Predictive factors of local-regional recurrences following parotid sparing intensity modulated or 3D conformal radiotherapy for head and neck cancer.
Predictive factors for local-regional (LR) failures after parotid-sparing, Intensity modulated (IMRT) or 3D conformal radiotherapy for head and neck (HN) cancers were assessed. One hundred and fifty-eight patients with mostly stages III-IV HN squamous cell carcinoma underwent curative bilateral neck irradiation aimed at sparing the parotid glands. Patient, tumor, and treatment factors were analyzed as predictive factors for LR failure. Twenty-three patients had LR recurrence (19 in-field and four marginal). No differences were found in the doses delivered to the PTVs of patients with or without in-field recurrences. In univariate analysis, tumor site was highly predictive for LR failure in both postoperative and definitive RT patients. In postoperative RT patients, pathologic tumor size, margin status, extracapsular extension (ECE) and number of lymph node metastases, were also significantly predictive. Multivariate analysis showed tumor site (oropharynx vs. other sites) to be a significant predictor in all patients, and involved margins and number of involved lymph nodes in postoperative patients. Clinical rather than dosimetric factors predicted for LR failures in this series, and were similar to those reported following standard RT. These factors may aid in the selection of patients for studies of treatment intensification using IMRT.


Confirmation of no impact from different anticoagulant counter ions on bioanalytical method.
In the past several years, the impact of changing counter ions while keeping the same anticoagulant in bioanalytical LC-MS/MS methods has become a highly discussed topic. In order to confirm that there is no impact from counter ions, matrix effect and stability evaluations were performed on bicalutamide LC-MS/MS bioanalytical methods. Independently from the anticoagulant counter ion used, the matrix effect evaluation met acceptance criteria, even when using conditions expected to increase matrix effect, such as protein precipitation with an analog internal standard. Freeze-thaw along with storage stabilities, namely short- and long-term, demonstrated less than 8% deviation regardless of the counter ion used. Differences in the anticoagulant counter ion used has no impact on the bicalutamide bioanalytical LC-MS/MS method.


Modifications of masticatory behavior after trigeminal deafferentation in the rabbit.
Bilateral trigeminal deafferentation was performed in the rabbit in order to assess the role of orofacial inputs in regulation of the pattern of jaw movements during chewing. After bilateral combined section of the maxillary and inferior alveolar nerves, the animals did not eat food by themselves in the first postoperative week. However, they could chew and swallow when food was inserted into the mouth by an experimenter. The pattern of jaw movements and associated EMG activities of masticatory muscles during chewing were modulated remarkably by deafferentation. These modifications include 1) decrease in the horizontal excursions of the mandible at the power phase, 2) decrease in the maximum gape, 3) insufficient occlusion at the power phase (or increase in the minimum gape), 4) irregular patterns of jaw movements, 5) facilitation of the chewing rate, 6) increase in the number of chewing cycles in a masticatory sequence (the process from acceptance of food to swallowing), and 7) decrease in jaw-closing muscle activities. The findings indicate that deafferentation of the trigeminal sensory branches reduced masticatory force. On the other hand, no significant change was seen in the animals with disruption of cutaneous sensations of the face due to bilateral section of the infraorbital and mental nerves. Intraoral sensations rather than extraoral sensations may thus be important for regulation of masticatory force and jaw movements during chewing. Jaw movements during chewing were also analyzed in the animals with either bilateral ablation of the cortical masticatory area (CMA) or bilateral lesion of the ventral posteromedial nucleus (VPM) of the thalamus in order to examine whether profound effects of trigeminal deafferentation are produced via the transcortical loop. The animals with lesion of either the CMA or VPM demonstrated disturbances in feeding behavior, including the dropping of ingested food from the mouth, elongation of a masticatory process, reduction in the chewing efficiency, etc. However, the pattern of jaw movements during chewing were essentially similar to that in the preoperative period. These results do not necessarily deny a contribution of the CMA to regulation of jaw movements but suggest that the transcortical feedback loop via the CMA and thalamic VPM nucleus would not primarily be responsible for pattern formation of jaw movements during chewing in the rabbit. Probably, the sensory feedback via the transcortical loop may indirectly facilitate activities of the brain stem CPG, which facilitates the chewing rhythm or enables masticatory sequences to be conducted smoothly.


Community-based instruction with profoundly mentally retarded persons: client and public responsiveness.
Three experiments were conducted to evaluate the effects of a training program implemented in a community setting for teaching receptive language skills to profoundly mentally retarded persons. In Experiment 1, the program was implemented in a local department store and consisted of a least-to-most intrusive prompting paradigm and contingent consequences. The community-based training strategy was effective in teaching receptive identification of three objects to a profoundly mentally retarded adolescent. Additionally, generalized improvements occurred in other store locations, although cross-modal generalization in terms of changes in expressive skills did not occur. These results were replicated in Experiment 2 with two other clients in the same store, and in Experiment 3 with another client in an outdoor recreational area. Also, a questionnaire survey indicated that store employees in the first two experiments had very favorable reactions to the program. Results are discussed in regard to continued research with community-based training as a means of expanding educational opportunities for individuals who are profoundly mentally retarded.


Individualized functional connectome identified generalizable biomarkers for psychiatric symptoms in transdiagnostic patients.
Substantial clinical heterogeneity and comorbidity inherent amongst mental disorders limit the identification of neuroimaging biomarkers that can reliably track clinical symptoms. Strategies that enable generation of meaningful and replicable neurobiological markers at the individual level will push the field of neuropsychiatry forward in developing efficacious personalized treatment. The current study included 142 adult patients with a primary diagnosis of schizophrenia (SCZ), bipolar (BP), or attention deficit/hyperactivity disorder (ADHD), and 67 patient ratings across four behavioral measures. Using functional connectivity derived from a personalized fMRI approach, we identified several candidate imaging markers related to dimensional phenotypes across disorders, assessed the internal and external generalizability of these markers, and compared the probability of replicating findings across datasets using individual and group-averaged defined functional regions. We identified subject-specific connections related to three different clinical domains (attention deficit, appetite-energy, psychosis-positive) in a discovery dataset. Importantly, these connectivity biomarkers were robust and were reproduced in an independent validation dataset. For markers related to neurovegetative symptoms (attention deficit, appetite-energy symptoms), the brain connections involved showed similar connectivity patterns across the different diagnoses. However, psychosis-positive symptoms were associated with connections of varying strength across disorders. Finally, we found that markers for symptom domains were replicable for individually-specified connections, but not for group template-derived connections. Our personalized strategies allowed us to identify meaningful and generalizable imaging markers for symptom domains in patients who exhibit high levels of heterogeneity. These biomarkers may shed new light on the connectivity underpinnings of psychiatric symptoms and lead to personalized interventions.


Intracellular cyclic nucleotide analogues inhibit in vitro mitogenesis and activation of fibroblasts derived from obstructed rat kidneys.
As several studies indirectly suggest that inhibiting the intracellular breakdown of cyclic nucleotides may inhibit fibrogenesis, this study used membrane permeable cyclic nucleotide analogues to examine the role of cAMP and cGMP signaling pathways in the regulation of renal fibroblast function. Fibroblasts were isolated by explant outgrowth culture of rat kidneys post unilateral ureteric obstruction. Subcultured cells were exposed to 10- 1,000 microM of the cyclic nucleotide analogues 8-bromo-cAMP (8br-cAMP) and 8-bromo-cGMP (8br-cGMP). Functional parameters examined included mitogenesis (thymidine incorporation), collagen synthesis (proline incorporation), myofibroblast differentiation (Western blotting for alpha-smooth muscle actin; alpha-SMA) and expression of CTGF (Northern blotting), a TGF-beta(1)-driven immediate early response gene. Serum-stimulated mitogenesis was decreased 27 +/- 4% by 100 microM 8br-cAMP (p < 0.01), 49 +/- 6% by 1,000 microM 8br-cAMP (p < 0.001) and 43 +/- 7% by 1,000 microM 8br-cGMP (p < 0.01). 1,000 microM 8br-cAMP and 8br-cGMP reduced basal collagen synthesis by 80 +/- 5 and 60 +/- 21% respectively (both p < 0.05). Maximum dose of 8br-cAMP but not 8br-cGMP inhibited basal expression of the differentiation marker alpha-SMA by 43 +/- 33 (p < 0.05), resulted in a more rounded cell morphology and reduced expression of CTGF by 39 +/- 24% (p < 0.05). Measurement of mitochondrial activity confirmed that effects were independent of cell toxicity. In conclusion, cyclic nucleotides inhibit fibrogenesis in vitro. Strategies which elevate intracellular cyclic nucleotide concentrations may therefore be therapeutically valuable in preventing the proliferation and activation of fibroblasts in progressive renal disease.


Development of the performance reference compound approach for the calibration of "polar organic chemical integrative sampler" (POCIS).
The purpose of the Water Framework Directive is to ensure the quality of the natural water across Europe. In this context, passive samplers have shown interesting capacities for the monitoring of contaminants in aqueous ecosystems. They allow the measurement of time-weighted average concentrations, overcoming many drawbacks of the spot-sampling techniques known to be expensive and time consuming. However, application of passive samplers such as polar organic chemical integrative samplers (POCIS) for the monitoring of hydrophilic contaminants requires calibration to define compound sampling rates; key parameters to deduce the pollutant water concentrations from the amounts of pollutants accumulated by the device. Unfortunately, sampling rates are influenced by a range of environmental factors; in that respect, a question remains: is it not evident to know to what extent the sampling rates obtained in laboratory experiments can be used in field conditions? The problem can be solved for hydrophobic samplers by using performance reference compounds (PRCs), and an ongoing challenge for POCIS is focused on the improvement of the quantitative aspect of this family of samplers. In this study, potential PRCs have been selected during a specific experiment and their performance was tested in the laboratory under two hydrodynamic conditions. Results revealed a good proportionality between elimination rates of PRCs and sampling rates of chemicals. Afterwards, the application of the approach under environmental conditions was assessed by deploying POCIS in the Arcachon Bay (France) where POCIS-PRC-derived water concentrations appear to be close to the simultaneous grab-sampling results.


