category; or those dealing with the methodology or evaluation of benchmarking. Of 1,817 articles identified in total, 24 were included in the study. Articles were categorized into: pathway benchmarking, institutional benchmarking, articles on benchmark methodology or -evaluation and benchmarking using a patient registry. There was a large degree of variability:(1) study designs were mostly descriptive and retrospective; (2) not all studies generated and showed data in sufficient detail; and (3) there was variety in whether a benchmarking model was just described or if quality improvement as a consequence of the benchmark was reported upon. Most of the studies that described a benchmark model described the use of benchmarking partners from the same industry category, sometimes from all over the world. Benchmarking seems to be more developed in eye hospitals, emergency departments and oncology specialty hospitals. Some studies showed promising improvement effects. However, the majority of the articles lacked a structured design, and did not report on benchmark outcomes. In order to evaluate the effectiveness of benchmarking to improve quality in specialty hospitals, robust and structured designs are needed including a follow up to check whether the benchmark study has led to improvements.


Mutagenesis Objective Search and Selection Tool (MOSST): an algorithm to predict structure-function related mutations in proteins.
Functionally relevant artificial or natural mutations are difficult to assess or predict if no structure-function information is available for a protein. This is especially important to correctly identify functionally significant non-synonymous single nucleotide polymorphisms (nsSNPs) or to design a site-directed mutagenesis strategy for a target protein. A new and powerful methodology is proposed to guide these two decision strategies, based only on conservation rules of physicochemical properties of amino acids extracted from a multiple alignment of a protein family where the target protein belongs, with no need of explicit structure-function relationships. A statistical analysis is performed over each amino acid position in the multiple protein alignment, based on different amino acid physical or chemical characteristics, including hydrophobicity, side-chain volume, charge and protein conformational parameters. The variances of each of these properties at each position are combined to obtain a global statistical indicator of the conservation degree of each property. Different types of physicochemical conservation are defined to characterize relevant and irrelevant positions. The differences between statistical variances are taken together as the basis of hypothesis tests at each position to search for functionally significant mutable sites and to identify specific mutagenesis targets. The outcome is used to statistically predict physicochemical consensus sequences based on different properties and to calculate the amino acid propensities at each position in a given protein. Hence, amino acid positions are identified that are putatively responsible for function, specificity, stability or binding interactions in a family of proteins. Once these key functional positions are identified, position-specific statistical distributions are applied to divide the 20 common protein amino acids in each position of the protein's primary sequence into a group of functionally non-disruptive amino acids and a second group of functionally deleterious amino acids. With this approach, not only conserved amino acid positions in a protein family can be labeled as functionally relevant, but also non-conserved amino acid positions can be identified to have a physicochemically meaningful functional effect. These results become a discriminative tool in the selection and elaboration of rational mutagenesis strategies for the protein. They can also be used to predict if a given nsSNP, identified, for instance, in a genomic-scale analysis, can have a functional implication for a particular protein and which nsSNPs are most likely to be functionally silent for a protein. This analytical tool could be used to rapidly and automatically discard any irrelevant nsSNP and guide the research focus toward functionally significant mutations. Based on preliminary results and applications, this technique shows promising performance as a valuable bioinformatics tool to aid in the development of new protein variants and in the understanding of function-structure relationships in proteins.


Rational Design of Self-Assembled Mitochondria-Targeting Lytic Peptide Conjugates with Enhanced Tumor Selectivity.
Membrane lytic peptides (MLP) are widely explored as cellular delivery vehicles or antitumor/antibacterial agents. However, the poor selectivity between cancer and normal cells slims their prospects as potential anti-tumor drugs. Herein, we have developed a rationally designed self-assembly strategy to enhance tumor selectivity of MLP-based conjugates, incorporating a hydrophobic triphenylphosphonium (TPP) group for mitochondria targeting, and a hydrophilic arginine-glycine-aspartic acid (RGD) sequence targeting integrins. The self-assembly nanoparticles can enhance the stability of the peptides in vitro plasma and be endocytosed selectively into the cancer cells. The histidine-rich lytic peptide component assists the disruption of endosomal/lysosomal membranes and subsequent the mitochondria membrane, which leads to apoptosis. This rational design of MLP-based conjugates provides a practical strategy to increase the application prospects of lytic peptides in cancer treatment.


