Social cognition by food-caching corvids. The western scrub-jay as a natural psychologist.
Food-caching corvids hide food, but such caches are susceptible to pilfering by other individuals. Consequently, the birds use several counter strategies to protect their caches from theft, e.g. hiding most of them out of sight. When observed by potential pilferers at the time of caching, experienced jays that have been thieves themselves, take further protective action. Once the potential pilferers have left, they move caches those birds have seen, re-hiding them in new places. Naive birds that had no thieving experience do not do so. By focusing on the counter strategies of the cacher when previously observed by a potential pilferer, these results raise the intriguing possibility that re-caching is based on a form of mental attribution, namely the simulation of another bird's viewpoint. Furthermore, the jays also keep track of the observer which was watching when they cached and take protective action accordingly, thus suggesting that they may also be aware of others' knowledge states.


Clinical studies on ampicillin-cloxacillin for intravenous injection (Rectocillin 'Kyowa') (author's transl).
(1) Ampicillin-cloxacillin for intravenous injection (Rectocillin 'Kyowa') was administered to 9 patients 1 g or 2 g daily for protection of postoperative infections, and good result was obtained in all cases. Eight out of 9 cases were with renal insufficiency. No side effect was encountered. (2) Rectocillin was administered to 14 patients with infections. The treatment was remarkably effective in 4 cases, and effective in 6 cases. In the cases with renal insufficiency, a daily dose of 1 g was effective. The dose administered to the patients with normal renal function was 2 g or 4 g daily. Neither clinical nor laboratory findings showed evidence of side effect.


[Roentgenoendoscopic therapy of ureteral injuries after obstetric-gynecological surgery].
Ureteral injuries as a complication of obstetric-gynecological operations occur in 0.37% of cases and are accompanied by formation of stricture or ureteral obliteration, development of uretero-vaginal fistula. Roentgenoendoscopic technologies offer a new solution of the problem of restoration of ureteral passability and elimination of urogenital fistulas. Roentgenoendoscopic treatment of ureteral injuries was made in 14 patients: for obliteration of the lower third of the ureter in 5 cases, stricture of the lower third of the ureter in 9 cases, stricture in combination with uretero-vaginal fistula. The length of the injury varied from 0.2 to 1.5 cm (mean--0.6 cm). Two patients have undergone optic buerginage of ureteral stricture followed by balloon dilation, 7 patients--optic endoureterotomy, 5--ureteral recanalization. Three patients with ureterovaginal fistulas had one-stage fistula fulguration. The operations finished with internal stenting for 6-18 weeks. Normal urine passage recovered in 12 of 14 (85.7%) patients. The fistula disappeared in 3 patients. Thus, roentgenoendoscopic treatment of ureteral injuries after obstetric-gynecological surgery produce positive results in most cases and raises quality of the patients' life.


[Effect of the low frequency physical factors on seeds].
The influence of weak low frequency (50 Hz-10 kHz) physical factors: sound, alternating electric current and impulse light on the germination and root growth rate of barley corns was estimated. Several mechanisms of this effect were proposed: change in penetration of membranes, in enzymes and microflora activity. The dependence between the germination activity of corn and the frequency was represented in the form of universal curve--"Low Frequency Activity Spectrum".


Corpus callosum in Alzheimer's disease and vascular dementia--a quantitative magnetic resonance study.
We investigated atrophic alterations in different regions of the corpus callosum in Alzheimer's disease (AD) and vascular dementia (VD) with respect to clinical changes. 32 patients with AD (NINCDS-ADRDA criteria), 17 patients with VD (NINDS-AIREN criteria) and 13 healthy control subjects were included. 3-D MRI sequences were acquired using a 1.5T MRI scanner. The size of the corpus callosum and its subdivisions was sampled on 5 mid-saggital slices using a personal computer-based software. Total callosal size was significantly reduced in AD but not in VD. Furthermore, the most rostral parts of the corpus callosum were significantly smaller in AD when compared to controls. Again, these changes were not found in patients with VD. Severity of dementia was significantly correlated with the size of the midbody of the corpus callosum in AD. Callosal atrophy in AD may reflect the severity and pattern of cortical neuronal damage occurring mostly in the inferior frontal, anterior parietal and midtemporal regions. Correlations between regional callosal atrophy and severity of dementia indicate that interhemispheric cortico-cortical disconnections may contribute to the dementia syndrome.


Diagnostic, treatment, and reporting criteria for non-specific genital infection in sexually transmitted disease clinics in England and Wales. 1: Diagnosis.
The current methods of diagnosis for non-specific genital infection (NSGI) in clinics in England and Wales are described. In most clinics (92%) microscopical findings were used by consultants to establish the diagnosis of non-specific urethritis (NSU) in male patients. However, the microscopical criteria that they used in reaching a diagnosis varied between clinics. The most commonly applied criterion was that of less than five leucocytes per high power field. NSGI in female patients and non-specific proctitis in passive homosexuals were recognised as distincy in 60% of clinics and the latter in 57%. Among those who recognised these conditions the diagnostic criteria varied. The establishment of acceptable and uniform criteria for diagnosis are discussed.


Stochastic dispersal increases the rate of upstream spread: A case study with green crabs on the northwest Atlantic coast.
Dispersal heterogeneity is an important process that can compensate for downstream advection, enabling aquatic organisms to persist or spread upstream. Our main focus was the effect of year-to-year variation in larval dispersal on invasion spread rate. We used the green crab, Carcinus maenas, as a case study. This species was first introduced over 200 years ago to the east coast of North America, and once established has maintained a relatively consistent spread rate against the dominant current. We used a stage-structured, integro-difference equation model that couples a demographic matrix for population growth and dispersal kernels for spread of individuals within a season. The kernel describing larval dispersal, the main dispersive stage, was mechanistically modeled to include both drift and settlement rate components. It was parameterized using a 3-dimensional hydrodynamic model of the Gulf of St Lawrence, which enabled us to incorporate larval behavior, namely vertical swimming. Dispersal heterogeneity was modeled at two temporal scales: within the larval period (months) and over the adult lifespan (years). The kernel models variation within the larval period. To model the variation among years, we allowed the kernel parameters to vary by year. Results indicated that when dispersal parameters vary with time, knowledge of the time-averaged dispersal process is insufficient for determining the upstream spread rate of the population. Rather upstream spread is possible over a number of years when incorporating the yearly variation, even when there are only a few "good years" featured by some upstream dispersal among many "bad years" featured by only downstream dispersal. Accounting for annual variations in dispersal in population models is important to enhance understanding of spatial dynamics and population spread rates. Our developed model also provides a good platform to link the modeling of larval behavior and demography to large-scale hydrodynamic models.


Exploring a new frontier in cancer treatment: targeting the ubiquitin and ubiquitin-like activating enzymes.
The labeling of proteins with small ubiquitin (Ub) and ubiquitin-like (Ubl) modifiers regulates a plethora of activities within the cell, such as protein recycling, cell cycle modifications, and protein translocation. These processes are often overactive in diseased cells, leading to unregulated cell growth and disease progression. Therefore, in systems where Ub/Ubl protein labeling is dysregulated, the development of drugs to selectively and potently disrupt Ub/Ubl protein labeling offers a targeted molecular approach for sensitizing these diseased cells. This Perspective outlines the progress that has been made in the context of inhibitor development for targeting Ub/Ubl pathways.


Quantitative anatomy of the primary ossification center of the squamous part of temporal bone in the human fetus.
Detailed numerical data about the development of primary ossification centers in human fetuses may influence both better evaluation and early detection of skeletal dysplasias, which are associated with delayed development and mineralization of ossification centers. To the best of our knowledge, this is the first report in the medical literature to morphometrically analyze the primary ossification center of the squamous part of temporal bone in human fetuses based on computed tomography imaging. The present study offers a precise quantitative foundation for ossification of the squamous part of temporal bone that may contribute to enhanced prenatal care and improved outcomes for fetuses with inherited cranial defects and skeletodysplasias. The examinations were carried out on 37 human fetuses of both sexes (16 males and 21 females) aged 18-30 weeks of gestation, which had been preserved in 10% neutral formalin solution. Using CT, digital image analysis software, 3D reconstruction and statistical methods, the size of the primary ossification center of the squamous part of temporal bone was evaluated. With neither sex nor laterality differences, the best-fit growth patterns for the primary ossification center of the squamous part of temporal bone was modelled by the linear function: y = -0.7270 + 0.7682 × age ± 1.256 for its vertical diameter, and the four-degree polynomial functions: y = 5.434 + 0.000019 × (age)4 ± 1.617 for its sagittal diameter, y = -4.086 + 0.00029 × (age)4 ± 2.230 for its projection surface area and y = -25.213 + 0.0004 × (age)4 ± 3.563 for its volume. The CT-based numerical data and growth patterns of the primary ossification center of the squamous part of temporal bone may serve as age-specific normative intervals of relevance for gynecologists, obstetricians, pediatricians and radiologists during screening ultrasound scans of fetuses. Our findings for the growing primary ossification center of the squamous part of temporal bone may be conducive in daily clinical practice, while ultrasonically monitoring normal fetal growth and screening for inherited cranial faults and skeletodysplasias.


Garcinol and Related Polyisoprenylated Benzophenones as Topoisomerase II Inhibitors: Biochemical and Molecular Modeling Studies.
Garcinol, a polyisoprenylated benzophenone isolated from Garcinia genus, has been reported to inhibit eukaryotic topoisomerase I and topoisomerase II at concentrations comparable to that of etoposide (∼25-100 μM). With the aim to clarify the underlying molecular mechanisms by which garcinol inhibits human topoisomerase IIα and topoisomerase IIβ, biochemical assays along with molecular docking and molecular dynamics studies were carried out on garcinol and six congeners. The biochemical results revealed that garcinol derivatives appear to act as catalytic inhibitors of topoisomerase II and to inhibit ATP hydrolysis by topoisomerase II via some form of mixed inhibition. The computational investigation identified the structural elements responsible for binding to the biological target and also provided information for the eventual design of more selective and potent analogues. Collectively, our data suggest that garcinol-type agents may bind to the DNA binding surface and/or ATP domain of type II topoisomerases to antagonize function.