Stretched penile length and anogenital distance in Egyptian boys aged one month to five years.
In children with isolated unilateral undescended testis mechanical anomalies are commonly implicated and a diagnosis of simple hypospadius implies that the rest of the external genitalia are normal. Patients with disorders of sexual development, by contrast, have other associated genital anomalies including micropenis and should be referred to the endocrinologist for hormonal assessment before surgical correction of undescended testis or hypospadius. Early diagnosis of abnormal penile size is important but proper assessment begins with defining the normal population-specific age-appropriate reference range. Anogenital distance (AGD) reflects prenatal and early postnatal testosterone levels. The aim of our study was to establish mean reference values and percentile curves for strtetched penile length (SPL) and AGD in healthy Egyptian males from the age of one month to five years and to determine the mean monthly increase in SPL and AGDs from 1 to 13 months of age (a reflection of mini-puberty). This was a descriptive cross-sectional study conducted in Cairo University and Mataria Hosptals, Egypt to determine SPL and AGD in 2972 Egyptian males aged from one month to five years from October 2016-December 2018. In addition, we measured length/height, weight and body mass index. SPL increased gradually from a mean ± SD of 3.55 ± 0.51 cm in the first year of life to 5.52 ± 0.67 cm by five years of age with a growth from 1 to 12 months of life of 0.6 cm. SPL showed smaller values in infants 6-9 months old compared to younger infants. AGD increased from 7.48 ± 1.47 cm in the first year of life to 12.83 ± 0.58 cm by 5 years of age with a growth from 1 to 12 months of 4.34 cm. SPL and AGD Z-scores correlated positively with each other and with age (months), and Z-scores of height/length, weight and BMI (p < 0.001). The rapid increases in SPL and AGD observed in our study group in the first few months of life reflect the effects of mini-puberty. The fact that SPL and AGD correlated positively with other anthropometric measurements suggests that SPL and AGD may be controlled by nutritional and/or hormonal factors. We suggest that waning testosterone levels marking the end of minipuberty might explain smaller values for SPL in our group of 6-9 month old infants compared with younger infants. We have not included children under one month old. It is important for each country to develop its own national percentile curves for all growth parameters. This will allow the physician to identify normal differences in the population and to pick up disorders at an age when intervention may yield better results We have developed percentile curves for SPL and AGD that can be used as references for Egyptian male infants and young children.


Australian Psychologists Experiences with Digital Mental Health: a Qualitative Investigation.
Digital mental health is changing the landscape of service delivery by addressing challenges associated with traditional therapy. However, practitioners' use of these resources remains underexamined. This study explored psychologists' attitudes and experiences with digital mental health intervention. Taking a qualitative exploratory approach via thematic analysis, the study sought to answer the following research questions: (i) How do psychologists perceive digital mental health? and (ii) What is their experience using digital mental health as part of routine practice? Ten practising psychologists participated in online semi-structured interviews (approximately 50 min), with interviews then transcribed verbatim. Interview data were analysed according to the six-phase approach to thematic analysis proposed by Braun and Clarke. Three themes were identified: (1) attitudes towards digital mental health; (2) use within routine practice; and (3) perspectives on an effective model for implementation. Practitioners play a major role in the design and delivery of digital mental health services. Barriers and facilitators at the practitioner-level (e.g. knowledge and competence with tools, perceptions on the utility of digital interventions) and the service-level (e.g. government support for digital health) should be considered in the future design of digital mental health resources and service delivery. The online version contains supplementary material available at 10.1007/s41347-022-00271-5.


Environmental effects on CO2 efflux from riparian tundra in the northern foothills of the Brooks Range, Alaska, USA.
Carbon dioxide efflux and soil microenvironmental factors were measured diurnally in Carex aquatilus-and Eriophorum angustifolium-dominated riparian tundra communities to determine the relative importance of soil environmental factors controlling ecosystem carbon dioxide exchange with the atmosphere. Measurements were made weekly between 18 June and 24 July 1990. Diurnal patterns in carbon dioxide efflux were best explained by changes in soil temperature, while seasonal changes in efflux were correlated with changes in depth to water table, depth to frozen soil and soil moisture. Carbon dioxide efflux rates were lowest early in the growing season when high water tables and low soil temperatures limited microbial and root activity. Individual rainfall events that raised the water table were found to strongly reduce carbon dioxide efflux. As the growing season progressed, rainfall was low and depth to water table and soil temperatures increased. In response, carbon dioxide efflux increased strongly, attaining rates late in the season of approximately 10 g CO2 m-2 day-1. These rates are as high as maxima recorded for other arctic sites. A mathematical model is developed which demonstrates that soil temperature and depth to water table may be used as efficient predictors of ecosystem CO2 efflux in this habitat. In parallel with the field measurements of CO2 efflux, microbial respiration was studied in the laboratory as a function of temperature and water content. Estimates of microbial respiration per square meter under field conditions were made by adjusting for potential respiring soil volume as water table changed and using measured soil temperatures. The results indicate that the effect of these factors on microbial respiration may explain a large part of the diurnal and seasonal variation observed in CO2 efflux. As in coastal tundra sites, environmental changes that alter water table depth in riparian tundra communities will have large effects on ecosystem CO2 efflux and carbon balance.


Novel aminotetrazole derivatives as selective STAT3 non-peptide inhibitors.
The development of inhibitors blocking STAT3 transcriptional activity is a promising therapeutic approach against cancer and inflammatory diseases. In this context, the selectivity of inhibitors against the STAT1 transcription factor is crucial as STAT3 and STAT1 play opposite roles in the apoptosis of tumor cells and polarization of the immune response. A structure-based virtual screening followed by a luciferase-containing promoter assay on STAT3 and STAT1 signaling were used to identify a selective STAT3 inhibitor. An important role of the aminotetrazole group in modulating STAT3 and STAT1 inhibitory activities has been established. Optimization of the hit compound leads to 23. This compound inhibits growth and survival of cells with STAT3 signaling pathway while displaying a minimal effect on STAT1 signaling. Moreover, it prevents lymphocyte T polarization into Th17 and Treg without affecting their differentiation into Th1 lymphocyte.


The (CCTTT)n microsatellite polymorphism in the nitric oxide synthase 2 gene may influence bladder cancer pathogenesis.
We analyzed whether the NOS2 promoter microsatellite (CCTTT)n polymorphism influences bladder cancer pathogenesis. We genotyped 359 patients with bladder cancer in a population based cohort and 164 population controls by DNA fragment analysis and sequencing. Genotypes were combined with information on tumor stage, grade and stage, grade progression and cancer specific death. Clinical followup was 5 years. We divided (CCTTT)n alleles into short-10 or fewer, intermediate-11 or 12 and long-13 or greater repeats. Patients homozygous for 13 or longer (CCTTT)n repeats were at decreased odds ratio for bladder cancer (p = 0.010). However, after illness developed they were at 3-fold increased hazard ratio for stage progression (p = 0.062) and 4-fold increased hazard ratio for death from bladder cancer (p = 0.056). We discovered what is to our knowledge a previously undescribed polymorphism at position 23105343 (C/T). There was no difference in frequency between bladder cancer cases and population controls for this polymorphism. No associations were found between tumor stage, grade or stage and grade progression. However, patients with bladder cancer with the heterozygous CT genotype were at 3-fold increased hazard ratio of death from cancer (p = 0.011). Nitric oxide can induce proliferation or apoptosis depending on the cellular context. Results suggest that the (CCTTT)n NOS2 microsatellite may influence bladder cancer risk and aggressiveness. This polymorphism may have an impact on disease pathogenesis, possibly by affecting intracellular nitric oxide levels.


Long non-coding RNA TRPM2 antisense RNA as a potential therapeutic target promotes tumorigenesis and metastasis in esophageal cancer.
Esophageal cancer (EC) is one type of aggressive gastrointestinal cancers. The treatment of EC is challenging. Effective therapeutic targets require development. Long non-coding RNA TRPM2 antisense RNA (LncRNA TRPM2-AS) is considering a novel biomarker and therapeutic target for various types of cancer. However, the role of lncRNA TRPM2-AS in EC remains unknown. This study aimed to illustrate effects of LncRNA TRPM2-AS on EC growth and metastasis and potential underlying molecular mechanisms. LncRNA TRPM2-AS expression was determined in both EC tissues and cell lines by quantitative real-time polymerase-chain reaction (qRT-PCR). Cell proliferation ability was evaluated by cell counting kit-8 and colony formation assays. Cell apoptosis was analyzed by flow cytometry. Cell migration and invasion were determined using transwell. Epithelial-mesenchymal transition (EMT)-related markers expression were determined using qRT-PCR and Western blotting. Furthermore, potential lncRNA TRPM2-AS targeting miRNAs were predicted by public databases. The expression of five selected miRNAs were validated by qRT-PCR. We found that lncRNA TRPM2-AS expression was increased in EC tissues and cell lines compared with respective control. Silencing lncRNA TRPM2-AS suppressed EC cell proliferation, migration, and invasion while promoted cell apoptosis. Moreover, lncRNA TRPM2-AS knockdown reduced neural cadherin, vimentin, and matrix metallopeptidase 9 gene and protein expressions while increased epithelial cadherin expression. Furthermore, lncRNA TRPM2-AS knockdown promoted microRNA (miR)-1291, miR-6852-5p, and miR-138-5p expressions. Taken together, this study for the first time demonstrates that upregulation of lncRNA TRPM2-AS in EC promotes the growth and metastasis of EC likely through interacting with miR-1291, miR-6852-5p, and miR-138-5p.