Infant-feeding practices in Al-Ain, United Arab Emirates.
A survey was conducted to study the practices of infant-feeding and the influencing factors in Al-Ain, United Arab Emirates. It involved 375 mothers of different nationalities and backgrounds and 300 healthy infants. The mothers were interviewed at four primary health care clinics in Al-Ain. Results showed that 46% of infants were breastfed for 4-6 months. The mother's nationality and her educational status were significant influences on the mother's decision to exclusively breast-feed the infant, for how long and when to introduce supplementary food. Fresh cow and goat milk were the most common supplements. Inclusion of baby formula as a supplement generally occurred early, perhaps because of advertising and the affluence in Al-Ain.


Depressed mood and frailty among older people in Tokyo during the COVID-19 pandemic.
The study aim was to identify depressed mood and frailty and its related factors in older people during the coronavirus disease 19 pandemic. Since 2010, we have conducted questionnaire surveys on all older residents, who are not certified in the long-term care insurance, living in one district of Tokyo municipality. These residents are divided into two groups by birth month, that is those born between April and September and those born between October and March, and each group completes the survey every 2 years (in April and May). Study participants were older residents who were born between April and September and who completed the survey in spring 2018 and in spring 2020, the pandemic period. Depressed mood and frailty were assessed using the Kihon Checklist, which is widely used by local governments in Japan. We had no control group in this study. A total of 1736 residents responded to both surveys. From 2018 to 2020, the depressed mood rate increased from 29% to 38%, and frailty increased from 10% to 16%. The incidence of depressed mood and frailty was 25% and 11%, respectively. Incidence of depressed mood was related to subjective memory impairment and difficulty in device usage, and incidence of frailty was related to being older, subjective memory impairment, lack of emotional social support, poor subjective health, and social participation difficulties. Older people with subjective memory impairment may be a high-risk group during the coronavirus pandemic. Telephone outreach for frail older people could be an effective solution. We recommend extending the scope of the 'reasonable accommodation' concept beyond disability and including older people to build an age-friendly and crisis-resistant community.


[Aerobic and facultatively anaerobic bacteria isolated from surgical infection patients].
The ecological structure of infections in surgical patients with different postoperative complications (suppurative wounds, abscesses, peritonitis, etc.) and suppurative lung diseases were studied. During the period of 6 years (1975-1980) 5401 samples of clinical material were studied. 1380 samples (25.6%) were sterile, from 2254 samples (41.7%) monocultures were isolated, in 1767 samples (32.7%) microbial associations were detected. Of 5962 isolated cultures, 1816 (30.5%) were Gram-negative bacteria (GNB), 3532 (59.2%) were Gram-positive bacteria (GPB) and 614 (10.6%) were yeastlike fungi. The tendency towards the increase of the role of GNB in the etiology of postoperative complications was observed. Among GNB Pseudomonas aeruginosa strains were prevalent (36.2%). In the group of GPB coagulase-negative staphylococci were rather frequently found to be the causative agents of surgical infections.


Comparison of Aquitaine and Rioja Red Wines: Characterization of Their Phenolic Composition and Evolution from 2000 to 2013.
Wine chemical analysis was carried out on 194 commercial blended red wines produced by two major wine-growing areas-the Aquitaine (France) and Rioja (Spain) regions-in order to compare the wines of both regions. Anthocyanins and derived pigments, tannins and derivatives were identified and quantified by HPLC-DAD-ESI-MS/MS (high pressure liquid chromatography coupled to diode array detector and mass spectrometry using the electrospray ionization interface). Mean degree of polymerization (mDP) was determined. The influence of the wine-growing region and the predominance of the properties of some grape varieties used are confirmed by the significant differences observed between both regions. Rioja and Bordeaux "generic" (Bordeaux and Bordeaux-Supérieur appellations) red wines showed the highest anthocyanic content and the highest mDP, as these wines are in a majority made from Merlot (Bordeaux "generic") and Tempranillo (Rioja). On the contrary, Bordeaux "specific" regions (Blayais, Médoc, Graves, and Libournais) showed the red wines with the highest total phenolic content and tannin concentration, as the predominant grape variety used is Cabernet Sauvignon. A principal component analysis (PCA) and a hierarchical ascendant classification (HAC) suggesting patterns between the chemical parameters and the distribution of the red wines in three groups were proposed. The comparison of the two wine-growing areas also reveals some similarities between the various grape varieties used. A general effect of a progressive decrease in anthocyanins, anthocyanin-derived pigment and tannins is observed for older wines.