Framework towards more Sustainable Chemical Synthesis Design - A Case Study of Organophosphates.
In recent years, the advancement of sustainable chemistry concepts and approaches along with their demonstrated application has become a central part of the design, synthesis, and manufacture of a chemical. Sustainable chemistry not only utilizes the principles of green chemistry, but also expands to incorporate economic, societal, and environmental aspects. This is further elucidated by the incorporation of life cycle assessment/thinking to include the raw material production, manufacture, processing, and use and disposal stages, allowing for a comprehensive evaluation of the environmental and human health impacts attributed to a chemical. This contribution outlines an approach for the development of a preliminary framework for the sustainable synthesis of a chemical that is identified as an alternative for an existing chemical of concern. The framework is introduced concurrently with a case study for organophosphates that are selected as potential replacements for brominated flame retardants (BFRs). This framework is designed to apply existing knowledge of green chemistry to the synthesis of alternatives, along with its integration into Life Cycle Assessment culminating in the development of a more overall sustainable chemical entity when compared to its predecessor.


DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: call for a drug label update.
The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and gastric cancer. In the current drug labels of 5-FU and capecitabine in the European Union and the United States, no adaptive dosing strategies are incorporated for polymorphic metabolism of 5-FU. Although treatment with fluoropyrimidines is generally well tolerated, a major clinical limitation is that a proportion of the treated population experiences severe, sometimes life-threatening, fluoropyrimidine-related toxicity. This toxicity is strongly affected by interindividual variability in activity of dihydropyrimidine dehydrogenase (DPD), the main metabolic enzyme for inactivation of fluoropyrimidines, with an estimated 3%-8% of the population being partially DPD deficient. A reduced functional or abrogated DPD enzyme is often caused by genetic polymorphisms in DPYD, the gene encoding for DPD, and heterozygous carriers of such DPYD polymorphisms have a partial DPD deficiency. When these partially DPD deficient patients are treated with a full dose of fluoropyrimidines, they are generally exposed to toxic levels of 5-FU and its metabolites, and the risk of developing severe treatment-related toxicity is therefore significantly increased.Currently, functional and clinical validity is well established for four DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A), as those variants have retrospectively and in a large population study prospectively been shown to be associated with increased risk of fluoropyrimidine-associated toxicity. Patient safety of fluoropyrimidine treatment can be significantly improved by pre-emptive screening for DPYD genotype variants and dose reductions in heterozygous DPYD variant allele carriers, thereby normalizing 5-FU exposure. Based on the critical appraisal of currently available data, adjusting the labels of capecitabine and 5-FU by including recommendations on pre-emptive screening for DPYD variants and DPYD genotype-guided dose adjustments should be the new standard of care.


Development and evaluation of a coculture technique for identification of anaerobic organisms.
We investigated a method to reduce oxygen tension and produce anaerobic conditions conveniently by coculture with a nonfermentative organism. The biochemical reactions of 94 strains representing 41 different species were determined using prereduced media and gas chromatography according to standard methods. The standard reactions were compared with those obtained by preparing similar media, modified by containing no cysteine or resazurin, under aerobic conditions. Preincubation of the modified biochemical media with a standard suspension of a culture of Acinetobacter lwoffi provided reducing conditions. In 1,449 individual tests using 22 different biochemicals, 1,349 (93%) of the reactions agreed. Only two misidentifications resulted when using the modified media, one each at the species and genus levels. Two strains of Actinomyces odontolyticus failed to grow in coculture.


Epidemiology of shoulder impingement in upper arm sports events.
An epidemiological survey was conducted to collect data relating to the prevalence and frequency of shoulder pain and other related problems among different athletic groups that demanded vigorous upper arm activities. A questionnaire was administered on site thus ensuring that the response rate was 100 percent. Analysis of results revealed that of the 372 respondents there were 242 male (65.1 percent) and 130 female subjects (34.9 percent), with seven (1.9 percent) above the age of 40, 119 (32 percent) between the ages of 25 and 40, and 246 (66.1 percent) below 25 years of age. A total of 163 athletes (43.8 percent) indicated that they had shoulder problems, 109 (29 percent) suffering pain. Diffuse pain was indicated by 20 respondents (5.4 percent), while localized pain during movement was reported in 89 (23.9 percent). The prevalence of shoulder pain ranked highest among volley ball players (N = 28) followed by swimmers (N = 22), while badminton, basketball and tennis participants were equally affected (N = 10).


Compound identification using partial and semipartial correlations for gas chromatography-mass spectrometry data.
Compound identification is a key component of data analysis in the applications of gas chromatography-mass spectrometry (GC-MS). Currently, the most widely used compound identification is mass spectrum matching, in which the dot product and its composite version are employed as spectral similarity measures. Several forms of transformations for fragment ion intensities have also been proposed to increase the accuracy of compound identification. In this study, we introduced partial and semipartial correlations as mass spectral similarity measures and applied them to identify compounds along with different transformations of peak intensity. The mixture versions of the proposed method were also developed to further improve the accuracy of compound identification. To demonstrate the performance of the proposed spectral similarity measures, the National Institute of Standards and Technology (NIST) mass spectral library and replicate spectral library were used as the reference library and the query spectra, respectively. Identification results showed that the mixture partial and semipartial correlations always outperform both the dot product and its composite measure. The mixture similarity with semipartial correlation has the highest accuracy of 84.6% in compound identification with a transformation of (0.53,1.3) for fragment ion intensity and m/z value, respectively.


Establishment of a Robust and Simple Corneal Organ Culture Model to Monitor Wound Healing.
The use of in vitro systems to investigate the process of corneal wound healing offers the opportunity to reduce animal pain inflicted during in vivo experimentation. This study aimed to establish an easy-to-handle ex vivo organ culture model with porcine corneas for the evaluation and modulation of epithelial wound healing. Cultured free-floating cornea disks with a punch defect were observed by stereomicroscopic photo documentation. We analysed the effects of different cell culture media and investigated the impact of different wound sizes as well as the role of the limbus. Modulation of the wound healing process was carried out with the cytostatic agent Mitomycin C. The wound area calculation revealed that after three days over 90% of the lesion was healed. As analysed with TUNEL and lactate dehydrogenase assay, the culture conditions were cell protecting and preserved the viability of the corneal tissue. Wound healing rates differ dependent on the culture medium used. Mitomycin C hampered wound healing in a concentration-dependent manner. The porcine cornea ex vivo culture ideally mimics the in vivo situation and allows investigations of cellular behaviour in the course of wound healing. The effect of substances can be studied, as we have documented for a mitosis inhibitor. This model might aid in toxicological studies as well as in the evaluation of drug efficacy and could offer a platform for therapeutic approaches based on regenerative medicine.


Abnormal supranuclear eye movements in the child: a practical guide to examination and interpretation.
Abnormal eye movements in the infant or voting child can be congenital or acquired. They may be a result of abnormal early visual development or a sign of underlying neurologic or neuromuscular disease. It is important to be able to detect these abnormalities and to distinguish them from normal but immature eye movements. The spectrum of disease in children differs from that in adults. Serious, potentially fatal but treatable disorders can be acquired in infancy, and abnormal eye movements in a sometimes apparently well child should never be labeled as congenital or benign without careful investigation. Eye movement analysis can indicate the presence of an underlying condition and help the clinician to classify different neurologic diseases. It is important to carefully examine the ocular motor system in any children at risk of neurologic disease. This review provides a practical guide to the examination and interpretation of eye movements in the child and includes recent literature on eye movement disorders of childhood. We describe supranuclear abnormalities of the ocular motor system in the order in which we would normally examine it: saccades, pursuit, convergence, vestibulo-ocular reflex, and optokinetic nystagmus. Nystagmus, internuclear ophthalmoplegia, cranial nerve abnormalities, and "miswiring" phenomena (such as Duane's syndrome and synergistic divergence) are not discussed.


Simultaneous analysis of classical neuroleptics, atypical antipsychotics and their metabolites in human plasma.
A high-performance liquid chromatographic method has been developed for the simultaneous determination of classical neuroleptics (chlorpromazine, haloperidol, loxapine and clotiapine), atypical antipsychotics (clozapine, quetiapine and risperidone) and their active metabolites (N-desmethylclozapine, clozapine N-oxide and 9-hydroxyrisperidone) in human plasma. Separation was obtained by using a C8 reversed-phase column and a mobile phase composed of 70% aqueous phosphate buffer containing triethylamine at pH 3.0 and 30% acetonitrile. The UV detector was set at 238 nm and amitriptyline was used as the internal standard. A careful pre-treatment procedure of plasma samples was developed, using solid-phase extraction with cyanopropyl cartridges, which gives high extraction yields (>or=93%). The limits of quantitation (LOQ) were always lower than 2.6 ng mL-1 and the limits of detection (LOD) were always lower than 0.9 ng mL-1 for all analytes. The method was applied with success to plasma samples from schizophrenic patients undergoing polypharmacy with two or more different antipsychotics. Precision data and accuracy results were satisfactory and no interference from other central nervous system (CNS) drugs was found. Hence the method is suitable for the therapeutic drug monitoring (TDM) of the analytes in psychotic patients' plasma.


Is Metal-On-Metal Total Hip Arthroplasty Associated With Neurotoxicity?
Isolated case reports in the literature describe systemic neurologic side effects associated with metal-on-metal (MOM) bearing surfaces, yet the incidence of these effects have not been evaluated beyond individual cases. The purpose of this study was to compare new diagnoses of these side effects described in isolated cases in large patient cohorts of MOM vs metal on polyethylene (MOP). We queried the entire Medicare database from 2005 to 2012. Total hip arthroplasty (THA) and bearing surface were determined using International Classification of Diseases, 9th revision procedure codes. Patients with 5-year follow-up were selected. Using International Classification of Diseases, 9th revision codes, we identified new diagnoses of previously reported neurologic side effects: peripheral neuropathy, sensorineural hearing loss, visual impairment, paresthesias, tinnitus, and vertigo. Comorbidities and demographics were collected. Odds ratios, CIs, and P values were calculated. Overall, 29,483 MOM THAs and 23,587 age- and gender-matched MOP THAs were identified. The average Charlson Comorbidity Index was 5 for both groups. MOM and MOP patients had 26 of 30 identical prevalence of Elixhauser-measure comorbidities. There was no statistically significant difference in new diagnoses of any of the side effects at any time point between the 2 groups over 5 years. This study represents, to our knowledge, the first longitudinal analysis of systemic neurotoxicity after THA in a large cohort of patients. The results of our study suggest that on the large scale, neurologic side effects previously described do not occur as a common attributable complication. Rather, these cases may be due to individual patient hypersensitivity to metal ions.