Severe acute pancreatitis concurrent with lethal rupture of cerebral aneurysm: A case report and review of the literature.
With high incidence and mortality, severe acute pancreatitis (SAP) is an inflammatory disease of pancreas. When concurrent with systemic inflammatory response syndrome (SIRS), multiple organ failure syndrome (MODS) or pancreatic encephalopathy (PE), it will significantly augment the mortal rate. Herein, we report the first SAP case complicated with fatal rupture of cerebral aneurysm and pre-existing cerebral arteriovenous malformation; meanwhile, numerous examinations indicated the occurrence of SIRS and MODS. A 34-year-old male was admitted for these complaints of fixed and continuous epigastric distending pain, nausea and vomiting for nearly 6 h after his greasy lunch. Imaging and experimental examinations indicated SAP concurrent with SIRS and MODS in this patient. Conventional therapies stabled him, but he developed unconscious for fatal rupture of cerebral aneurysm based on cerebral magnetic resonance imaging results. Subsequent treatments failed and this patient died from lethal systemic complications. After reviewed relevant literature in detail, we unveil the potential mechanisms in this case that systemic inflammation initiated by necrotic tissues of pancreas will disrupt blood-brain barrier (BBB), increase BBB permeability, trigger neuroinflammation and eventually damage cerebral vascular. Therefore, to prevent lethal complications of PE or cerebral hemorrhage (CM) in severe pancreatitis, more attentions are recommended to be paid on identifying inflammation-induced brain dysfunction and applying prompt anti-inflammatory therapies.


The higher the serum albumin, the better? Findings from the PRACTICE study.
The relation between hypoalbuminemia and coronary artery disease (CAD) has been established. However, the association of increased albumin level and outcomes of CAD has not been investigated. There were 14 994 CAD patients from the PRACTICE study, which is a large, single center prospective cohort study based on case records and follow-up registry performed in the First Affiliated Hospital of Xinjiang Medical University from Dec. 2016 to Oct. 2021 in the present study. All the 14 994 patients were divided into five categories according albumin levels: <35 g/L group (n = 1 478), 35-40 g/L group (n = 5 007), 40-45 g/L group (n = 6 076), 45-50 g/L group (n = 1 835), and ≥50 g/L group (n = 598). A total of 448 all-cause deaths(ACD), 333 cardiac deaths (CD), 1 162 MACEs and 1 276 MACCEs were recorded during up to 60-months follow-up period. After adjusting for confounders, we observed a non-linear relation for either MACE or MACCE with the lowest risk at 45 g/L of albumin levels. A threshold value of albumin ≥50 g/L was associated with an increased risk for either MACE (adjusted HR=1.617, 95%CI:1.130-2.315, P = 0.009) or MACCE (adjusted HR= 1.439, 95%CI: 1.007-2.056, P = 0.045) in multivariable Cox regression model. For mortality, we only found decreased (<35 g/L) but not increased albumin level was associated with either ACD (HR=2.744, 95%CI: 1.631-4.617, P<0.001) or CD (HR=2.736, 95%CI: 1.484-5.045, P = 0.001). In the present study, a U-shaped curve relation was identified between albumin levels and MACE and MACCE in CAD patients, with the lowest risk at 45 g/L levels.


Antigenic analysis of bean pod mottle virus using linear and cyclized synthetic peptides.
The antigenic structure of the comovirus bean pod mottle virus (BPMV) was studied using synthetic peptides selected on the basis of the exposed location of certain regions of the viral protein. Three regions of domain A, four regions of domain B and two regions of domain C of BPMV coat protein were studied. Each of four regions were synthesized in the form of linear and cyclized peptides while the others were synthesized as linear peptides only. The peptides were tested for their ability to be recognized by antibodies directed against BPMV. The peptides were also used for producing rabbit antisera, which were tested for their ability to react with various BPMV antigens as well as with the linear and cyclized peptides. All the peptides were found to correspond to epitopes of BPMV coat protein. Several of the antigenic sites of BPMV located on exposed loops of the coat protein occupy positions which correspond to known epitopes in the structurally related picornaviruses. Only in some cases did cyclization sufficiently improve the level of conformational mimicry between peptides and the viral protein to allow cross-reactions between them to be observed.


Taming Fabry-Pérot resonances in a dual-metasurface multiband antenna with beam steering in one of the bands.
Metasurfaces are artificial materials that can provide properties not readily available in nature for the interaction with acoustic, elastodynamic, or electromagnetic waves. In Electromagnetics, metasurfaces allow particular functionalities to antennas, which in turn lately have been increasingly pushed to a multiband operation. To fully exploit metasurfaces' capabilities, the use of a metasurface reflector and a metasurface superstrate surrounding a radiating element in multiband antennas is interesting. However, such topology generally creates multiple reflections inside the formed cavity, known as Fabry-Pérot resonances. Here we show that one should tame this phenomenon to use two parallel metasurfaces surrounding a planar radiating element. We present the conditions to obtain directive, multiband antennas under such circumstances. The concepts are validated with a compact device for 5G/4G/Wi-Fi 2.4/5/6E performing a beam steering in the 5G without disturbing the radiation patterns of the other bands. This device demonstrates that the functionalities of two metasurfaces may be exploited in a single design if the presented conditions are respected. We also anticipate our work to be a starting point for other studies in the wave domain. For example, compact, multiband, beam-steerable microphones or sonar transducers with two parallel metasurfaces could be investigated in the future.


Pharmacological inhibition of MERTK induces in vivo retinal degeneration: a multimodal imaging ocular safety assessment.
The receptor tyrosine kinase, MERTK, plays an essential role in homeostasis of the retina via efferocytosis of shed outer nuclear segments of photoreceptors. The Royal College of Surgeons rat model of retinal degeneration has been linked to loss-of-function of MERTK, and together with the MERTK knock-out mouse, phenocopy retinitis pigmentosa in humans with MERTK mutations. Given recent efforts and interest in MERTK as a potential immuno-oncology target, development of a strategy to assess ocular safety at an early pre-clinical stage is critical. We have applied a state-of-the-art, multi-modal imaging platform to assess the in vivo effects of pharmacological inhibition of MERTK in mice. This involved the application of mass spectrometry imaging (MSI) to characterize the ocular spatial distribution of our highly selective MERTK inhibitor; AZ14145845, together with histopathology and transmission electron microscopy to characterize pathological and ultra-structural change in response to MERTK inhibition. In addition, we assessed the utility of a human retinal in vitro cell model to identify perturbation of phagocytosis post MERTK inhibition. We identified high localized total compound concentrations in the retinal pigment epithelium (RPE) and retinal lesions following 28 days of treatment with AZ14145845. These lesions were present in 4 of 8 treated animals, and were characterized by a thinning of the outer nuclear layer, loss of photoreceptors (PR) and accumulation of photoreceptor outer segments at the interface of the RPE and PRs. Furthermore, the lesions were very similar to that shown in the RCS rat and MERTK knock-out mouse, suggesting a MERTK-induced mechanism of PR cell death. This was further supported by the observation of reduced phagocytosis in the human retinal cell model following treatment with AZ14145845. Our study provides a viable, translational strategy to investigate the pre-clinical toxicity of MERTK inhibitors but is equally transferrable to novel chemotypes.


Effects of different levels of TGF-β expression and tumor cell necrosis rates in osteosarcoma on the chemotherapy resistance of osteosarcoma.
The clinical significance of transforming growth factor β (TGF-β) and tumor cell necrosis rate (TCNR) in the expression of osteosarcoma and its effects of chemotherapy resistance on osteosarcoma were explored. 94 cases of neoadjuvant chemotherapy osteosarcoma patients at the Third Affiliated Hospital of Kunming Medical University between January 2014 and January 2019 were collected. Samples tested for TGF-β were collected before chemotherapy, the tumor cell necrosis rate of pathological samples before and after chemotherapy was determined. Others analyzed covariates included 12 prognostic factors that may be associated with chemotherapy resistance in previous studies: age, BMI, initial diagnosis time (The time from symptom onset to first medical attention), KPS score, initial tumor size, lymphocytes/leukocytes rate (LWR), neutrophils/lymphocytes rate (NLR), albumin, aspartate transaminase (AST), low density lipoprotein (LDL), blood urea nitrogen (BUN), alkaline phosphatase (ALP), the endpoints included progression-free survival (PFS) and overall survival (OS), response evaluation criteria in solid tumours by RECIST guideline (version 1.1). 1. A total of 94 cases were examined for expression of TGF-β in pathological specimens, 45 cases were TGF-β high expression (47.9%) and 49 cases were TGF-β low expression (52.1%); 2. The BMI, LDL, ALP, NLR in TGF-β high expression group was significantly increased compared to TGF-β low expression group; the Initial diagnosis time, KPS in TGF-β high expression group was significantly decreased compared to TGF-β low expression group, all P < 0.05; 3. Effect of chemotherapy was positively with positive cell rate (P < 0.01 r = 0.337) and TGF-β total score (P < 0.0001 r = 0.635), while effect of chemotherapy was no correlation with degree of dyeing score (P > 0.05); there was significant difference in change from baseline after chemotherapy between TGF-β high expression group and TGF-β low expression group (P = 0.045); 4. Median OS 61.4 months in the TGF-β high expression group, median OS 68.1 months in the TGF-β low expression group, one-year survival rate, there was statistically significant difference in two groups (P = 0.045); median PFS 44.8 months in the TGF-β high expression group, median PFS 56.2 months in the TGF-β low expression group, There was no statistically significant difference in two groups (P > 0.05); 5. A total of 92 cases were examined for TCNR after chemotherapy, 62 were TCNR ≤ 90% (67.4%), 30 were TCNR > 90% (32.6%); 6. the Initial diagnosis time, KPS, in TCNR > 90% group was significantly increased compared to TCNR ≤ 90% group; the initial tumor size, BUN, ALP in TCNR > 90% group was significantly decreased compared to TCNR ≤ 90% group, all P < 0.05; 7. TCNR was negatively correlated with the change from baseline after chemotherapy (P < 0.001 r = -0.411); there was no statistically significant difference between TCNR > 90% group and TCNR ≤ 90% group in change from baseline after chemotherapy (P > 0.05); 8. Median OS 67.8 months in the TCNR > 90% group, median OS 61.7 months in the TCNR ≤ 90% group, there was statistically significant difference between two groups (P = 0.040); median PFS 57.4 months in the TCNR > 90% group, median PFS 40.5 months in the TCNR ≤ 90% group, there was statistically significant difference between two groups (P = 0.036); 9. TGF-β total score was negatively correlated with TCNR (P < 0.001 r = -0.571). The results of this study suggested that the higher expression of TGF-β, the lower expression of TCNR, which more likely to induce chemotherapy resistance among patients with osteosarcoma and lead to poor prognosis.