School-based systems change for obesity prevention in adolescents: outcomes of the Australian Capital Territory 'It's Your Move!'
The Australian Capital Territory 'It's Your Move!' (ACT-IYM) was a three-year (2012-2014) systems intervention to prevent obesity among adolescents. The ACT-IYM project involved three intervention schools and three comparison schools and targeted secondary students aged 12-16 years. The intervention consisted of multiple initiatives at individual, community, and school policy level to support healthier nutrition and physical activity. Intervention school-specific objectives related to increasing active transport, increasing time spent physically active at school, and supporting mental wellbeing. Data were collected in 2012 and 2014 from 656 students. Anthropometric data were objectively measured and behavioural data self-reported. Proportions of overweight or obesity were similar over time within the intervention (24.5% baseline and 22.8% follow-up) and comparison groups (31.8% baseline and 30.6% follow-up). Within schools, two of three the intervention schools showed a significant decrease in the prevalence of overweight and obesity (p<0.05). There was some evidence of effectiveness of the systems approach to preventing obesity among adolescents. Implications for public health: The incorporation of systems thinking has been touted as the next stage in obesity prevention and public health more broadly. These findings demonstrate that the use of systems methods can be effective on a small scale.


[Polypous rhinosinusitis in the context of the asthma triad].
The present study included 37 patients at the age from 18 to 65 years suffering polypous rhinosinusopathy (PRS). Endoscopic examination of their nasal cavity and anterior rhinoscopy revealed the presence of large- and medium-sized polyps (stages II-III according to the classification of G.M. Portenko).. All the patients were treated with longidase either injected directly into the polyps at a dose of 3,000 IU or used to irrigate the affected nasal mucosa (10 seances). Positive effect of the treatment was documented in 32 (86%) patients of both groups who reported restoration of nasal breathing, showed improved functional characteristics, and significantly reduced size of local polyps upon the endoscopic examination of the nasal cavity. It is concluded that longidase is an efficacious and safe preparation for the conservative treatment of polypous rhinosinusitis.


Association between methylenetetrahydrofolate reductase polymorphisms, alcohol intake and oropharyngolaryngeal carcinoma in northern Italy.
Folate metabolism dysregulation may lead to abnormal cell proliferation and predispose to carcinogenesis by inducing DNA hypomethylation. Folate pathways may be modified by polymorphisms in relevant genes, such as that for methylenetetrahydrofolate reductase (MTHFR), or by alcohol consumption. We investigated the relationship between MTHFR mutations at nucleotides C677T and A1298C, which cause reduced MTHFR enzyme activity, and susceptibility to oropharyngolaryngeal carcinoma in 65 patients and 100 controls. We isolated DNA from peripheral blood leukocytes. In oropharyngolaryngeal carcinoma cases the C677T heterozygous genotype was more frequent (p = 0.018), the allele frequency of MTHFR 677T was greater (p = 0.019) and the genotype 677TT/1298AA was more frequent (p = 0.001). A higher risk of carcinoma was found in the case of moderate drinkers with mutant MTHFR homozygosis or double heterozygosis (OR = 21.2 and OR = 9.1, respectively; p trend = 0.002), and the association was maintained for the different cancer sites (glottic, supraglottic, oropharyngeal). Our findings support the hypothesis that the interaction of alcohol intake and MTHFR polymorphisms might contribute to susceptibility to carcinogenesis of the oropharyngolaryngeal tract.