Spinal deformities in patients with spinal muscle atrophy: a review of 36 patients.
Thirty-six patients diagnosed as having spinal muscle atrophy were reviewed. The process was usually recognized in infancy, and spinal deformity commonly developed by age 6, kyphosis developed before age 3, and scoliosis or kyphoscoliosis thereafter. Orthotics may slow progression in most cases, but very young patients must be carefully monitored for chest-wall deformity. Surgery was utilized to stabilize orthotically uncontrollable curves, orthotically controlled curves after maturation, and the severely involved when risks were acceptable. Complications were noted in older or more deformed patients and less frequently in younger, less involved ones. A stabilized spine with head centered over pelvis was usually achieved.


Biportal Endoscopic Lumbar Decompression for Lumbar Disk Herniation and Spinal Canal Stenosis: A Technical Note.
Background and Study Aims Endoscopic lumbar diskectomy through the interlaminar window is gaining recognition. Most of the literature describes these endoscopic procedures using specialized uniportal multichannel endoscopes. However, a single portal limits the motion of the instruments and obscures visualization of the operating field. To overcome this limitation, we propose a new technique that utilizes two portals to access the spinal canal. The biportal endoscopic lumbar decompression (BELD) technique uses two portals to treat difficult lumbar disk herniations and also lumbar spinal stenoses. Patients and Methods Seventeen patients were treated with BELD for 11 lumbar disk herniations and 6 lumbar spinal stenoses. Preoperative back and leg visual analog scale (VAS-B and VAS-L, respectively) scores and the Oswestry Disability Index (ODI) were recorded and compared with corresponding values on final follow-up. Results There was an average follow-up of 14 months. For the disk herniation group, preoperative VAS-L (7.8750 ± 1.24) and ODI (51.73 ± 18.57) was significantly different from follow-up postoperative VAS-L (0.87 ± 0.64, p = 0.000) and ODI (9.37 ± 4.83, p = 0.001). For the stenosis group, preoperative VAS-B (6.17 ± 1.94), VAS-L(7.83 ± 1.47), and ODI (63.27 ± 7.67) were significantly different from follow-up postoperative values (2.5 ± 1.04, p = 0.022; 2.00 ± 1.67, p = 0.001; 24.00 ± 6.45, p = 0.000, respectively). One patient underwent revision microdiskectomy for incomplete decompression. Conclusions BELD can achieve a similar decompression effect as microdiskectomy and unilateral laminotomy for bilateral decompression with a smaller incision than tubular diskectomy.


The tree shrew as a model for infectious diseases research.
Despite major advances in medicine, infectious diseases still pose a significant threat to humanity. Mammalian models of disease have proved extremely useful in adding to the understanding of infectious diseases and the development of prophylactic and/or therapeutic interventions. Arguably the most important considerations of any animal model are (I) the similarity of the model to humans with respect to anatomy, physiology, immunology and disease progression, and (II) the expense of conducting experiments using the model organism. Often the choice of a model represents a compromise between these factors. Here we review the Northern Tree shrew (Tupaia belangeri), or tupaia, as a useful model for the study of infectious diseases. Tupaias are non-human primates similar in size to squirrels that are indigenous to Asia. Their genome has been sequenced and, overall, shows relatively high similarity to humans. There is also a close homology of many aspects of tupaia biology with human biology. Importantly, from an infectious diseases viewpoint, tupaias are susceptible to infection with unadapted human pathogens and manifest clinical signs akin to human infections. Overall, the relatively small size of the tupaia, their homology to humans and their susceptibility to human pathogens make them a useful model for the study of infectious diseases.


Implicit memory in amnesic patients: when is auditory priming spared?
Amnesic patients often exhibit spared priming effects on implicit memory tests despite poor explicit memory. In previous research, we found normal auditory priming in amnesic patients on a task in which the magnitude of priming in control subjects was independent of whether speaker's voice was same or different at study and test, and found impaired voice-specific priming on a task in which priming in control subjects is higher when speaker's voice is the same at study and test than when it is different. The present experiments provide further evidence of spared auditory priming in amnesia, demonstrate that normal priming effects are not an artifact of low levels of baseline performance, and provide suggestive evidence that amnesic patients can exhibit voice-specific priming when experimental conditions do not require them to interactively bind together word and voice information.


Monte Carlo-based inverse treatment planning.
A Monte Carlo based inverse treatment planning system (MCI) has been developed which combines arguably the most accurate dose calculation method (Monte Carlo particle transport) with a 'guaranteed' optimization method (simulated annealing). A distribution of photons is specified in the tumour volume; they are transported using an adjoint calculation method to outside the patient surface to build up an intensity distribution. This intensity distribution is used as the initial input into an optimization algorithm. The dose distribution from each beam element from a number of fields is pre-calculated using Monte Carlo transport. Simulated annealing optimization is then used to find the weighting of each beam element, to yield the optimal dose distribution for the given criteria and constraints. MCI plans have been generated in various theoretical phantoms and patient geometries. These plans show conformation of the dose to the target volume and avoidance of critical structures. To verify the code, an experiment was performed on an anthropomorphic phantom.


Leveraging single-cell RNA sequencing to unravel the impact of aging on stroke recovery mechanisms in mice.
Aging compromises the repair and regrowth of brain vasculature and white matter during stroke recovery, but the underlying mechanisms remain elusive. To understand how aging jeopardizes brain tissue repair after stroke, we performed single-cell transcriptomic profiling of young adult and aged mouse brains at acute (3 d) and chronic (14 d) stages after ischemic injury, focusing a priori on the expression of angiogenesis- and oligodendrogenesis-related genes. We identified unique subsets of endothelial cells (ECs) and oligodendrocyte (OL) progenitors in proangiogenesis and pro-oligodendrogenesis phenotypic states 3 d after stroke in young mice. However, this early prorepair transcriptomic reprogramming was negligible in aged stroke mice, consistent with the impairment of angiogenesis and oligodendrogenesis observed during the chronic injury stages after ischemia. In the stroke brain, microglia and macrophages (MG/MΦ) may drive angiogenesis and oligodendrogenesis through a paracrine mechanism. However, this reparative cell-cell cross talk between MG/MΦ and ECs or OLs is impeded in aged brains. In support of these findings, permanent depletion of MG/MΦ via antagonism of the colony-stimulating factor 1 receptor resulted in remarkably poor neurological recovery and loss of poststroke angiogenesis and oligodendrogenesis. Finally, transplantation of MG/MΦ from young, but not aged, mouse brains into the cerebral cortices of aged stroke mice partially restored angiogenesis and oligodendrogenesis and rejuvenated sensorimotor function and spatial learning and memory. Together, these data reveal fundamental mechanisms underlying the age-related decay in brain repair and highlight MG/MΦ as effective targets for promoting stroke recovery.


[Clinical observation on 112 cases with non-Hodgkin's lymphoma treated by Chinese herbs combined with chemotherapy].
To seek for the effective therapeutical method in treating non-Hodgkin's lymphoma (NHL). One hundred and sixty seven patients with non-Hodgkin's lymphoma were randomly divided into two groups, the treatment group, which consisted of 112 cases using Chinese herbs combined with chemotherapy and 55 cases of control group were treated by chemotherapy only. The effective rate (CR + PR) in the combined group was 91.96% and survival rates of 1-, 3- and 5-year were 85.7%, 54.5% and 29.5% respectively, and median survival time was 554 days. In control group the effective rate was 72.73% and 1-, 3- and 5-year survival rates were 76.4%, 38.2% and 18.2% respectively, and the median survival time was 465 days. The difference of effective rates or 3-year survival rates between two groups was significant (P < 0.05). In the combined group the activity of NK cell, OKT3, OKT4 and ratio of OKT4/OKT8 were obviously raised after treatment (P < 0.01). And the level of platelet adhesion rate and the blood viscosity markedly decreased (P < 0.01), but in the control group the values of these indexes did not distinctly change. Chinese herbs could enhance the immunologic function and improve the viscosity of blood of the patients with NHL. The side effect in the combination therapy group was less and milder than that in the chemotherapy group. These showed that Chinese herbs combined with chemotherapy was a safe and effective method for treating NHL and deserve to be recommended.


Breathing helium-hyperoxia and tolerance of partitioned exercise in patients with COPD.
Partitioning exercise by 1-legged cycling is more effective than conventional training in patients with chronic obstructive pulmonary disease. Similarly, inhaling helium-hyperoxia can extend conventional exercise tolerance. This study aimed to determine whether breathing helium-hyperoxia could increase the tolerance of a high-intensity exercise session achieved by 1-legged cycling. Participants completed 2 high-intensity, constant power, 1-legged cycle tests to intolerance (tlimit). In a randomized order, they inspired 40% oxygen with the balance helium via mask and 1-way valve, 1-legged helium-hyperoxia (1L-HH), or room air with supplemental oxygen via a nasal cannula, 1-legged nitrogen-hyperoxia (1L-NH). We assessed quadriceps fatigue from the change in maximal voluntary contraction (FMVC) and transcutaneously stimulated twitch force (Ftwitch). Fifteen participants (forced expiratory volume in 1 second [SD] = 36 [18]% predicted; forced expiratory volume in 1 second/forced vital capacity = 34 [14]%; peak oxygen uptake = 12.8 [2.9] mL · kg · min) completed the study. Self-reported "leg fatigue" was a reason for stopping 25 of 30 tests. There was no significant difference in tlimit (0.2 [-1.4 to 1.8] min) between 1L-HH (12.2 [5.2] min) and 1L-NH (12.0 [4.1] min), or in FMVC measured shortly after HH and NH tests (P= .09). The Ftwitch was less after exercise (P< .05) in both conditions, without a difference between conditions (P= .46). Inspiring a helium-hyperoxia mixture does not increase the endurance of what would be a typical training session, breathing supplemental oxygen, of high-intensity 1-legged constant power exercise. Leg muscle fatigue was similar after 1-legged exercise with and without breathing the helium mixture.