A green, simplified, and efficient experimental setup for a high-throughput screening of agri-food by-products - From polar to nonpolar metabolites in sugarcane solid residues.
From an environmental perspective, searching for useful compounds in agri-food by-products by employing inefficient and polluting analytical procedures is paradoxical. This work aimed to develop a green, simplified, and highly efficient experimental setup for extracting and tentatively identifying the broadest range of metabolites in sugarcane solid by-products collected directly within the industrial mills. Nine different extraction approaches were investigated side-by-side, including three reference methods. Based on the extraction and environmental performances assessed by two complementary metrics called Analytical-Eco Scale and the Analytical Greenness Calculator, it was possible to reach two highly efficient two liquid-phase extractions while avoiding harmful solvents and traditional time, energy, and solvent consuming sample preparation steps, such as solvent evaporation, metabolite concentration, re-suspension, and derivatization. The simultaneously produced hydroethanolic and n-heptane extracts were directly analyzed by ultra-high-performance liquid chromatography and gas chromatography, both coupled to mass spectrometry, respectively, leading to the annotation of a large dynamic range of compounds from information rich spectral data. Up to 111 metabolites were identified in a single matrix, from highly polar sucrose to nonpolar wax ester C53 in a single extraction. Orientin, apigenin-6-C-glucosylrhamnoside, 1-octacosanol, octacosanal, and other bioactive compounds were identified in these abundantly available by-products, which are currently just burned to produce energy. The best two methods developed here (Two-Liquid-Phase Ultrasound-Assisted Extraction with Probe and Two-Liquid-Phase Dynamic Maceration) appeared as a green, simplified, and highly efficient procedures to qualitatively profile metabolites in complex solid matrices.


[Transparency: can the effect of governmental surveillance be quantified?].
To explore the feasibility of using existing data to measure the impact of surveillance by the Health Care Inspectorate (IGZ) on public health. Retrospective, descriptive. We examined the magnitude of the health problems of suicide, pressure ulcers and medication errors before and after surveillance by the IGZ. To do this, we used data from the IGZ, external data files and data from the literature. In addition, we assessed definitions and possible underreporting and overreporting of the results. We then determined whether an estimate could be made of the effect of the surveillance on the magnitude of the health problem using a time series design. Medication errors were not sufficiently defined to measure an effect of surveillance. The prevalence of pressure ulcers and the incidence of suicide could be quantified reliably using data from the Inspectorate. A time series design showed that both health problems declined after surveillance by the Inspectorate. However, these trends could not be attributed to the surveillance since there was no insight into the external factors that might have played a role. In case of clearly defined health problems, the extent of the problem can be defined using IGZ data and trends can be observed using a time series design. However, establishing a causal relationship between supervision and observed trends requires an experimental research design, such as a prospective randomized study or a stepped wedge design.


Overview of sexual dysfunction in patients with cancer.
Among survivor's patients with cancer, sexual dysfunction (SD) is a common treatment-related disturbance that significantly affects their quality of life. The disorder can be a short-term effect, but frequently it can be permanent and patients often do not receive adequate support to overcome the problem. The characteristics of SD may differ depending on the type of neoplasm and oncological treatment. The most common long-term effects are those related to treatment-induced menopause, ablative oncologic surgery, and altered gonadal function. Breast, prostate, and gynecologic cancers are the tumors most commonly associated with disturbances in sexual health, although there is evidence of SD in patients with other types of neoplasms. It is necessary for the healthcare team caring for oncological patients to be aware of the characteristics of sexual dysfunction in this population. This will make it possible to offer patients a comprehensive and personalized approach to improve their quality of life.


BNCT research facility at MARIA reactor - Numerical models and preliminary measurements.
In NCBJ, Poland a new laboratory for BNCT research is being constructed at MARIA reactor. In the first phase it will provide a thermal neutron beam for experiments with cellular samples and small animals. In the next step, a converter will be mounted to provide fast neutron beam. Beam shaping assembly will moderate the beam to epithermal energies allowing for irradiation human phantoms. The laboratory infrastructure as well as radiation shielding of the laboratory are being designed using MCNP6 software.


Endothelin and endothelium-derived relaxing factor control of basal renovascular tone in hydronephrotic rat kidneys.
1. In order to investigate the control of renal vascular tone by endothelin (ET) and endothelium-derived relaxing factor (EDRF) under basal conditions, we infused intravenously anti-ET-1/3 antibodies (a-ET-1/3) and NG-nitro-L-arginine methyl ester (L-NAME) in split hydronephrotic rat kidneys. 2. A 25 min I.V. infusion of a-ET-1/3 (4.0 x 10(-13) mol kg-1 min-1) induced a time-dependent vasodilatation of arcuate (16.5%) and interlobular arteries (18.6%) as well as an increase of glomerular blood flow (GBF) by 32%. 3. Inhibition of EDRF synthesis by L-NAME produced a marked vasoconstriction of arcuate arteries (17.1%) and efferent (20.1%) arterioles and a decrease of GBF by 43%. 4. Co-infusion of a-ET-1/3 and L-NAME induced efferent vasoconstriction by 19.5%, whereas preglomerular vessel diameters remained unchanged. 5. The specificity of a-ET-1/3 effects was confirmed by simultaneous I.V. application of a-ET-1/3 and ET-1 (160 ng I.V.) which produced no significant vascular effects. Injection of ET-1 alone constricted arcuate arteries and decreased glomerular blood flow by 25%. 6. Experiments in normal rat kidneys with a-ET-1/3 I.V. revealed an increase of renal blood flow by 21%. 7. Our results demonstrate a physiological control of basal vascular tone in larger preglomerular arterioles by ET and EDRF. Efferent arteriolar tone is predominantly controlled by EDRF.


Characterization of biofilm production by Pseudomonas fluorescens isolated from refrigerated raw buffalo milk.
Pseudomonas fluorescens can often be isolated from refrigerated raw milk. Two strains of P. fluorescens PL5.4 and PL7.1, isolated from raw buffalo milk, were evaluated for their proteolytic capacity, exopolysaccharide production and biofilm production. Proteolytic activity was observed in both strains. The P. fluorescens PL5.4 strain presented fluorescence in the presence of calcofluor, indicating exopolysaccharide production. Both strains were able to produce biofilm at 7 °C for 72 h. For the biofilm production test on stainless steel, adherent cell counts of up to 7.1, 7.3 and 8.8 log CFU/cm2 at 7, 23 and 30 °C were obtained. Through scanning electron microscopy, it was possible to observe the biofilm produced by the P. fluorescens PL5.4 strain. Proper cleaning and disinfection practices in order are important to reduce bacterial contamination and extend the useful life of raw material and its derivatives.


Changes with aging in the levels of amino acids in rat CNS structural elements. II. Taurine and small neutral amino acids.
Taurine (Tau) and the small neutral amino acids glycine (Gly), serine (Ser), threonine (Thr), and alanine (Ala) were measured in 53 brain areas of 3- and 29-month-old male Fisher 344 rats. The ratio of highest to lowest level was 34 for Tau, 9.1 for Thr, 7.6 for Gly and Ser, and 6.5 for Ala. The heterogeneity was found in numerous areas; for example, Tau levels were more than 90 nmol/mg protein in 6 areas, and less than 20 nmol/mg protein in 10 areas. Similar heterogeneity was found with the other amino acids. The relative distribution of the small neutral amino acids showed several similarities; Tau distribution was different. With age, four amino acids decreased in 10-18 areas, and increased in only 1-3, while Thr increased in more areas than it decreased. The five amino acids of this paper, and the four of the previous paper, are among the amino acids at highest level in the brain; the sequence in their levels shows considerable regional heterogeneity.


Application of fluorescence lifetime imaging (FLIM) in latent finger mark detection.
Fluorescence lifetime imaging (FLIM) in frequency domain enables the mapping of the spatial distribution of fluorescence lifetimes of a specimen. It has been extensively applied in biology. In this paper, a theoretical analysis for the fluorescence lifetime determination of latent finger mark samples is described, which is followed by the feasibility study of using FLIM in frequency domain for latent finger marks detection. Preliminary experiments are carried out with latent finger marks treated with a fluorescent powder on two different substrates. The resulting fluorescence lifetime image of finger mark revealed a good contrast, and was able to detect the latent finger marks clearly.


[Does the nursing shortage in neonatal intensive care units (NICU) threaten the warranty of healthcare for newborns? : The "Mary and Joseph" project].
Germany has been experiencing a dramatic shortage of nursing staff for years that particularly affects neonatal intensive care units (NICUs). It is assumed that this situation leads to reductions in bed capacities, resulting in negative effects on the healthcare of newborns. These were investigated through a retrospective observational study using the example of three NICUs at the University Hospital of Munich (LMU). For the four-year observation period from August 2017 to May 2021, time series data from the "Quality Assurance Guideline for Premature and Mature Infants" (QFR-RL) of the Federal Joint Committee, bed resource analysis, planned personnel statistics, clinical logout data, and rescue service data were mutually examined using descriptive statistics and regression analysis. During the observation period, around 21% of the necessary nursing staff positions were vacant, although the quality of nursing care for newborns seemed to have been guaranteed. However, to ensure quality, given the staff shortage, several available beds had to be blocked. In this context, both an increase in the number of hours the wards were logged off from population care and an increase in the relative risk of neonatal intensive care transfer were observed, resulting in a transfer every three days on average. A shortage of nursing staff reduces the neonatal hospital bed capacity, since neonatal nursing care quality is regulated by strict legally binding guidelines, the QFR-RL. This is why the consequences for the security of care for the population through hospital cancellations and a risk of transfer must be accepted on a regular basis.