Prenatal THC Exposure Induces Sex-Dependent Neuropsychiatric Endophenotypes in Offspring and Long-Term Disruptions in Fatty-Acid Signaling Pathways Directly in the Mesolimbic Circuitry.
Despite increased prevalence of maternal cannabis use, little is understood regarding potential long-term effects of prenatal cannabis exposure (PCE) on neurodevelopmental outcomes. While neurodevelopmental cannabis exposure increases the risk of developing affective/mood disorders in adulthood, the precise neuropathophysiological mechanisms in male and female offspring are largely unknown. Given the interconnectivity of the endocannabinoid (ECb) system and the brain's fatty acid pathways, we hypothesized that prenatal exposure to Δ9-tetrahydrocannabinol (THC) may dysregulate fetal neurodevelopment through alterations of fatty-acid dependent synaptic and neuronal function in the mesolimbic system. To investigate this, pregnant Wistar rats were exposed to vehicle or THC (3 mg/kg) from gestational day (GD)7 until GD22. Anxiety-like, depressive-like, and reward-seeking behavior, electrophysiology, and molecular assays were performed on adult male/female offspring. Imaging of fatty acids using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) was performed at prepubescence and adulthood. We report that PCE induces behavioral, neuronal, and molecular alterations in the mesolimbic system in male and female offspring, resembling neuropsychiatric endophenotypes. Additionally, PCE resulted in profound dysregulation of critical fatty acid pathways in the developing brain lipidome. Female progeny exhibited significant alterations to fatty acid levels at prepubescence but recovered from these deficits by early adulthood. In contrast, males exhibited persistent fatty acid deficits into adulthood. Moreover, both sexes maintained enduring abnormalities in glutamatergic/GABAergic function in the nucleus accumbens (NAc). These findings identify several novel long-term risks of maternal cannabis use and demonstrate for the first time, sex-related effects of maternal cannabinoid exposure directly in the developing neural lipidome.


PDXNet portal: patient-derived Xenograft model, data, workflow and tool discovery.
We created the PDX Network (PDXNet) portal (https://portal.pdxnetwork.org/) to centralize access to the National Cancer Institute-funded PDXNet consortium resources, to facilitate collaboration among researchers and to make these data easily available for research. The portal includes sections for resources, analysis results, metrics for PDXNet activities, data processing protocols and training materials for processing PDX data. Currently, the portal contains PDXNet model information and data resources from 334 new models across 33 cancer types. Tissue samples of these models were deposited in the NCI's Patient-Derived Model Repository (PDMR) for public access. These models have 2134 associated sequencing files from 873 samples across 308 patients, which are hosted on the Cancer Genomics Cloud powered by Seven Bridges and the NCI Cancer Data Service for long-term storage and access with dbGaP permissions. The portal includes results from freely available, robust, validated and standardized analysis workflows on PDXNet sequencing files and PDMR data (3857 samples from 629 patients across 85 disease types). The PDXNet portal is continuously updated with new data and is of significant utility to the cancer research community as it provides a centralized location for PDXNet resources, which support multi-agent treatment studies, determination of sensitivity and resistance mechanisms, and preclinical trials.


Malignant Melanoma Presenting as a Mediastinal Malignant Melanoma Presenting as a Mediastinal Unknown Primary Origin?
The most common site of primary malignant melanoma is the skin, however, virtually any organ system may be involved. Metastatic melanoma of unknown primary origin accounts for approximately 2-6% of all melanoma cases. The mediastinum as the site for malignant melanoma is extremely rare, both as a primary or metastatic lesion. Primary malignant melanoma of mediastinum is very rare with only a handful of reports in the literature. We hereby report a rare case of malignant melanoma of mediastinum in a 31 year old male who was initially misdiagnosed on fine needle aspiration cytology as adenocarcinoma for which he received chemotherapy with clinical deterioration. Even on extensive meticulous search, no primary was discovered.


Generalized lysosome-associated membrane protein-2 defect explains multisystem clinical involvement and allows leukocyte diagnostic screening in Danon disease.
Danon disease, an X-linked dominant disorder, results from mutations in the lysosome-associated membrane protein-2 (LAMP2) gene and presents with hypertrophic cardiomyopathy, skeletal myopathy, and mental retardation. To investigate the effects of LAMP2 gene mutations on protein expression in different tissues, we screened LAMP2 gene mutations and LAMP-2 protein deficiency in the skeletal muscle of nine unrelated patients with hypertrophic cardiomyopathy and vacuolar myopathy. We identified three novel families (including one affected mother) with unreported LAMP2 gene null mutations and LAMP-2 protein deficiency in skeletal and myocardial muscle, leukocytes, and fibroblasts. LAMP-2 protein deficiency was detectable in various tissues, including leukocytes, explaining the multisystem clinical involvement. Skeletal muscle immunopathology showed that mutant protein was not localized in the Golgi complex, vacuolar membranes expressed sarcolemmal-specific proteins, and the degree of muscle fiber vacuolization correlated with clinical muscle involvement. In our female patient, muscle histopathology and LAMP-2 protein analysis was inconclusive, indicating that diagnosis in females requires mutation identification. The random X-chromosome inactivation found in muscle and leukocytes excluded the possibility that selective involvement of some tissues in females is due to skewed X-chromosome inactivation. Therefore, biochemical analysis of leukocytes might be used for screening in male patients, but genetic screening is required in females.