Sexual selection on morphological and physiological traits and fluctuating asymmetry in the yellow dung fly.
Previous univariate studies of the yellow dung fly (Scathophaga stercoraria) have demonstrated strong sexual selection, in terms of mating success, on male size (estimated as hind tibia length). To identify specific target(s) of selection on body size and possible conflicting selection pressures on particular body parts, two multivariate field studies of sexual selection were conducted. In one study using point samples from three populations, we assessed several morphological traits, including genital traits and measures of fluctuating asymmetry (FA) of all paired traits. There was sexual selection for large male size in general, confirming previous, univariate studies. With the possible exception of thorax width, which was selected in the opposite direction, no main target of selection was identified, as most morphological traits were highly correlated. There was no detectable sexual selection on the male external genital structures assessed. In a second study using multiple samples from one population, we included physiological measures of energy reserves (lipids, glucose and glycogen) known to affect mating success, in addition to trait size and FA of wings and legs. Inclusion of physiological traits is rare in phenomenological studies of selection. This study again confirmed the mating advantage of large males, and additionally showed independent positive influences of lipid and glucose but not glycogen levels. FA in paired traits generally did not affect male mating success, but was negatively correlated with energy reserves. Our study suggests that inclusion of physiological measures and genital traits in phenomenological studies of selection would be fruitful in other species.


Self-criticism is a key predictor of eating disorder dimensions among inpatient adolescent females.
Although the unipolar depression-eating disorder comorbidity is adequately documented, examination of the role of depressive personality styles in eating disorders is relatively scarce. Associations between depressive symptoms, depressive risk and resilience (i.e., dependency, self-criticism, and sense of efficacy), and eating disorder symptoms (as measured by the Eating Disorder Inventory-2) were examinedin inpatient adolescent females (N = 81). Self-criticism emerged as independent, robust, and strong predictor of eating disorder symptoms. Patients self-criticism should be targeted in psychotherapy and might serve as an obstacle for successful inpatient treatment. The role of self-derogation in eating disorders should be examined further.


Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells.
Altered metabolism in cancer cells is suspected to contribute to chemoresistance, but the precise mechanisms are unclear. Here, we show that intracellular ATP levels are a core determinant in the development of acquired cross-drug resistance of human colon cancer cells that harbor different genetic backgrounds. Drug-resistant cells were characterized by defective mitochondrial ATP production, elevated aerobic glycolysis, higher absolute levels of intracellular ATP, and enhanced HIF-1α-mediated signaling. Interestingly, direct delivery of ATP into cross-chemoresistant cells destabilized HIF-1α and inhibited glycolysis. Thus, drug-resistant cells exhibit a greater "ATP debt" defined as the extra amount of ATP needed to maintain homeostasis of survival pathways under genotoxic stress. Direct delivery of ATP was sufficient to render drug-sensitive cells drug resistant. Conversely, depleting ATP by cell treatment with an inhibitor of glycolysis, 3-bromopyruvate, was sufficient to sensitize cells cross-resistant to multiple chemotherapeutic drugs. In revealing that intracellular ATP levels are a core determinant of chemoresistance in colon cancer cells, our findings may offer a foundation for new improvements to colon cancer treatment.


Novel cardioprotection strategies for the aged heart: evidence from pre-clinical studies.
The incidence of cardiovascular disease is rising as the population ages. This has led to an increase in the need to perform cardiac surgery in older patients. However, aged hearts are particularly susceptible to reperfusion injury following periods of myocardial ischaemia that occur during cardiac surgery. Indeed, older adults experience myocardial dysfunction and reduced survival post-surgery compared to younger people and certain groups, including older women and frail older adults, are at particular risk. This highlights the need to design cardioprotective strategies specifically for the ageing heart. Cardioprotection during surgery is often accomplished by perfusing the heart with chemical arresting agents, known as cardioplegic solutions. New protective strategies have been developed and tested in animal models, where cardioplegic solutions have been modified by changing their temperature, chemical components and/or the frequency of delivery. In addition, drugs designed to activate cardioprotective mechanisms or to inhibit mechanisms involved in injury have been added to improve the efficacy of these solutions. However, most experimental studies have developed and optimized cardioplegic solutions in hearts from younger male animals. This review discusses pre-clinical models used to optimize cardioplegic solutions, with an emphasis on the few studies that have used hearts from older animals. Pharmacologic agents that have been shown to enhance the benefits of cardioplegia in younger hearts and could, in theory, protect vulnerable older hearts are also considered. We emphasize the need to conduct studies in frail older animals of both sexes to facilitate translation of laboratory-based observations to the clinic.


Investigation of carbon metabolism in "Dehalococcoides ethenogenes" strain 195 by use of isotopomer and transcriptomic analyses.
Members of the genus "Dehalococcoides" are the only known microorganisms that can completely dechlorinate tetrachloroethene and trichloroethene to the innocuous end product, ethene. This study examines the central metabolism in "Dehalococcoides ethenogenes" strain 195 via (13)C-labeled tracer experiments. Supported by the genome annotation and the transcript profile, isotopomer analysis of key metabolites clarifies ambiguities in the genome annotation and identifies an unusual biosynthetic pathway in strain 195. First, the (13)C-labeling studies revealed that strain 195 contains complete amino acid biosynthesis pathways, even though current genome annotation suggests that several of these pathways are incomplete. Second, the tricarboxylic acid cycle of strain 195 is confirmed to be branched, and the Wood-Ljungdahl carbon fixation pathway is shown to not be functionally active under our experimental conditions; rather, CO(2) is assimilated via two reactions, conversion of acetyl-coenzyme A (acetyl coenzyme A [acetyl-CoA]) to pyruvate catalyzed by pyruvate synthase (DET0724-0727) and pyruvate conversion to oxaloacetate via pyruvate carboxylase (DET0119-0120). Third, the (13)C-labeling studies also suggested that isoleucine is synthesized from acetyl-CoA and pyruvate via citramalate synthase (CimA, EC 126.96.36.199), rather than from the common pathway via threonine ammonia-lyase (EC 18.104.22.168). Finally, evidence is presented that strain 195 may contain an undocumented citrate synthase (>95% Re-type stereospecific), i.e., a novel Re-citrate synthase that is apparently different from the one recently reported in Clostridium kluyveri.


Effect of intravenous administration of d-lysergic acid diethylamide on subsequent protein synthesis in a cell-free system derived from brain.
An initiating cell-free protein synthesis system derived from brain was utilized to demonstrate that the intravenous injection of d-lysergic acid diethylamide (LSD) to rabbits induced a transient inhibition of translation following a brief stimulatory period. Subfractionation of the brain cell-free system into postribosomal supernatant (PRS) and microsome fractions demonstrated that LSD in vivo induced alterations in both of these fractions. In addition to the overall inhibition of translation in the cell-free system, differential effects were noted, i.e., greater than average relative decreases in in vitro labeling of certain brain proteins and relative increases in others. The brain proteins of molecular weights 75K and 95K, which were increased in relative labeling under conditions of LSD-induced hyperthermia, are similar in molecular weight to two of the major "heat shock" proteins reported in tissue culture systems. Injection of LSD to rabbits at 4 degrees C prevented LSD-induced hyperthermia but behavioral effects of the drug were still apparent. The overall decrease in cell-free translation was still observed but the differential labeling effects were not. LSD appeared to influence cell-free translation in the brain at two dissociable levels: (a) an overall decrease in translation that was observed even in the absence of LSD-induced hyperthermia and (b) differential labeling effects on particular proteins that were dependent on LSD-induced hyperthermia.


Evaluation of bending strength of five interdental fixation apparatuses applied to canine mandibles.
Strength in bending was determined for interdental fixation apparatuses applied to hemimandibles obtained from 24 canine cadavers. Hemimandibles were osteotomized perpendicular to the long axis between the third and fourth premolars, and segments were stabilized with 1 of 5 interdental fixation apparatuses: Erich arch bar (EAB, n = 6); Stout loop (SL, n = 6); acrylic (A, n = 6); Stout loop and acrylic (SLA, n = 24); and Erich arch bar and acrylic (EABA, n = 6). Ultimate strengths (mean +/- SEM) of EAB, SL, A, SLA, and EABA were 395 +/- 48; 523 +/- 57; 1,106 +/- 102; 1,306 +/- 156; and 2,707 +/- 504 N.m, respectively. Stiffness (mean +/- SEM) of EAB, SL, A, SLA, and EABA were 2,944 +/- 357; 6,322 +/- 2,201; 16,010 +/- 5,017; 15,777 +/- 1,026; and 27,079 +/- 5,576 N.m/radian, respectively. Yield strengths (mean +/- SEM) of EAB, SL, A, SLA, and EABA were 66 +/- 6; 264 +/- 19; 911 +/- 126; 1,114 +/- 159; and 1,855 +/- 401 N.m, respectively. There were no significant differences in acrylic weight, cross-sectional area of the acrylic, or area moment of inertia of acrylic at the osteotomy site among A, SLA, and EABA; and there were no significant differences in osteotomy surface area and area moment of inertia at the osteotomy site among all apparatuses (P > 0.05). The EABA apparatus had significantly higher mean ultimate strength, mean stiffness, and mean yield strength compared to other interdental fixation apparatuses. There were no significant differences in the mean ultimate strength, mean stiffness, or mean yield strength between EAB and SL (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Spermatogenic cycle length and spermatogenic efficiency in the gerbil (Meriones unguiculatus).
The gerbil (Meriones unguiculatus) is a rodent native of the arid regions of Mongolia and China. Because the gerbil can be easily bred in laboratory conditions, this species has been largely used as an experimental model in biomedical research. However, there is still little information concerning the testis structure and function in the gerbil. In this regard, we performed a detailed morpho-functional analysis of the gerbil testis and estimated the spermatogenic cycle length utilizing 3H-thymidine as a marker for germ cell progression during their evolution through the spermatogenic process. The stage frequencies of the XII stages characterized according to the acrosome formation and development were (I-XII) 13.8, 10.1, 8.1, 7.8, 4.0, 11.2, 7.5, 7.1, 5.9, 7.6, 8.1, and 8.9. The mean duration of each seminiferous epithelium cycle was determined to be 10.6 +/- 1.0 days and the total duration of spermatogenesis, based on 4.5 cycles, was approximately 47.5 days. The volume density of tubular and interstitial compartments was approximately 92% and 8%, respectively. Based on the volume occupied by seminiferous tubules in the testis and the tubular diameter, about 9 and 18 m of seminiferous tubules were found per testis and per gram of testis, respectively. Twelve primary spermatocytes were formed from each type A1 spermatogonia. The meiotic index was 2.8, indicating that 30% of cell loss occurs during meiosis. The number of Leydig and Sertoli cells per gram of the testis was 28 million and each Sertoli cell was able to support approximately 13 spermatids. The daily sperm production per gram of testis (spermatogenic efficiency) was 33 million. Taken together, these data indicate that, mainly due to the high seminiferous tubule volume density and Sertoli cell support capacity for germ cells, the gerbil presents high spermatogenic efficiency compared with other mammalian species already investigated. The data obtained in the present study might provide the basis for future research involving the reproductive biology in this species.