Prostacyclin degradation in patients with quantitative platelet disorders.
Plasma prostacyclin (PGI2) degradation rates were measured at 1, 5, 15 and 30 min in a group of patients with platelet quantitative disorders of various pathogeneses, including 13 with thrombocytosis, 16 with thrombocytopenia from impaired production in the bone marrow, 11 with thrombocytopenia from peripheral destruction, and 28 normal, healthy persons. Patients with thrombocytosis had a low PGI2 degradation rate, whereas patients with thrombocytopenia due to impaired production had a high PGI2 degradation rate. Of the patients with thrombocytopenia caused by peripheral destruction, six with idiopathic thrombocytopenia purpura (ITP) had a slow PGI2 degradation in contrast to five with systemic lupus erythematosus (SLE) - four concurrently had cryoglobulinemia - who had a rapid PGI2 degradation. The findings suggest that: (1) a platelet-derived substance in the human plasma may have a PGI2 stabilising activity; (2) presence of cryoglobulin or immune complex in plasma may interfere with PGI2 stability.


HIV persistence in the setting of antiretroviral therapy: when, where and how does HIV hide?
Advances in the treatment of HIV infection have dramatically reduced the death rate from AIDS and improved the quality of life of many HIV-infected individuals. However, the possible long-term toxicity associated with antiretroviral therapy (ART), stigma and cost, all contribute to the necessity of finding a cure for HIV infection. In infected individuals taking ART, HIV persists in a small number of cells that can survive for the lifetime of the infected person. These persistently infected cells, usually referred as the 'reservoirs for HIV infection', are the main barriers to a cure. The diversity of the tissues and cellular types in which HIV persists, as well as the multiplicity of the molecular mechanisms contributing to HIV persistence, complicate the efforts to develop a safe, effective, and globally accessible cure for HIV. In this review, we summarise recent data that contribute to our understanding of HIV persistence during ART by addressing three questions pertaining to the HIV reservoir: (1) when is the reservoir established; (2) where is the reservoir maintained; and (3) how does the reservoir persist?


[Levels and clinical significance of CD44 (intron 9) and CD44v6 in malignant cerebroma].
To investigate the expression of CD44 (intron 9) and CD44v6 in brain neoplasm. CD44 (intron 9) and CD44v6 were detected in malignant meningoma, encephalic glioma, and normal encephalic tissues around the brain noeplasm respectively by using RT-PCR. The positive expression rate of CD44v6 was 92.86% (26/28) in malignant meningoma and 88.0% (22/25) in encephalic glioma. They were significantly higher than 5.0% (1/20) in normal encephalic tissues (P < 0.01). Mass values of malignant meningoma and encephalic glioma were higher than that of normal encephalic tissues (P < 0.01). The expression of CD44 (intron 9) was higher in malignant meningoma and encephalic glioma than in normal encephalic tissues (P < 0.01). Detection of CD44 (intron 9) and CD44v6 might be helpful to the diagnosis of malignant cerebroma.


Overexpressing MhNPR1 in transgenic Fuji apples enhances resistance to apple powdery mildew.
Fuji is susceptible to fungal diseases like apple powdery mildew. Non-expressor of pathogenesis-related gene 1 (NPR1) plays a key role in regulating salicylic acid (SA)-mediated systemic acquired resistance (SAR). Previous studies show that overexpressing the Malus hupehensis-derived NPR1 (MhNPR1) gene in tobacco induces the transcript expression of pathogenesis-related genes (PRs) and resistance to the fungus Botrytis cinerea. In this study we introduced the MhNPR1 gene into the 'Fuji' apple via Agrobacterium-mediated transformation. Four transgenic apple lines were verified by PCR and RT-PCR. The semi-quantitative RT-PCR results showed that transcript overexpression of the MhNPR1 gene induced the expression of MdPRs and MdMLO genes known to interact with powdery mildew. Furthermore, the transgenic apple plants resisted infection by apple powdery mildew better than the wild-type plants. As a result, transcript overexpression of the MhNPR1 gene induced SAR and enhanced the Fuji apple's resistance to fungal disease.


Hypoglycemic mechanism of intestinal bypass surgery in type 2 diabetic rats.
To investigate the effect of duodenal-jejunal bypass (DJB) surgery on postoperative blood glucose in type 2 diabetic rats, and further explore possible mechanisms for the effect of surgical treatment of type 2 diabetes. Forty rats with type 2 diabetes were randomly assigned to 4 groups (n = 10 rats per group), which subsequently underwent DJB, new biliopancreatic diversion (NBPD) or duodenal-jejunal exclusion (DJE) surgery or a sham operation (SHAM). Fasting glucose, 2-h postprandial glucose and blood lipids were measured, and the mRNA in liver and intestinal tissue for bile acid receptor (FXR), as well as the FXR protein expression in the liver tissues were determined. Postprandial blood glucose and fasting TG and FFA in the DJB and NBPD groups were significantly lower than those in the SHAM group and preoperative (p < 0.05) at 8 weeks postoperation. Liver FXR protein was expressed at significantly higher in the DJB and NBPD groups than in the other two (p < 0.05), and the intestinal FXR mRNA in the DJE group were highest. DJB up-regulates the expression of bile acid receptors in the liver and down-regulates those receptors in the intestinal tract via biliopancreatic diversion. This process reduces TG levels, and subsequently any lipotoxicity to islet cells to produce a hypoglycemic effect.


Reduced detection and levels of protective antibodies to hepatitis B vaccine in under 2-year-old HIV positive South African children at a paediatric outpatient clinic.
The study evaluated and compared the prevalence of anti-HBs and exposure to hepatitis B virus (HBV) in vaccinated South African babies aged between 5 and 24 months from the Expanded Programme on Immunisation clinic [EPI group] and paediatric outpatient clinic [OPD group], and results were stratified by HIV status. A total of 303 (243 EPI group and 60 OPD group) babies were studied. All sera were tested for anti-HBs, HBsAg and anti-HBc, while IgM anti-HBc and HBV DNA were only tested in samples positive for HBsAg and/or anti-HBc. Overall, there was a gross difference in the prevalence of anti-HBs marker between the EPI and OPD groups. The EPI group demonstrated higher levels of seroconversion (89.3% vs. 81.7%; p=0.105) and seroprotection rates (86.0% vs. 75.0%; p=0.038), compared to the OPD babies. When the overall results were stratified by HIV status, seroprotection was 85.7% for the HIV-negatives and 78.1% for the HIV-positives, although this was not statistically significant (p=0.125). The seroprotection rates were almost comparable between the HIV-positives (84.3%; n=51) and the HIV-negatives (86.5%; n=192) (p=0.695) in the EPI group. In contrast, reduced seroprotection rates were observed between the HIV-positives (63.6%; n=22) and HIV-negatives (81.6%; n=38) in the OPD group, although this was not statistically significant (p=0.123). Interestingly, no HBsAg or anti-HBc marker was detected in the OPD group, compared to total exposure rate of 4.9% (HBsAg carriage was 1.2%) in the EPI group.


Folding and stability of the b subunit of the F(1)F(0) ATP synthase.
The F(1)F(0) ATP synthase is a reversible molecular motor that employs a rotary catalytic cycle to couple a chemiosmotic membrane potential to the formation/hydrolysis of ATP. The multisubunit enzyme contains two copies of the b subunit that form a homodimer as part of a narrow, peripheral stalk structure that connects the membrane (F(0)) and soluble (F(1)) sectors. The three-dimensional structure of the b subunit is unknown making the nature of any interactions or conformational changes within the F(1)F(0) complex difficult to interpret. We have used circular dichroism and analytical ultracentrifugation analyses of a series of N- and C-terminal truncated b proteins to investigate its stability and structure. Thermal denaturation of the b constructs exhibited distinct two-state, cooperative unfolding with T(m) values between 30 and 40 degrees C. CD spectra for the region comprising residues 53-122 (b(53-122)) showed theta;(222)/theta;(208) = 0.99, which reduced to 0.92 in the presence of the hydrophobic solvent trifluoroethanol. Thermodynamic parameters for b(53-122) (DeltaG, DeltaH and DeltaC(p)) were similar to those reported for several nonideal, coiled-coil proteins. Together these results are most consistent with a noncanonical and unstable parallel coiled-coil at the interface of the b dimer.


The transcription map of mouse mitochondrial DNA.
Nine transcripts complementary to mouse L cell mitochondrial DNA have been detected, sized and mapped to restriction fragments using the method of Berk and Sharp (1977). RNA isolated from L cell mitochondria was hybridized to 32P-labeled, cloned L cell mitochondrial DNA restriction fragments in 70% formamide under conditions 5 degrees C above the melting temperature of the DNA-DNA duplex, but approximately 15 degrees C below the melting temperature of the RNA-DNA duplex. The heteroduplexed material was then treated with the single-strand-specific nuclease S1, whick cleaves the single-stranded DNA not protected by RNA-DNA duplex formation into oligonucleotides and leaves intact 32P-labeled, single-stranded DNA replicas complementary to the transcripts. The single-stranded DNA replicas were then resolved and sized by alkaline agarose gel electrophoresis. Hybridization to strand-separated, 32P-labeled L cell mitochondria DNA restriction fragments under the same conditions showed that all nine transcripts hybridized exclusively to the heavy strand (H strand) of restriction fragments isolated as the dense strand from alkaline CsCl gradients, indicating that all stable transcripts 300 bases or longer detected by this technique originate from genes on the H strand. The two most abundant transcripts homologous to mitochondrial DNA map adjacent to the origin of replication. This result is consistent with map positions assigned to the large and small mitochondrial ribosomal RNAs isolated from Xenopus laevis and HeLa cells. Six of the other seven transcripts map continuously in approximately 40% of the genome. Only one transcript of 950 bases maps in the first quadrant of the genome as defined by the origin and direction of mitochondrial DNA replication, and it does not lie within the D loop region. The genetic function of the remaining 75% of this region of the genome is yet to be determined.