Anaerobic sulfamethoxazole degradation is driven by homoacetogenesis coupled with hydrogenotrophic methanogenesis.
In this study, microbial community dynamics were assessed in two lab-scale anaerobic sequencing batch reactors (ASBRs). One of the reactors was fed by synthetic pharmaceutical industry wastewater with sulfamethoxazole (SMX) as the test reactor and the other without sulfamethoxazole as the control reactor. DNA based DGGE results indicated that Clostiridum sp. became dominant in the SMX reactor while the inoculum was dominated with Firmicutes (61%) and Methanomicrobiales (28%). However their abundances in active community decreased through the last phase. Also the abundance of hydrogenotrophs was high in each phase, while acetoclastic methanogens disappeared in the last phase. Q-PCR analysis revealed that there is a significant reduction in the bacterial community approximately 84%, while methanogens increased to 97% through the operation. Additionally an increase in the expression level of bacterial and methanogenic 16S rRNA (60% and 20%, respectively) was detected. Significant correlation between microbial community and the reactor operation data was found. The study demonstrated that the microbial community maintains the system stability under high antibiotic concentration and long-term operation by homoacetogenesis coupled with hydrogenotrophic methanogenesis.


Examination of the distribution of the bioreductive drug AQ4N and its active metabolite AQ4 in solid tumours by imaging matrix-assisted laser desorption/ionisation mass spectrometry.
AQ4N (banoxatrone) (1,4-bis-{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione) is an example of a bioreductive prodrug in clinical development. In hypoxic cells AQ4N is reduced to the topoisomerase II inhibitor AQ4 (1,4-bis- {[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione). By inhibition of topoisomerase II within these hypoxic areas, AQ4N has been shown to sensitise tumours to existing chemo- and radiotherapy treatments. In this study the distribution of AQ4N and AQ4 in treated H460 human tumour xenografts has been examined by imaging matrix-assisted laser desorption/ionisation mass spectrometry. Images of the distribution of AQ4N and AQ4 have been produced that show little overlap. The distribution of ATP in the tumour xenografts was also studied as an endogenous marker of regions of hypoxia since concentrations of ATP are known to be decreased in these regions. The distribution of ATP was similar to that of AQ4N, i.e. in regions of abundant ATP there was no evidence of conversion of AQ4N into AQ4. This indicates that the cytotoxic metabolite AQ4 is confined to hypoxic regions of the tumour as intended.


The Rayleigh Color Matches in Idiopathic Macular Holes Treated by Vitrectomy.
Purpose: The Rayleigh color matches were measured to investigate the optical density in the cone photopigment of the central retina in patients with macular holes that had closed after vitrectomy.Methods: The Rayleigh equation was measured with the IF-2 anomaloscope in 7 patients with macular holes in one eye, that had closed after vitrectomy and gained an improvement in visual acuity of 0.5 or better. Reductions in the pigment optical density of cone photoreceptors of the opposite eyes were estimated with Rayleigh equations obtained in this experiment.Result: The Rayleigh equations of the affected eyes were shifted toward protanomalous setting compared with that of the opposite eyes. The optical densities of cone photoreceptors of the affected eyes were lower than those in the opposite eyes, even in patients with visual acuity of 1.0 or better.Conclusion: These findings suggest that the recovery of the visual acuity may precede that of the optical density in cone photopigment of central retina. The Rayleigh equation is more sensitive than visual acuity for evaluating visual function after vitrectomy for macular holes.