Interleukin-1 primes human mesenchymal stem cells towards an anti-inflammatory and pro-trophic phenotype in vitro.
Inflammation is a key contributor to central nervous system (CNS) injury such as stroke, and is a major target for therapeutic intervention. Effective treatments for CNS injuries are limited and applicable to only a minority of patients. Stem cell-based therapies are increasingly considered for the treatment of CNS disease, because they can be used as in-situ regulators of inflammation, and improve tissue repair and recovery. One promising option is the use of bone marrow-derived mesenchymal stem cells (MSCs), which can secrete anti-inflammatory and trophic factors, can migrate towards inflamed and injured sites or can be implanted locally. Here we tested the hypothesis that pre-treatment with inflammatory cytokines can prime MSCs towards an anti-inflammatory and pro-trophic phenotype in vitro. Human MSCs from three different donors were cultured in vitro and treated with inflammatory mediators as follows: interleukin (IL)-1α, IL-1β, tumour necrosis factor alpha (TNF-α) or interferon-γ. After 24 h of treatment, cell supernatants were analysed by ELISA for expression of granulocyte-colony stimulating factor (G-CSF), IL-10, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), IL-1 receptor antagonist (IL-1Ra) and vascular endothelial growth factor (VEGF). To confirm the anti-inflammatory potential of MSCs, immortalised mouse microglial BV2 cells were treated with bacterial lipopolysaccharide (LPS) and exposed to conditioned media (CM) of naïve or IL-1-primed MSCs, and levels of secreted microglial-derived inflammatory mediators including TNF-α, IL-10, G-CSF and IL-6 were measured by ELISA. Unstimulated MSCs constitutively expressed anti-inflammatory cytokines and trophic factors (IL-10, VEGF, BDNF, G-CSF, NGF and IL-1Ra). MSCs primed with IL-1α or IL-1β showed increased secretion of G-CSF, which was blocked by IL-1Ra. Furthermore, LPS-treated BV2 cells secreted less inflammatory and apoptotic markers, and showed increased secretion of the anti-inflammatory IL-10 in response to treatment with CM of IL-1-primed MSCs compared with CM of unprimed MSCs. Our results demonstrate that priming MSCs with IL-1 increases expression of trophic factor G-CSF through an IL-1 receptor type 1 (IL-1R1) mechanism, and induces a reduction in the secretion of inflammatory mediators in LPS-activated microglial cells. The results therefore support the potential use of preconditioning treatments of stem cells in future therapies.


Part I: Minimum Quality Threshold in Preclinical Sepsis Studies (MQTiPSS) for Study Design and Humane Modeling Endpoints.
Preclinical animal studies are mandatory before new treatments can be tested in clinical trials. However, their use in developing new therapies for sepsis has been controversial because of limitations of the models and inconsistencies with the clinical conditions. In consideration of the revised definition for clinical sepsis and septic shock (Sepsis-3), a Wiggers-Bernard Conference was held in Vienna in May 2017 to propose standardized guidelines on preclinical sepsis modeling. The participants conducted a literature review of 260 most highly cited scientific articles on sepsis models published between 2003 and 2012. The review showed, for example, that mice were used in 79% and euthanasia criteria were defined in 9% of the studies. Part I of this report details the recommendations for study design and humane modeling endpoints that should be addressed in sepsis models. The first recommendation is that survival follow-up should reflect the clinical time course of the infectious agent used in the sepsis model. Furthermore, it is recommended that therapeutic interventions should be initiated after the septic insult replicating clinical care. To define an unbiased and reproducible association between a new treatment and outcome, a randomization and blinding of treatments as well as inclusion of all methodological details in scientific publications is essential. In all preclinical sepsis studies, the high standards of animal welfare must be implemented. Therefore, development and validation of specific criteria for monitoring pain and distress, and euthanasia of septic animals, as well as the use of analgesics are recommended. A set of four considerations is also proposed to enhance translation potential of sepsis models. Relevant biological variables and comorbidities should be included in the study design and sepsis modeling should be extended to mammalian species other than rodents. In addition, the need for source control (in case of a defined infection focus) should be considered. These recommendations and considerations are proposed as "best practices" for animal models of sepsis that should be implemented.


Receiver operating characteristic (ROC) curve for medical researchers.
Sensitivity and specificity are two components that measure the inherent validity of a diagnostic test for dichotomous outcomes against a gold standard. Receiver operating characteristic (ROC) curve is the plot that depicts the trade-off between the sensitivity and (1-specificity) across a series of cut-off points when the diagnostic test is continuous or on ordinal scale (minimum 5 categories). This is an effective method for assessing the performance of a diagnostic test. The aim of this article is to provide basic conceptual framework and interpretation of ROC analysis to help medical researchers to use it effectively. ROC curve and its important components like area under the curve, sensitivity at specified specificity and vice versa, and partial area under the curve are discussed. Various other issues such as choice between parametric and non-parametric methods, biases that affect the performance of a diagnostic test, sample size for estimating the sensitivity, specificity, and area under ROC curve, and details of commonly used softwares in ROC analysis are also presented.


Nasopharyngeal endoscopic resection in the management of selected malignancies: ten-year experience.
To evaluate the feasibility of endoscopic surgery in the management of selected nasopharyngeal cancers. Three different types of nasopharyngeal endoscopic resections (NER) are described. From January 1997 to October 2008, 17 consecutive patients (mean age: 50 years) with previously untreated (5) or recurrent nasopharyngeal tumours (12) were treated with curative intent by pure endoscopic resection. The extent of surgical resection was classified as follows: type I NER: resection limited to the postero-superior nasopharyngeal wall; type 2 NER: resection superiorly extended to the sphenoid sinus; type 3 NER: resection with lateral extension including the cartilaginous portion of the Eustachian tube and parapharyngeal space. Type 1 NER was performed in 4 cases, type 2 in 6, and type 3 in 7. No intra- or post-operative complications were observed. Mean hospitalization time was 4 days (range: 1-7). Follow-up ranged from 10 to 138 months (mean: 41.2±38). At the time of writing, 12 (71/%) patients were free of disease, 3 (17%) alive with disease, and 2 (12%) dead of disease. NER is a feasible surgical technique that can be tailored in relation to tumour extension. Larger series and longer follow-up are needed to further validate the long-term results.


Acute radiological investigation of oesophagus and stomach in the event of massive upper gastro-intestinal tract bleeding.
Acute radiological investigation of the oesophagus, stomach and duodenum is a routine in patients admitted to the first surgical department of Kommunehospitalet, Copenhagen, with upper gastro-intestinal tract hemorrhage. In the period 1969-1972, 294 patients were admitted with hematemesis and/or melena. The acute radiological study was undertaken in 190 of these patients (65%). Whenever possible, confirmation of the acute primary radiological diagnosis was sought at acute operation, subsequent elective operation, by repeated radiological study, by gastroscopy, or at post mortem. 19 acute investigations were inadequate, and in a further 20 patients no studies subsequent to the acute study were made. There remain 151 patients, and the primary diagnosis could be confirmed in 111 (74%). 45 patients underwent acute operation, and primary diagnosis was confirmed in 66%. The most frequent primary diagnosis was duodenal ulcer (78 of 151 patients), which was verified in 63 instances (81%). In 8% of these patients subsequent definitive diagnosis of gastric ulcer was made, and in 11% no cause of bleeding could be demonstrated. Primary diagnosis of gastric ulcer in 28 patients could be confirmed in 85%. Primary diagnosis of oesophageal varices was made in 9 patients and confirmed in 7 (78%). One patient had a carcinoma of the stomach, and this was also the acute radiological diagnosis. In one patient primary diagnosis of oesophageal ulcer was made, but this could not be confirmed. In 34 patients the acute study failed to point the cause of bleeding, and in 50% of these patients subsequent examination was also non-productive. 26% subsequently evidenced duodenal ulcer; 11% gastric ulcer; 6% carcinoma of the stomach; 3% oesophageal varices; and 3%--one patient--a bleeding vessel in the fundus of the stomach. The acute radiological study was complication free. The place of the study in acute diagnosis of the patient with upper gastro-intestinal tract bleeding is discussed.


Transmission of group B streptococci. Traced by use of multiple epidemiologic markers.
During a three-week period, septicemia caused by group B Streptococcus, serotype III, developed in four infants born at a community hospital. The first infant had early-onset disease; late-onset disease that appeared, from epidemiologic data, to be nosocomial developed in the other three infants. Bacteriophage typing and antimicrobial susceptibility testing confirmed the relatedness of the isolates. A prospective study designed to differentiate between vertical and nosocomial transmission of group B Streptococcus showed that of 82 infants, 21 (26%) were culture-positive during their hospitalization, and nine of these infants (43%) had been culture-negative at birth. Although serotype III strains were recovered from four of nine infants with apparently nosocomial acquisition, none of the isolates displayed an antibiogram or bacteriophage type similar to that of the isolates involved in the recent cluster. Bacteriophage typing and antimicrobial susceptibility testing in addition to the use of serotyping may be helpful in epidemiologic studies of group B Streptococcus.