Sending-or-not-sending twin-field quantum key distribution in practice.
Recently, the twin field quantum key distribution (TF-QKD) protocols have been investigated extensively. In particular, an efficient protocol for TF-QKD with sending or not sending the coherent state has been given in. Here in this paper, we present results of practical sending-or-not-sending (SNS) twin field quantum key distribution. In real-life implementations, we need consider the following three requirements, a few different intensities rather than infinite number of different intensities, a phase slice of appropriate size rather than infinitely small size and the statistical fluctuations. We first show the decoy-state method with only a few different intensities and a phase slice of appropriate size. We then give a statistical fluctuation analysis for the decoy-state method. Numerical simulation shows that, the performance of our method is comparable to the asymptotic case for which the key size is large enough. Our method can beat the PLOB bound on secret key capacity. Our results show that practical implementations of the SNS quantum key distribution can be both secure and efficient.


The Role of Sugars in Plant Responses to Stress and Their Regulatory Function during Development.
Due to their role as energy and carbon sources and their regulatory functions, sugars influence all phases of the plant life cycle, interact with other signaling molecules, including phytohormones, and control plant growth and development [...].


Arsenic in groundwaters of the Lower Mekong.
Increasing incidence and awareness of arsenic in many alluvial aquifers of South-east Asia has raised concern over possible arsenic in the Lower Mekong Basin. Here, we have undertaken new research and reviewed many previous small-scale studies to provide a comprehensive overview of the status of arsenic in aquifers of Cambodia and the Cuu Long Delta of Vietnam. In general natural arsenic originates from the Upper Mekong basin, rather than from the local geology, and is widespread in soils at typical concentrations of between 8 and 16 ppm; (dry weight). Industrial and agricultural arsenic is localised and relatively unimportant compared to the natural alluvial arsenic. Aquifers most typically contain groundwaters of no more than 10 microg L(-1), although scattered anomalous areas of 10 to 30 microg L(-1 )are also quite common. The most serious, but possibly ephemeral arsenic anomalies, of up to 600 microg L(-1), are associated with iron and organic-rich flood-plain sediments subject to very large flood-related fluctuations in water level, resulting in transient arsenopyrite dissolution under oxidizing conditions. In general, however, high-arsenic groundwaters result from the competing interaction between sorption and dissolution processes, in which arsenic is only released under reducing and slightly alkaline conditions. High arsenic groundwaters are found both in shallow water-tables, and in deeper aquifers of between 100 and 120 m depth. There is no evidence of widespread arsenicosis, but there are serious localised health-hazards, and some risk of low-level arsenic ingestion through indirect pathways, such as through contaminated rice and aquaculture. An almost ubiquitous presence of arsenic in soils, together with the likelihood of greatly increased groundwater extraction in the future, will require continuing caution in water resources development throughout the region.


Prevalence of End Stage Kidney Disease and distribution of treatment modalities
On the occasion of the 20th anniversary of the REIN (French Renal Epidemiology and Information Network), a summary work on the contributions of the national French ESKD register was carried out. On the issue of ESKD prevalence, the following key messages were retained. While chronic kidney disease affects all age groups, there always are more patients to treat in the older age groups, with a median age of 71.1 years (IIQ 60.3-80.0) under dialysis and 58.7 years (IIQ 47.4-68.3) under renal transplant. Despite an increase in transplant activity and improved survival of grafts, the gap between the number of dialysis patients and transplant patients at the end of each year is only moderately reduced. There has been a moderate decrease in the proportion of in-centre haemodialysis that is explained by a significant increase in medicalised dialysis units (out-centre haemodialysis) and a decrease in self-care haemodialysis. Finally, a stable home-based care has been observed despite the ministerial incentives and the recommendations of the French-speaking scientific society (SFNDT-white paper).


Exercise preconditioning improves electrocardiographic signs of myocardial ischemic/hypoxic injury and malignant arrhythmias occurring after exhaustive exercise in rats.
Exercise preconditioning (EP) has a good myocardial protective effect. This study explored whether EP improves electrocardiographic (ECG) signs of myocardial ischemic/hypoxic injury and the occurrence of malignant arrhythmia after exhaustive exercise. A total of 120 male SD rats were randomly divided into the control group (group C), early exercise preconditioning group (group EEP), late exercise preconditioning group (group LEP), exhaustive exercise group (group EE), early exercise preconditioning + exhaustive exercise group (group EEP + EE) and late exercise preconditioning + exhaustive exercise group (group LEP + EE). Changes in heart rate (HR), ST segment, T wave and QT corrected (QTc) intervals on ECG; hematoxylin-basic fuchsin-picric acid (HBFP) staining; and cTnI levels were used to study myocardial injury and the protective effect of EP. Compared with those in group C, the levels of plasma markers of myocardial injury, HBFP staining and ECG in group EE were significantly increased (P < 0.05). Compared with those in group EE, the levels of plasma markers of myocardial injury, HBFP staining and ECG in group EEP + EE and group LEP + EE were significantly decreased (P < 0.05). The results suggested that EP improved ECG signs of myocardial ischemic/hypoxic injury and malignant arrhythmias that occur after exhaustive exercise. The ST segment and T wave could also serve as indexes for evaluating exhaustive exercise-induced myocardial ischemia/hypoxia.


Since the previous 2013 and 2016 recommendations for clinical practice (RPC) Nice/Saint-Paul-de-Vence for gynecological cancers, the management of ovarian cancer has become more complex with the evolution of the quality criteria recommended for surgery and the integration of molecular biology for the decision of medical treatments, especially for high grade epithelial ovarian cancers. Surgical indications have become more precise both in the first line and in the context of relapse. Treatments with PARP inhibitors is a major advance in medical management with significant efficacy in maintenance after response to platinum-based chemotherapy. The benefit already known in the case of late relapse has also been demonstrated in first-line treatment with progression-free survival never observed in this pathology with patients with very long responses, especially in the case of BRCA gene abnormalities (somatic or constitutional). In 2021, medical and surgical strategies in front line including PARP inhibitors associated or not with bevacizumab as a maintenance complement after platinum chemotherapy are guided by both response to platinum agents and molecular profiling including BRCA (somatic or constitutional) genetic status and homologous recombination pathway (HRD) abnormalities, that should be early tested. On behalf of the GINECO national oncologist group, we have updated the guidelines for high grade ovarian epithelial cancer (excepted rare tumors) in order to allow rapid dissemination of the latest advances to the medical community and improve daily practice.


A novel fluorescence in situ hybridization assay for synovial sarcoma.
Synovial sarcoma, which is difficult to diagnose precisely, is one of the most common childhood nonrhabdomyosarcoma soft-tissue sarcomas. The purpose of this study is to develop new molecular cytogenetic assay. We used two sets of two-color break-apart FISH probes, flanking either the SSX1/SSX4 or SSX2 locus. Each set of probes is composed of differentially labeled DNA fragments complementary to sequences proximal or distal to the break point within the SSX1/SSX4 or SSX2 locus, which are applied separately to histopathological sections. Interphase nuclei containing a translocation that disrupts either SSX1, SSX2, or SSX4 locus will display two single-color signals that have "broken apart" from each other. We applied it to two synovial sarcoma cell lines and clinical samples. This assay can detect translocation at either SSX1/SSX4, or SSX2 locus on interphase spread prepared from synovial sarcoma cell line and histopathological sections, which is sufficient to diagnose as synovial sarcoma. Our new FISH assay has several advantages, including its applicability to paraffin-embedded samples, discrimination of the SS18-SSX1 and SS18-SSX2 translocations particularly in cases with aneuploidy, and potentially detecting translocations in all cases of synovial sarcoma, even with variant translocations. Our strategy will improve the accuracy of diagnoses, thereby facilitating appropriate treatment planning.


Bone marrow mesenchymal stromal cells in a 3D system produce higher concentration of extracellular vesicles (EVs) with increased complexity and enhanced neuronal growth properties.
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have been demonstrated to possess great potential in preclinical models. An efficient biomanufacturing platform is necessary for scale up production for clinical therapeutic applications. The aim of this study is to investigate the potential differences in neuro-regenerative properties of MSC-derived EVs generated in 2D versus 3D culture systems. Human bone marrow MSCs (BM-MSCs) were cultured in 2D monolayer and 3D bioreactor systems. EVs were isolated using ultracentrifugation followed by size and concentration measurements utilizing dynamic light scattering (NanoSight) and by fluorescence staining (ExoView). Mouse trigeminal ganglia (TG) neurons were isolated from BALB/c mice and cultured in the presence or absence of EVs derived from 2D or 3D culture systems. Neuronal growth and morphology were monitored over 5 days followed by immunostaining for β3 tubulin. Confocal images were analyzed by Neurolucida software to obtain the density and length of the neurites. The NanoSight tracking analysis revealed a remarkable increase (24-fold change) in the concentration of EVs obtained from the 3D versus 2D culture condition. ExoView analysis showed a significantly higher concentration of CD63, CD81, and CD9 markers in the EVs derived from 3D versus 2D conditions. Furthermore, a notable shift toward a more heterogeneous phenotype was observed in the 3D-derived EVs compared to those from 2D culture systems. EVs derived from both culture conditions remarkably induced neurite growth and elongation after 5 days in culture compared to untreated control. Neurolucida analysis of the immunostaining images (β3 tubulin) showed a significant increase in neurite length in TG neurons treated with 3D- versus 2D-derived EVs (3301.5 μm vs. 1860.5 μm, P < 0.05). Finally, Sholl analysis demonstrated a significant increase in complexity of the neuronal growth in neurons treated with 3D- versus 2D-derived EVs (P < 0.05). This study highlights considerable differences in EVs obtained from different culture microenvironments, which could have implications for their therapeutic effects and potency. The 3D culture system seems to provide a preferred environment that modulates the paracrine function of the cells and the release of a higher number of EVs with enhanced biophysical properties and functions in the context of neurite elongation and growth.