A novel anticonvulsant modulates voltage-gated sodium channel inactivation and prevents kindling-induced seizures.
Here, we explore the mechanism of action of isoxylitone (ISOX), a molecule discovered in the plant Delphinium denudatum, which has been shown to have anticonvulsant properties. Patch-clamp electrophysiology assayed the activity of ISOX on voltage-gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy(kindling model). Quantitative transcription polymerase chain reaction (qRT-PCR) (QPCR) assessed brain-derived neurotrophic factor (BDNF) mRNA expression in kindled rats, and kindled rats treated with ISOX. ISOX suppressed sodium current (I(Na)) showing an IC50 value of 185 nM in cultured neurons. ISOX significantly slowed the recovery from inactivation (ISOX τ = 18.7 ms; Control τ = 9.4 ms; p < 0.001). ISOX also enhanced the development of inactivation by shifting the Boltzmann curve to more hyperpolarized potentials by -11.2 mV (p < 0.05). In naive and electrically kindled cortical neurons, the IC50 for sodium current block was identical to that found in cultured neurons. ISOX prevented kindled stage 5 seizures and decreased the enhanced BDNF mRNA expression that is normally associated with kindling (p < 0.05). Overall, our data show that ISOX is a potent inhibitor of VGSCs that stabilizes steady-state inactivation while slowing recovery and enhancing inactivation development. Like many other sodium channel blocker anti-epileptic drugs, the suppression of BDNF mRNA expression that usually occurs with kindling is likely a secondary outcome that nevertheless would suppress epileptogenesis. These data show a new class of anti-seizure compound that inhibits sodium channel function and prevents the development of epileptic seizures.


[Cytogenetic study of a recent case of trisomy 12p].
A case of trisomy for the short arm and a part of the long arm of chromosome 12 is reported. Before the pregnancy sterility was noted during several years. Birth weight was normal; the newborn with multiple congenital defects died before the 4th day. Her mother, grandmother, and two brothers of the latter showed a balanced translocation t (5 ; 12) (p15 ; q132). The affected child inherited the derived 12 as a 47th chromosome.


Salivary glucosyltransferase B as a possible marker for caries activity.
Bacteria-derived glucosyltransferases (Gtf) (EC 188.8.131.52), through synthesizing glucan polymers from sucrose and starch hydrolysates, play an essential role in the etiology and pathogenesis of caries. We attempted to correlate the levels of Gtf in whole saliva with the prevalence of carious lesions in young children. We examined saliva from children who were either free of overt carious lesions, or had severe early childhood caries (mean dmfs = 18.72 +/- 9.0 SD), for Gtf by direct enzyme assay. The levels of GtfB, GtfC and GtfD from Streptococcus mutans in the saliva using monoclonal/specific antibodies in an enzyme-linked immunosorbent assay were determined. Multiple logistic regression analyses with model selection showed that GtfB levels correlated with dmfs values of the subjects (p = 0.006). There was no correlation between total Gtf activity as measured by direct enzyme assay and dmfs values. There was a strong correlation between mutans streptococci populations in saliva and caries activity. Collectively, these data show that GtfB levels in saliva correlate strongly with presence of clinical caries and with number of carious lesions in young children. It is also possible to measure different Gtfs, separately, in whole saliva. These observations may have important clinical implications, may lead to development of a chair side caries activity test and support the importance of GtfB in the pathogenesis of dental caries.


Interference of fetal hemoglobin with the spectrophotometric measurement of carboxyhemoglobin.
We measured the concentration of carboxyhemoglobin (HbCO) in blood samples from 32 neonates by spectrophotometry (IL282 CO-Oximeter) and gas chromatography, finding a strong positive correlation (r = 0.89) between the concentration of fetal hemoglobin (Hb F) and HbCO as measured by spectrophotometry, but not by gas chromatography. Thus, Hb F interferes with the determination of HbCO by spectrophotometric techniques by falsely increasing apparent HbCO in direct proportion to Hb F. We conclude that, when Hb F is known or suspected to be present, blood HbCO cannot be reliably determined by methods based on spectrophotometry.


Effects of aerobic and anaerobic shock on catabolite repression in cyclic AMP suppressor mutants of Escherichia coli.
Cultures of Escherichia coli K-12 grown on glucose or gluconate under aerobic conditions exhibited catabolite repression of beta-galactosidase synthesis. Depression occurred when these cultures were subjected to anaerobic shock. These states of repression and depression were found to be associated with low and high differential rates of cyclic AMP synthesis, respectively. This observation is consistent with the view that cyclic AMP plays a central role in the catabolite repression phenomenon. We report here, however, that identical stages of repression and derepression occur in mutant strains possessing cya crp(Csm) genotypes and therefore unable to synthesize cyclic AMP. These results suggest that cyclic AMP is not the sole regulator involved in catabolite repression.