Capacity building of midwifery faculty to implement a 3-years midwifery diploma curriculum in Bangladesh: A process evaluation of a mentorship programme.
When a midwifery diploma-level programme was introduced in 2010 in Bangladesh, only a few nursing faculty staff members had received midwifery diploma-level. The consequences were an inconsistency in interpretation and implementation of the midwifery curriculum in the midwifery programme. To ensure that midwifery faculty staff members were adequately prepared to deliver the national midwifery curriculum, a mentorship programme was developed. The aim of this study was to examine feasibility and adherence to a mentorship programme among 19 midwifery faculty staff members who were lecturing the three years midwifery diploma-level programme at ten institutes/colleges in Bangladesh. The mentorship programme was evaluated using a process evaluation framework: (implementation, context, mechanisms of impact and outcomes). An online and face-to-face blended mentorship programme delivered by Swedish midwifery faculty staff members was found to be feasible, and it motivated the faculty staff members in Bangladesh both to deliver the national midwifery diploma curriculum as well as to carry out supportive supervision for midwifery students in clinical placement. First, the Swedish midwifery faculty staff members visited Bangladesh and provided a two-days on-site visit prior to the initiation of the online part of the mentorship programme. The second on-site visit was five-days long and took place at the end of the programme, that being six to eight months from the first visit. Building on the faculty staff members' response to feasibility and adherence to the mentorship programme, the findings indicate opportunities for future scale-up to all institutes/collages providing midwifery education in Bangladesh. It has been proposed that a blended online and face-to-face mentorship programme may be a means to improving national midwifery programmes in countries where midwifery has only recently been introduced.


Interventions for stroke rehabilitation: analysis of the research contained in the OTseeker evidence database.
To analyse the stroke content in OTseeker in terms of the quantity of the research evidence, the quality of the randomised controlled trials (RCTs), and the types of interventions and outcome measures used. A survey of stroke-related content in the OTseeker database was conducted in 2007. The year of publication and intervention categories used in each stroke-related RCT and systematic review (SR) were recorded. The internal validity of RCTs using the PEDro scale (partitioned) and the outcome measures used were also recorded. Of the 4,369 articles indexed on OTseeker, 452 (10.3%) related to stroke were conducted between 1979 and 2006. The five most frequently studied intervention categories were movement training (43.2%), models of service delivery (31.2%), physical modalities/orthotics/splinting (30.1%), exercise/stretching/strength training (19.5%), and skill acquisition/training (9.3%). Random allocation (96.1%) was the most frequently satisfied internal validity criterion and therapist blinding (3.1%) was least often satisfied. The five most frequently used outcome measurement categories were basic and extended activities of daily living (70.1%), hand and upper limb function (56.1%), walking/gait (44.1%), movement/motor function (32.7%), and quality of life/general overall health (27.9%). The stroke-related content on OTseeker is useful for allied health professionals. This study highlights a need for better definitions of interventions and consensus about the best outcome measures. Few interventions or outcome measures were participation focused.


Individual variation in the milk yield response to bovine somatotropin in dairy cows.
The objective was to relate the short-term milk yield response (MYR) following use of exogenous bovine somatotropin (bST) to changes in plasma concentrations of metabolites and hormones. Twenty-four Holstein cows (52 +/- 4.1 d postpartum) received daily subcutaneous injections of saline for 1 wk followed by subcutaneous injections of 33 mg/d of bST for 2 wk (Trial 1). The difference in milk yield between wk 1 and 3 for each cow was used to determine the 5 cows with the highest (HR) and 5 with the lowest responses (LR) to bST. These 10 cows were then used in 3 further trials of the same design (Trials 2, 3, and 4, conducted at 122, 181, and 237 +/- 7.6 d postpartum, respectively). Blood samples were taken 2 h after the administration of bST on d 1, 3, 5, 15, 17, and 19 of each trial. The HR group had consistently greater MYR to bST than the LR group throughout their lactation. The LR group had a higher milk yield and lower plasma insulin like growth factor-I (IGF-I) concentrations during the saline treatment in all trials. The increase in plasma somatotropin concentrations following injections of bST was greater for the LR group, whereas the difference in plasma IGF-I level between wk 1 and 3 was greater for the HR group. The HR group had lower levels of 3-hydroxy-butyrate and nonesterified fatty acids before bST treatment. Low short-term response to bST was associated with plasma concentrations of hormones and metabolites that indicate negative energy balance, although other factors may be involved.


[Adherence and toxicity to tyrosine kinase inhibitor therapy in chronic myeloid leukemia].
To analyze adherence and toxicity of tyrosine kinase inhibitor (TKIs) therapy in patients diagnosed with chronic myeloid leukemia (CML). A 18-months retrospective observational study (January 2011-June 2012) which included all patients diagnosed with CML in a secondary hospital (550 beds) and were treated with imatinib, dasatinib or nilotinib. It was collected the following variables: sex, age at diagnosis, years of treatment and side effects. Adherence was evaluated using SMAQ questionnaire and recording dispensations. 25 patients were included and all but two (92.0%) experienced side effects to imatinib,83.3% to dasatinib and 66.7% to nilotinib. The average adherence was 71.3%. There was identified as possible parameters of lack of adherence the female patients (55.6 % vs. 66.7%, p = 0.586), older than 50 (55.6 % vs. 83.3 %, p = 0.125), more than four years of treatment (70.0 % vs. 57.1 %, p = 0.521) and the presence of certain side effects (gastrointestinal disorders and musculoeskeletal pain). Almost one third of patients were considered nonadherent to therapy. Although the sample size did not allow us to establish a statistically significant relation between adherence and the variables analyzed, the clinical relevance of these results show the importance of future studies with larger populations to confirm the trends established in this study.


Association study of brain-derived neurotrophic factor (BDNF) and LIN-7 homolog (LIN-7) genes with adult attention-deficit/hyperactivity disorder.
Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder with a large genetic component that has been shown to persist into adulthood in 30-60% of childhood ADHD cases. Adult ADHD confers an increased risk of ADHD in relatives when compared to childhood ADHD, possibly due to a greater genetic liability than the childhood form. Brain-derived neurotrophic factor (BDNF) is a neurotrophin expressed in the brain throughout life and is involved in survival, differentiation, and synaptic plasticity of several neuronal systems including dopaminergic pathways. Mammalian LIN-7 homolog is selectively expressed in specific neuronal populations and is involved in the postsynaptic density of neuronal synapses. LIN-7 is also a positional candidate, as it lies immediately downstream of BDNF. We tested for association between five BDNF polymorphisms, two LIN-7 polymorphisms and adult ADHD. The sample consisted of 80 trios comprised of an adult ADHD proband and their biological parents and an independent sample of 121 adult ADHD cases and a corresponding number of sex, age, and ethnically matched controls (total 201 probands). Allelic and haplotype association was found between both BDNF and adult ADHD, and LIN-7 and adult ADHD. HapMap indicates BDNF and LIN-7 occur in different haplotype blocks, though some linkage disequilibrium exists between the SNPs in these adjacent genes. Further investigations into the pathologic mechanisms of BDNF and LIN-7 in adult ADHD are required.


The Neglected Insulin: IGF-II, a Metabolic Regulator with Implications for Diabetes, Obesity, and Cancer.
When originally discovered, one of the initial observations was that, when all of the insulin peptide was depleted from serum, the vast majority of the insulin activity remained and this was due to a single additional peptide, IGF-II. The IGF-II gene is adjacent to the insulin gene, which is a result of gene duplication, but has evolved to be considerably more complicated. It was one of the first genes recognised to be imprinted and expressed in a parent-of-origin specific manner. The gene codes for IGF-II mRNA, but, in addition, also codes for antisense RNA, long non-coding RNA, and several micro RNA. Recent evidence suggests that each of these have important independent roles in metabolic regulation. It has also become clear that an alternatively spliced form of the insulin receptor may be the principle IGF-II receptor. These recent discoveries have important implications for metabolic disorders and also for cancer, for which there is renewed acknowledgement of the importance of metabolic reprogramming.


Malignant Pleural Mesothelioma: Accuracy of CT Against Immunohistochemical Test Among the Mexican Population.
Malignant pleural mesothelioma (MPM) is associated with occupational and environmental exposure to asbestos. The incidence is expected to increase as the use of asbestos is not prohibited in many countries, such as in Mexico. We undertook this study to determine sensitivity, specificity, predictive values and likelihood ratios of computed tomography (CT) in a sample from Mexican population with suspected MPM and other pleuropulmonary diseases. CT films of 38 patients suspected of having MPM were analyzed. A single observer was blinded to MPM diagnoses. The frequencies of ten CT findings were identified. A cut-off point of ≥5 CT findings was established to determine high MPM probability. Sensitivity, specificity, predictive values and likelihood ratio of the CT against biopsy using immunohistochemical testing (IHC) for MPM were calculated. Of the 38 patients, 31 had MPM and seven had lung adenocarcinoma. The five key findings were mediastinal pleural thickening 96.7% (n = 30), nodular pleural thickening 93.3% (n = 29), pleural mass 83.9% (n = 26), diminished lung 70.9% (n = 22) and contracted hemithorax 70.9% (n = 22). Sensitivity 96.8% (83.2-99.4), specificity 85.7% (42.2-97.6), positive likelihood ratio 6.7 (1.1-41.6), and negative likelihood ratio of 0.04 (0.01-0.2) were reported. Sensitivity and specificity in this study was greater than previously reported, 96.8% and 85.7 vs. 93.2 and 65.6%, respectively. CT is an easily accessible and useful tool that should be incorporated into the medical education of general physicians to improve MPM diagnosis of suspected cases.


Reviewing and assessing existing meta-analysis models and tools.
Over the past few years, meta-analysis has become popular among biomedical researchers for detecting biomarkers across multiple cohort studies with increased predictive power. Combining datasets from different sources increases sample size, thus overcoming the issue related to limited sample size from each individual study and boosting the predictive power. This leads to an increased likelihood of more accurately predicting differentially expressed genes/proteins or significant biomarkers underlying the biological condition of interest. Currently, several meta-analysis methods and tools exist, each having its own strengths and limitations. In this paper, we survey existing meta-analysis methods, and assess the performance of different methods based on results from different datasets as well as assessment from prior knowledge of each method. This provides a reference summary of meta-analysis models and tools, which helps to guide end-users on the choice of appropriate models or tools for given types of datasets and enables developers to consider current advances when planning the development of new meta-analysis models and more practical integrative tools.