A simple, effective technique for port-site closure after laparoscopy.
Fascial closure of port sites represents a challenging issue in laparoscopic surgery. The aim of this article is to introduce a procedure that allows the safe suturing of the abdominal fascia in these wounds. We herein describe a simple technique for fascial closure after laparoscopy using a transcutaneous approach and standard surgical instruments for suture. The method was used in 34 patients with no intraoperative incidents and no port-site hernias during a mean follow-up of 23.9 months (median 20.5, range 5 to 47). The procedure is easy to perform, safe, fast, and inexpensive.


Formin mDia1 contributes to migration and epithelial-mesenchymal transition of tubular epithelial cells exposed to TGF-β1.
Renal tubular epithelial cells may undergo epithelial-mesenchymal transition (EMT) in response to stimuli, such as transforming growth factor (TGF)-β1, leading to myofibroblast activation and renal fibrosis. The formin mDia1 is required for nucleation and polymerization of actin and the microtubule cytoskeleton. The present study sought to explore the role of mDia1 in EMT of tubular epithelial cells. A rat model of unilateral ureteral obstruction (UUO) was established. The expression of TGF-β1, collagen I, collagen III, and mDia1 in the kidneys was examined at day 7 after surgery. The effect of mDia1 on EMT was explored in NRK-52E cells by exposing them to TGF-β1. Increased expression of TGF-β1, collagen I, collagen III, and mDia1 was found in obstructive kidneys of UUO model rats. Exposing rat tubular epithelial cells to TGF-β1 promoted collagen I and collagen III expression but had no effect on mDia1 expression. Silencing mDia1 expression impeded epithelial cell migration as well as reduced TGF-β1, collagen, and Profilin1 expression, whereas mDia1 overexpression exerted an opposite effect. Furthermore, mDia1 regulated the expression of vimentin, α-smooth muscle actin, and E-cadherin and focal adhesion-kinase (FAK)/Src activation through Profilin1. Inhibition of the mDia1 activator RhoA by fasudil reversed EMT, and FAK/Src activation induced by mDia1. In conclusion, mDia1 regulated tubular epithelial cell migration, collagen expression, and EMT in NRK-52E cells exposed to TGF-β1. Thus, suppression of mDia1 activation might be a strategy to counteract renal fibrosis.


Distinction of basaloid carcinoma of the prostate from benign basal cell lesions by using immunohistochemistry for bcl-2 and Ki-67.
The distinction of rare basaloid carcinomas (BC) of the prostate from more common basal cell hyperplasia may be difficult, because basal cell hyperplasia (BCH) may have prominent nucleoli and may appear infiltrative. Using immunohistochemistry, we studied bcl-2 and p53 expression and Ki-67 proliferation index in eight cases of typical BCH, eight cases of BCH with nucleoli, and six cases of BC. Bcl-2 expression (P < .0001) and Ki-67 index (P=.005) were elevated in BC compared with typical BCH or BCH with nucleoli, whereas there was no significant difference between typical BCH and BCH with nucleoli. P53 was not discriminative in separating benign from malignant basal cell lesions of the prostate. Bcl-2 may play a role in the pathogenesis of basal cell lesions of the prostate. Elevated expression of bcl-2 and higher Ki-67 index may aid in the diagnosis of basal cell proliferative lesions of the prostate.


Pulmonary edema following retrobulbar block.
We report a patient requiring keratoplasty who developed acute pulmonary edema following the administration of a retrobulbar block for anesthesia. A variety of factors that may have been implicated in the genesis of this complication are discussed.


Distinct evolution of calcium channel antibody types in Lambert-Eaton myasthenic syndrome.
To determine whether titers of anti-P/Q type and anti-N type calcium channel antibodies provide distinct information, both types of assay were performed during follow-up of 7 patients with Lambert-Eaton myasthenic syndrome (LEMS). In 4 patients with both antibody responses, titers evolved independently and often in an inverse relationship. Two patients with squamous cell lung carcinoma (SqCLC) produced anti-N type channel antibodies, but no detectable anti-P/Q channel responses. These results suggest that anti-N channel autoantibodies constitute an immune response distinct from the anti-P/Q type channel specificity and can also correlate with clinical evolution. Consequently combined assays may provide more comprehensive information during follow-up of LEMS.


Ventricular mechanics in the bidirectional glenn procedure and total cavopulmonary connection.
The time course of ventricular efficiency in Fontan candidates who underwent both the bidirectional Glenn procedure (BDG) and total cavopulmonary connection (TCPC) were analyzed in this study. We previously reported that volume-load reduction of BDG preceding TCPC allowed for any afterload mismatch to be corrected, thereby improving ventricular efficiency after staged TCPC. We measured percent normal systemic ventricular end-diastolic volume (%N-EDV), contractility (end-systolic elastance [Ees]), afterload (effective arterial elastance [Ea]), and ventricular efficiency (ventriculoarterial coupling [Ea/Ees]) based on cardiac catheterization data before and after both BDG and staged TCPC in 30 patients. Ees and Ea were approximated as follows: Ees = mean arterial pressure/minimal ventricular volume, and Ea = maximal ventricular pressure/(maximal ventricular volume - minimal ventricular volume), and Ea/Ees was then calculated. Ventricular volume was divided by body surface area. The %N-EDV decreased both after BDG and after staged TCPC, thus resulting in an improvement of Ees. Although Ea increased both after BDG and after staged TCPC, Ea decreased during the interval between BDG and staged TCPC. These changes resulted in an improvement in Ea/Ees during the interval period and after staged TCPC, although Ea/Ees worsened after BDG. Correction of afterload mismatch during the interval period between BDG and staged TCPC is considered to be one of the most important factors for obtaining excellent clinical results when selecting a staged strategy to treat high-risk Fontan candidates.


Variations in expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in nasal mucosa of aspirin-sensitive versus aspirin-tolerant patients with nasal polyposis.
Matrix metalloproteinases (MMPs) are key enzymes responsible for extracellular matrix degradation contributing to the progressive histological changes seen in lower airway disease, including asthma. MMP-9 and TIMP-1 have also shown some role in the pathogenesis of chronic rhinosinusitis (CRS) and nasal polyposis (NP). We aim to determine variability in expression of MMP-9 and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), in sinus tissue from distinct patient populations presenting with nasal polyposis. The expression of MMP-9 and TIMP-1 was investigated in nasal polyp tissue from 6 aspirin-sensitive (AS) and 6 aspirin-tolerant (AT) patients undergoing endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis (CRSwNP). Sinus mucosa from 6 patients with chronic rhinosinusitis without nasal polyposis (CRSsNP) was used as control. The MMP-9 and TIMP-1 expression was measured using immunofluorescence technique and graded using manual and computerized methods. Expression of TIMP-1 was significantly reduced in the AS group when compared with both the AT and CRSsNP (control) groups (P < .001). The MMP-9/TIMP-1 ratio was significantly increased in the AS group when compared with other patient groups (P < .001). The MMP- 9 expression was similar between study and control groups. These results support the importance of MMP-9 and TIMP-1 expression in nasal polyp formation. The decreased expression of TIMP-1 in AS patients may promote the effects of MMP-9 expression and thus contribute to tissue remodeling and inflammatory changes. This finding may lead to further understanding of disease severity and resistance to treatment in this group of patients, as well as the pathogenesis of nasal polyps.


A segment of the cartilage proteoglycan core protein has lectin-like activity.
A segment of 130 residues near the COOH terminus of the proteoglycan core protein derived from rat cartilage is highly homologous to the carbohydrate-recognition domain of the chicken hepatic lectin and other vertebrate carbohydrate-binding proteins. This portion of the protein has been expressed in an in vitro transcription and translation system and has been tested for its ability to interact with carbohydrates using affinity chromatography on immobilized sugars. A distinct specificity of the binding interaction is demonstrable, with fucose and galactose being the preferred ligands. However, the affinity of the expressed domain of the proteoglycan core protein is lower than that of the other known binding domains, since it elutes from the columns even in the presence of Ca2+.


Outcome predictors and implications for management of scimitar syndrome.
Scimitar syndrome is a rare congenital anomaly. We evaluated risk factors for postoperative pulmonary vein stenosis or death and predictive factors for survival without scimitar vein surgery in patients with scimitar syndrome. The records of patients with scimitar syndrome evaluated at our medical center between 1964 and 2011 were reviewed. Scimitar syndrome was identified in 80 patients, with a median follow-up of 4.5 years. Patients presenting less than 1 year of age had a higher incidence of symptoms, aortopulmonary collaterals, coexisting congenital heart disease (CHD), extracardiac anomalies, and pulmonary hypertension. Of 36 patients having scimitar vein surgery, 18 had postoperative pulmonary vein obstruction that occurred with similar frequency after baffle or reimplantation procedures, early or late in the study period, and tended to be more common in infants (P = .10). Overall, 19 (24%) of 80 died. Multivariate risk factors for death included systolic pulmonary pressure >0.5 systemic level (P = .007) and left pulmonary vein stenosis (P = .009). Pulmonary artery systolic pressure <0.5 systemic level (P = .01) and absence of CHD excluding atrial septal defect (P = .01) were predictive factors in 28 patients who survived and did not have scimitar vein surgery; these patients had no or mild right ventricular dilation and a ratio of pulmonary-to-systemic flow <1.6 either at baseline, after coiling aortopulmonary collaterals or nonscimitar vein intervention. Postoperative pulmonary vein obstruction is common after scimitar vein surgery regardless of redirection technique. Pulmonary hypertension and left pulmonary vein stenosis are risk factors for death, whereas patients without significant pulmonary hypertension or associated CHD did well without scimitar vein surgery. These observations may guide management decisions in patients with scimitar syndrome.