Down-regulation of argininosuccinate synthetase is associated with cisplatin resistance in hepatocellular carcinoma cell lines: implications for PEGylated arginine deiminase combination therapy.
Many advanced human tumors, including hepatocellular carcinomas (HCC) are auxotrophic for arginine due to down-regulation of argininosuccinate synthetase (ASS1), the rate-limiting enzyme in arginine synthesis. The arginine-lowering agent PEGylated arginine deiminase (ADI-PEG 20) has shown efficacy as a monotherapy in clinical trials for treating arginine-auxotrophic tumors and is currently being evaluated in combination with cisplatin in other cancer types. Epigenetic silencing via methylation of the ASS1 promoter has been previously demonstrated in other cancer types, and a reciprocal relationship between ASS1 expression and cisplatin resistance has also been observed in ovarian cancer. However, the mechanism of ASS1 down-regulation, as well as the correlation with cisplatin resistance has not been explored in HCC. The present study investigates ADI-PEG 20 and cisplatin sensitivities in relation to ASS1 expression in HCC. In addition, we show how this biomarker is regulated by cisplatin alone and in combination with ADI-PEG 20. ASS1 protein expression in both untreated and drug treated human HCC cell lines was assessed by western blot. The correlation between ASS1 protein levels, ADI-PEG 20 sensitivity and cisplatin resistance in these cell lines was established using a luminescence-based cell viability assay. Epigenetic regulation of ASS1 was analyzed by bisulfite conversion and methylation-specific PCR. A good correlation between absence of ASS1 protein expression, ASS1 promoter methylation, sensitivity to ADI-PEG 20 and resistance to cisplatin in HCC cell lines was observed. In addition, cisplatin treatment down-regulated ASS1 protein expression in select HCC cell lines. While, at clinically relevant concentrations, the combination of ADI-PEG 20 and cisplatin restored ASS1 protein levels in most of the cell lines studied. ASS1 silencing in HCC cell lines is associated with simultaneous cisplatin resistance and ADI-PEG 20 sensitivity which suggests a promising combination therapeutic strategy for the management of HCC.


Investigating the Impact of Automation on the Health Care Workforce Through Autonomous Telemedicine in the Cataract Pathway: Protocol for a Multicenter Study.
While digital health innovations are increasingly being adopted by health care organizations, implementation is often carried out without considering the impacts on frontline staff who will be using the technology and who will be affected by its introduction. The enthusiasm surrounding the use of artificial intelligence (AI)-enabled digital solutions in health care is tempered by uncertainty around how it will change the working lives and practices of health care professionals. Digital enablement can be viewed as facilitating enhanced effectiveness and efficiency by improving services and automating cognitive labor, yet the implementation of such AI technology comes with challenges related to changes in work practices brought by automation. This research explores staff experiences before and after care pathway automation with an autonomous clinical conversational assistant, Dora (Ufonia Ltd), that is able to automate routine clinical conversations. The primary objective is to examine the impact of AI-enabled automation on clinicians, allied health professionals, and administrators who provide or facilitate health care to patients in high-volume, low-complexity care pathways. In the process of transforming care pathways through automation of routine tasks, staff will increasingly "work at the top of their license." The impact of this fundamental change on the professional identity, well-being, and work practices of the individual is poorly understood at present. We will adopt a multiple case study approach, combining qualitative and quantitative data collection methods, over 2 distinct phases, namely phase A (preimplementation) and phase B (postimplementation). The analysis is expected to reveal the interrelationship between Dora and those affected by its introduction. This will reveal how tasks and responsibilities have changed or shifted, current tensions and contradictions, ways of working, and challenges, benefits, and opportunities as perceived by those on the frontlines of the health care system. The findings will enable a better understanding of the resistance or susceptibility of different stakeholders within the health care workforce and encourage managerial awareness of differing needs, demands, and uncertainties. The implementation of AI in the health care sector, as well as the body of research on this topic, remain in their infancy. The project's key contribution will be to understand the impact of AI-enabled automation on the health care workforce and their work practices. PRR1-10.2196/49374.


Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders.
Neurodevelopmental disorders, including autism spectrum disorders, are highly male biased, but the underpinnings of this are unknown. Striatal dysfunction has been strongly implicated in the pathophysiology of neurodevelopmental disorders, raising the question of whether there are sex differences in how the striatum is impacted by genetic risk factors linked to neurodevelopmental disorders. Here we report male-specific deficits in striatal function important to reward learning in a mouse model of 16p11.2 hemideletion, a genetic mutation that is strongly associated with the risk of neurodevelopmental disorders, particularly autism and attention-deficit hyperactivity disorder. We find that male, but not female, 16p11.2 deletion animals show impairments in reward-directed learning and maintaining motivation to work for rewards. Male, but not female, deletion animals overexpress mRNA for dopamine receptor 2 and adenosine receptor 2a in the striatum, markers of medium spiny neurons signaling via the indirect pathway, associated with behavioral inhibition. Both sexes show a 50% reduction of mRNA levels of the genes located within the 16p11.2 region in the striatum, including the kinase extracellular-signal related kinase 1 (ERK1). However, hemideletion males show increased activation in the striatum for ERK1, both at baseline and in response to sucrose, a signaling change associated with decreased striatal plasticity. This increase in ERK1 phosphorylation is coupled with a decrease in the abundance of the ERK phosphatase striatum-enriched protein-tyrosine phosphatase in hemideletion males. In contrast, females do not show activation of ERK1 in response to sucrose, but notably hemideletion females show elevated protein levels for ERK1 as well as the related kinase ERK2 over what would be predicted by mRNA levels. These data indicate profound sex differences in the impact of a genetic lesion linked with neurodevelopmental disorders, including mechanisms of male-specific vulnerability and female-specific resilience impacting intracellular signaling in the brain.


In-vivo characterization of optical properties of pigmented skin lesions including melanoma using oblique incidence diffuse reflectance spectrometry.
In this letter, we report the first use of oblique incidence diffuse reflectance spectrometry to conduct in-vivo measurements of optical properties of three different types of pigmented skin lesions, including melanoma, dysplastic, and common nevi. Both absorption and reduced scattering coefficient spectra were estimated from the spatially resolved diffuse reflectance within the wavelength range of 455-765 nm for 144 pigmented skin lesions including 16 melanomas. The absorption and reduced scattering spectra were found to change with the malignancy of the skin lesions, which were generally higher for the malignant cases than the benign ones. Based on the measurement results, the physiological origin leading to the change of the absorption and scattering properties is also discussed.


Augmentation of surgical angiogenesis in vascularized bone allotransplants with host-derived a/v bundle implantation, fibroblast growth factor-2, and vascular endothelial growth factor administration.
We have previously shown experimental transplantation of living allogeneic bone to be feasible without long-term immunosuppression by development of a recipient-derived neoangiogenic circulation within bone. In this study, we examine the role of angiogenic cytokine delivery with biodegradable microspheres to enhance this process. Microsurgical femoral allotransplantation was performed from Dark Agouti to Piebald Virol Glaxo rats. Poly(D,L-lactide-co-glycolide) microspheres loaded with buffer, basic fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), or both, were inserted intramedullarly along with a recipient-derived arteriovenous (a/v) bundle. FK-506 was administered daily for 14 days, then discontinued. At 28 days, bone blood flow was measured using hydrogen washout. Microangiography, histologic, and histomorphometric analyses were performed. Capillary density was greater in the FGF+VEGF group (35.1%) than control (13.9%) (p < 0.05), and a linear trend was found from control, FGF, VEGF, to FGF+VEGF (p < 0.005). Bone formation rates were greater with VEGF (p < 0.01) and FGF+VEGF (p < 0.05). VEGF or FGF alone increased blood flow more than when combined. Histology rejection grading was low in all grafts. Local administration of vascular and fibroblast growth factors augments angiogenesis, bone formation, and bone blood flow from implanted blood vessels of donor origin in vascularized bone allografts after removal of immunosuppression.


A review of the anticancer activity of Azadirachta indica (Neem) in oral cancer.
Azadirachta indica (neem), belongs to the family of Meliaceae plants, is found in the Indian subcontinent. The neem tree is colloquially referred to as the village pharmacy due to its array of biological properties. Every part of the neem tree like its bark, leaves, sap, fruit, seeds, and twigs find a multitude of uses. It is customary to use them for management of skin diseases and various other infections.The anticancer properties of neem have been studied in the past and these include its ability to modulate the tumour environment, increase the cytotoxic ability of host monocytes and suppress the proliferation of tumour cells. The present review was conducted with the objective of scrutinizing and assimilating data about the usefulness Azadirachta indica in oral cancer from all the previously done work. A planned review was conducted of all the studies that investigated the role of Azadirachta indica in oral cancer. Literature search was carried out using PubMed, Scopus and Google scholar databases. In addition to electronic searching, hand searching, cross referencing and various internet engines were also used to collect data. The articles were perused and articles not pertinent to our search were omitted. The anticancer properties of neem were evaluated and the active constituents of neem have been demonstrated to unequivocally have preventive and therapeutic potential against oral cancer. Although, greater exploration of the anticancer properties of neem are required in order to effectively integrate it into the routine management of oral cancer.


Strong activation of ether-à-go-go-related gene 1 K+ channel isoforms by NS1643 in human embryonic kidney 293 and Chinese hamster ovary cells.
Two different mechanisms leading to increased current have been described for the small-molecule human ether-à-go-go-related gene (herg) activator NS1643 [1,3-bis-(2-hydroxy-5-trifluoromethylphenyl)-urea]. On herg1a channels expressed in Xenopus laevis oocytes, it mainly acts via attenuation of inactivation and for rat (r) erg1b channels expressed in human embryonic kidney (HEK)-293 cells, it strongly shifts the activation curve to the left. We now investigated the NS1643 effects on erg1b channels in more detail and performed comparative experiments with rat and human erg1a in different expression systems. Significant differences were observed between expression systems, but not between the rat and human isoform. In HEK-293 or Chinese hamster ovary (CHO) cells, activation of rat erg1b channels occurred in a dose-dependent manner with a maximum current increase of 300% obtained with 10 μM NS1643. In contrast, the NS1643-induced strong leftward shift in the voltage dependence of activation further increased with higher drug concentration, needed more time to develop, and exhibited use dependence. Coexpression of KCNE1 or KCNE2 did not attenuate this NS1643 effect on erg1 channel activation and did thus not mimic the lower drug potency on this parameter observed in oocytes. NS1643 (10 μM) slowed erg1b channel deactivation and recovery from inactivation without significant changes in activation and inactivation kinetics. With the exception of accelerated activation, NS1643 affected erg1a channels similarly, but the effect was less pronounced than in erg1b or erg1a/1b channels. It is noteworthy that rerg1b and herg1a inactivation estimated from fully activated current voltage relationships were unaltered in the continued presence of 10 μM NS1643 in the mammalian expression systems, indicating qualitative differences from NS1643 effects in X. laevis oocytes.


In Vitro Analysis of Selected Antioxidant and Biological Properties of the Extract from Large-Fruited Cranberry Fruits.
This study investigated the in vitro antioxidant and biological properties of ethanol extracts obtained from the fruits of the highbush cranberry. The produced extracts exhibited a high content of polyphenols (1041.9 mg 100 g d.m.-1) and a high antioxidant activity (2271.2 mg TE g 100 d.m.-1 using the DPPH method, 1781.5 mg TE g 100 d.m.-1 using the ABTS method), as well as a substantial amount of vitamin C (418.2 mg 100 g d.m.-1). These extracts also demonstrated significant in vitro biological activity. Studies conducted on the Saccharomyces cerevisiae cellular model revealed the strong antioxidant effects of the extract, attributed to a significant reduction in the levels of reactive oxygen species (ROS) within the cells, confirming the utility of the extracts in mitigating oxidative stress. Moreover, inhibitory properties were demonstrated against factors activating metabolic processes characteristic of inflammatory conditions. It was observed that the cranberry extract inhibits the activity of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) non-selectively. Additionally, the extract was found to be a highly active inhibitor of acetylcholinesterase (AChE), potentially suggesting the applicability of this extract in the prevention of neurodegenerative diseases, including Alzheimer's disease.


A Mixed Infection of Helenium Virus S With Two Distinct Isolates of Butterbur Mosaic Virus, One of Which Has a Major Deletion in an Essential Gene.
Multiple carlaviruses infect various ornamental plants, often having limited host ranges and causing minor symptoms, yet often reducing yield or quality. In this study we have identified a mixed infection of butterbur mosaic virus (ButMV) and helenium virus S (HelVS) from a plant of veronica (Veronica sp.) showing foliar mosaic and distortion. Carlavirus-like particles were observed by transmission electron microscopy (TEM), and RNA from partially purified virions was amplified by random RT-PCR, yielding clones of 439-1,385 bp. Two partially overlapping clones including coat protein (CP) sequence, and two of four partial replicase clones, were closely related to ButMV-J (AB517596), previously reported only from butterbur (Petasites japonicus) in Japan. Two other partial replicase clones showed lower identity to multiple carlaviruses. Generic primers which amplify the 3'-terminal region of multiple carlaviruses yielded clones of three distinct sequences: (1) with 98% nt identity to HelVS; (2) ButMV-A, showing 82% nt identity to ButMV-J; and (3) ButMV-B, with 78% nt identity to each of ButMV-J and ButMV-A. Further amplification of upstream fragments revealed that ButMV-B had an internal deletion in TGB1, confirmed using isolate-specific primers. Near-complete genomes of both ButMV-A and ButMV-B were obtained from next-generation sequencing (NGS), confirming the deletion within ButMV-B, which is presumably maintained through complementation by ButMV-A. HelVS was previously reported only from Helenium hybrids and Impatiens holstii. A near-complete HelVS genome was obtained for the first time by NGS from the same sample. Additional Veronica hybrids infected with HelVS were identified by TEM and RT-PCR, including cv. 'Sunny Border Blue' which was also subjected to NGS. This resulted in assembly of an 8,615 nt near-complete HelVS genome, with high identity to that from the mixed infection. The predicted CP sequence has 96% amino acid (aa) identity to HelVS from helenium (Q00556). Other ORFs show a maximum of 54% (TGB3) to 68% (NABP) aa identity to the equivalent ORFs of other carlaviruses. These results demonstrate for the first time maintenance by complementation of a carlavirus isolate with a major deletion in an essential gene, and confirm that HelVS is a distinct species in the genus Carlavirus.


Some practical conclusions following a longitudinal study of common macular lesions.
In a project which lasted 18 years, the natural history of five common macular lesions was followed in 268 patients, and the most significant clinical features selected in each. Methodology consisted of trichromatic analysis with direct ophthalmoscopy, contact lens fundoscopy including the triple mirror, refraction, and fundus photography. In several subjects in each group repeated fluorescence angiographies were carried out. Single eye records were kept and scattergrams of corrected visual acuities plotted. The latter--besides key clinical features--were then used to predict the probable course. Examples are related both to the biographies and to the clinical features to make the method more comprehensible. The five lesions studied were: cystoid macular degeneration, retinal pigment epithelial detachments, choroidal sclerosis, hyaline degenerations, and macular (foveal) degenerations. A new paramacular 'window' defect called a 'target' lesion is described and attention drawn to its close association with migraine. A feature of the study throughout was the frequency with which more than one of the lesions appeared in the same eye, although there was no set sequence. Thus a patient suffering from one macular lesion not infrequently ended by being blinded by another.


Increase in isoflavonoid content in Glycine max cells transformed by the constitutively active Ca2+ independent form of the AtCPK1 gene.
Calcium-dependent protein kinases (CDPKs) represent a class within a multigene family that plays an important role in biotic and abiotic plant stress responses and is involved in the regulation of secondary metabolite biosynthesis. Our previous study showed that overexpression of the mutant constitutively active Ca2+ independent form of the AtCPK1 gene (AtCPK1-Ca) significantly increased the biosynthesis of anthraquinones and stilbenes in Rubia cordifolia L. and Vitis amurensis Rupr. transgenic cell cultures, respectively. Here, we have established transgenic calli of soybean plants Glycine max (L.) Merr. that express the AtCPK1-Ca gene. Heterologous expression of the AtCPK1-Ca gene provoked a 5.2-fold increase in total isoflavone production up to 208.09 mg/L, along with an increase in isoflavone aglycones production up to 6.60 mg/L, which is 3-fold greater than that of the control culture. The production of prenylated isoflavones significantly increased, reaching 3.78 mg/L, 13-fold higher than in the control culture. The expression levels of 4-coumarate:CoA ligases, isoflavone synthases, 2-hydroxyisoflavanone dehydratase, isoflavone dimethylallyltransferase, and coumestrol 4-dimethylallyltransferase genes in transgenic cell cultures significantly increased. Thus, heterologous expression of the AtCPK1-Ca gene can be used to bioengineer plant cell cultures that produce isoflavonoids.


Complementemia in pregnancies with antiphospholipid syndrome.
Prognosis of pregnancies in women with antiphospholipid syndrome has dramatically improved over the past two decades using conventional treatment with low molecular weight heparin and low-dose aspirin. However, despite this regimen, 10-15% of antiphospholipid syndrome patients experience pregnancy losses. Several studies have been performed in order to identify risk factors predictive of complications. Thrombosis has been generally accepted as the key pathogenetic mechanism underlying pregnancy morbidity. However, the thrombogenic state alone is not able to explain all the different mechanisms leading to pregnancy failure. In fact, emerging evidence shows that complement pathway could play an important role in mediating clinical events in antiphospholipid syndrome. However, the exact mechanism through which complement mediates antiphospholipid syndrome complications remains unknown. Low complement levels (C3 and C4) are associated with poor pregnancy outcome in women with antiphospholipid syndrome in different studies. Hypocomplementemia could be indicated as an early predictor of adverse pregnancy outcome, available at the beginning of pregnancy for starting, if necessary, additional treatment to conventional therapy. However, future studies need to better understand the impact of low complement level on antiphospholipid syndrome pregnancy outcome.


[Reproduction of delayed evoked potentials during amygdaloid complex stimulation].
Influence of amygdaloid stimulation on retrieval of the electric correlate of time connection, delayed evoked potentials recorded in the cortex, midbrain reticular formation, lateral geniculate body and hippocampus, was studied in experiments on currarized unaesthetized cats. Delayed evoked potentials were formed after 10-400 pairings of light flash and hypothalamic stimulation and were manifested as potentials appearing in response to a conditioned stimulus with a delay equal to the interval between conditioned and unconditional stimuli. Amygdaloid stimulation facilitated their retrieval if they were previously extinguished or did not appear during initial testing.


Long-term in vitro growth of human insulin-secreting insulinoma cells.
Long-term in vitro maintenance of human insulin-secreting insulinoma cells. (1) Cell culture of ex vivo-derived insulinoma cell suspensions from 8 individual human donors, using various cell culture medium supplementations; (2) determination of insulin synthesis and secretion using immunocytochemistry and insulin and pro-insulin radioimmunoassays; (3) nestin-immunostaining of long-term in vitro grown insulinoma cell suspensions, and (4) phase-contrast light microscopy for analyzing the in vitro growth characteristics of the insulinoma cells. (1) Parallel persistence of in vitro insulinoma cell proliferation as well as insulin-synthesizing and -secreting capacity depended on both the co-culture of insulinoma cells with human fibroblasts and the supplementation of the cell culture medium with tissue culture supernatant derived from the rodent pituitary adenoma cell line GH-3; (2) immunostaining for insulin and secretagogin confirmed the neuroendocrine origin of the insulinoma cells grown in vitro; (3) insulin secretion capability persisted up to an observation period of 25 weeks; (4) insulin secretion rates after 6 weeks of in vitro growth ranged from 3.5 to 83.3 muU/ml/h/60,000 cells plated, and (5) after long-term in vitro growth of insulinoma-derived cell suspensions with persistent insulin-secreting capacity, nestin staining was observed predominantly in co-cultured fibroblasts. Our data describe for the first time the long-term in vitro culture of insulin-secreting human insulinomas and highlight the importance of beta-cell trophic factors for insulinoma cell growth.


Introduction to the updated Australasian consensus guidelines for the management of invasive fungal disease and use of antifungal agents in the haematology/oncology setting, 2021.
This article introduces the fourth update of the Australian and New Zealand consensus guidelines for the management of invasive fungal disease and use of antifungal agents in the haematology/oncology setting. These guidelines are comprised of nine articles as presented in this special issue of the Internal Medicine Journal. This introductory chapter outlines the rationale for the current update and the steps taken to ensure implementability in local settings. Given that 7 years have passed since the previous iteration of these guidelines, pertinent contextual changes that impacted guideline content and recommendations are discussed, including the evolution of invasive fungal disease (IFD) definitions. We also outline our approach to guideline development, evidence grading, review and feedback. Highlights of the 2021 update are presented, including expanded scope to provide more detailed coverage of common and emerging fungi such as Aspergillus and Candida species, and emerging fungi, and a greater focus on the principles of antifungal stewardship. We also introduce an entirely new chapter dedicated to helping healthcare workers convey important concepts related to IFD, infection prevention and antifungal therapy, to patients.