A novel Mutein of TNFalpha Containing the Arg-Gly-Asp Sequence Shows Reduced Toxicity in Intestine.
The effects of human tumour necrosis factor-alpha (TNFalpha), or its mutein (F4168) having the cell adhesive Arg-Gly-Asp sequence at the N-terminus, on intestinal injury, were examined. Histopathological examination revealed that an intravenous injection of TNFalpha resulted in marked haemorrhage or oedema in the caecum of rats, whereas F4168 showed no such effects even at the same therapeutic dose. Moreover, the number of neutrophils that adhered to endothelial cells or infiltrated the mucosal tissue was much higher after TNFalpha injection compared with F4168 in vivo. The enhanced adhesion of neutrophils on to human umbilical vein endothelial cells also occurred when the latter were pre-stimulated with TNFalpha but not with F4168 in vitro. The expression of the cell adhesion molecules including endothelial leukocyte adhesion molecule-1 or intercellular adhesion molecule-1 on F4168- stimulated human umbilical vein endothelial ceils was significantly lower than that stimulated with TNFalpha. These results suggest that the Arg-Gly-Asp sequence introduced into the TNFalpha molecule abrogates the side effect of this cytokine such as tissue injury or shock, and that F4168 could be useful for systemic therapy.


Visual dysfunction in retinal and optic nerve disease.
Visual perceptions seen with retinal and optic nerve disease may overlap with those resulting from retrochiasmal disorders. A few disorders typically present with distinctive perceptions, but the majority have less specific symptoms. Features include whether or not the visual phenomena are negative or positive, monocular or binocular, and the location and form of any deficits. Among negative phenomena, transient visual loss usually is the result of ischemic disease, but particular precipitants may suggest demyelination or photoreceptor degeneration. The pattern and location of visual field defects may help localize disorders to the level of the macula, papillomacular or other inner retina nerve fiber bundles, optic nerve, or chiasm. Altered brightness perception may point to optic nerve or photoreceptor disease. Decreased acuity is among the most common and least specific symptoms, but association with other symptoms may help to narrow the differential diagnosis. Dyschromatopsia points to either a photoreceptor or optic nerve pathologic condition (Table 7). Among positive phenomena, hallucinations resulting from anterior visual system disorders typically are unformed, although deafferentation of retrochiasmal pathways may produce formed hallucinations. The common "floaters" frequently are benign, but occasionally herald more concerning disorders. Various types of photopsias commonly occur with vitreal disorders or photoreceptor disorders. Macular disease typically leads to distortions of the central visual field, and other particular disorders lead to a host of characteristic distortions of color, form, or brightness. Careful attention to the ophthalmologic examination, visual fields, and subtle variance in symptomatology also help to distinguish among various disorders.


Dental abnormalities after chemotherapy in long-term survivors of childhood acute lymphoblastic leukemia 7-40 years after diagnosis.
Factors associated with the long-term dental effects after chemotherapy for childhood malignancies have not been well described. The primary aims of this study were as follows: (1) to assess whether age at diagnosis and treatment-related factors are associated with dental defects in survivors of childhood acute lymphoblastic leukemia (ALL) and (2) to assess the survivors' annual expenses for dental treatment compared to reference data. This cross-sectional study enrolled 111 Norwegian survivors of ALL diagnosed before the age of 16. All of the subjects completed a questionnaire and underwent medical and oral examinations. Dental defects were registered according to the individual defect index, with 0 = no defects and 140 = anodontia, and the caries experience was registered according to the decayed-missing-filled teeth index (DMFT). Age-matched reference data were drawn from a national general population survey (n = 555). The mean age at examination was 29.1 years (SD 7.2), and mean follow-up period was 22.9 years (SD 7.3). In a regression model, diagnoses occurring at ≤5 years of age (B = -9.6, p < 0.001) and a cumulative dose of anthracyclines >120 mg/m(2) (B = 11.5, p < 0.001) were strongly associated with more severe dental defects. Survivors treated after the age of 5 had experienced more caries than those treated at a younger age [DMFT 9.6 (SD 6.1) vs. 6.0 (SD 4.6), respectively; p = 0.001]. High annual expenses for dental treatment were reported by a larger percentage of the reference population compared to the survivor group (18 vs. 9 %, respectively; p = 0.02). The age at diagnosis and the dose of anthracyclines appear to be strongly associated with the severity of dental defects, although few survivors reported high annual expenses for dental treatment. The increased risk of dental defects during adulthood should be communicated to ALL survivors.


Sequence-specific inhibition of RNA elongation by actinomycin D.
We have developed a method to localize specific sites where RNA elongation is arrested due to DNA-bound ligands. The method was used to determine apparent binding sites for actinomycin D. We have found 14 strong RNA hindrance sites along nucleotide sequence of T7 and D111 T7 DNA of 380 nucleotides full length under low actinomycin D concentration conditions. Nucleotide sequence of all the sites is described by general formula XGCY where X not equal to G and Y not equal to C.


Potential benefits of warfarin monitoring by a clinical pharmacist in a long term care facility.
The primary objective of this study was to determine whether warfarin therapy monitoring by a pharmacist would benefit a long-term care facility, by maintaining patients within therapeutic INR range more consistently than the current practice of physician monitoring.Secondary objectives included whether adverse events resulting from non-therapeutic INR levels differed significantly between groups and whether pharmacist interventions resulted in decreased overall costs to the facility. A retrospective chart review was conducted on all patients treated with warfarin for a minimum of 14 days within a Long-Term Care (LTC) facility to compare Time within Therapeutic Range (TTR) between staff treated patients versus pharmacist treated patients. A total of 552 INRs were obtained for all patients during the study period: 499 (90.4%) under staff supervision and 53 (9.6%) under clinical pharmacist supervision. Of the 499 tests performed by the River Garden staff, 203 were within the desired range, compared with 29 of the 53 tests performed by the clinical pharmacist being in range. For the primary endpoint, a total of 1483 INRs were imputed, corresponding to the number of days between true INR measurements. INRs attributable to clinic staff management were within the therapeutic range 47.1% of the time, whereas INRs attributable to clinical pharmacist management were within the therapeutic range 58.7% of the time (P < 0.0001 for the comparison). Warfarin can be effectively monitored by a clinical pharmacist and routinely lead to appropriate INR levels in the nursing home setting, while potentially saving the facility healthcare dollars.


Segments of chromosomal DNA from Rhynchosciara americana that undergo additional rounds of DNA replication in the salivary gland DNA puffs have only weak ARS activity in yeast.
We have constructed a library of recombinant phage containing DNA from salivary gland chromosomes of Rhynchosciara americana. We have isolated phage from this library that carry sequences homologous to cDNA clones that hybridize in situ to the DNA puffs at the polytene chromosome regions C3 and C8. This has enabled us to demonstrate a 16-fold amplification of the genomic DNA sequences at these regions during DNA-puffing. At the C8 site there is a sequence element that has characteristics of 'scrambled' moderately repetitive DNA. This is located within 3 kb from the gene encoding a 1.95-kb mRNA. We have assayed restriction fragments from the two DNA puffs for Ars activity in yeast. The only strong Ars activity is associated with a part of the moderately repetitive DNA element from the C8 puff which is not present at this site in all animals.


Improved allele-specific PCR technique for Kidd blood group genotyping.
We developed an allele-specific polymerase chain reaction (AS-PCR) technique for Kidd blood group genotyping. Altogether, 340 blood samples from Thai blood donors at the National Blood Centre, Thai Red Cross Society, were tested with anti-Jk(a) and anti-Jk(b) using the gel technique and the direct urea lysis test was used for screening Jk(a-b-) phenotype. For AS-PCR technique, different types of primers were used for JK*01 and JK*02 allele detections in known DNA controls. Regarding JK*02 allele detection, the pseudopositve amplification products were found when using correctly matched forward primer and a single mismatch forward primer. Interestingly, one type of two mismatch pairing at the 3' end of the forward primer can be used together with the newly designed reverse primer for Kidd blood group genotyping. It was found that the typing results in all samples obtained by serological techniques and newly developed AS-PCR technique were in agreement and this PCR technique also gave 100% concordance of results in 30 samples randomly tested twice and demonstrated reproducible results. This study shows that the in-house AS-PCR is simple, cost-effective, and convenient for Kidd blood group genotyping in routine laboratories, especially, in resolving serologic investigations.


The evolving landscape of prostate cancer somatic mutations.
The landscape of somatic mutations in prostate cancer (PCa) has quickly evolved over the past years. This evolution was in part due to the improved quality and lower cost of genomic sequencing platforms available to an ever-larger group of clinicians and researchers. The result of these efforts is a better understanding of early and late mutations that are enriched or nearly exclusive to treated PCa. There are, however, some important limitations to the current knowledge. The expanding variety of next-generation sequencing (NGS) assays either capture a wide spectrum of mutations but at low coverage or are focused panels that cover a select number of genes, most often cancer-related, at a deep coverage. Both of these approaches have their advantages, but ultimately miss low-frequency mutations or fail to cover the spectrum of potential mutations. Additionally, some alterations, such as the common ETS gene fusions, require a mixture of DNA and RNA analysis to capture the true frequency. Finally, almost all studies rely on bulk PCa tumor samples, which fail to consider tumor heterogeneity. Given all these caveats, the true picture of the somatic landscape of PCa continues to develop. In this review, the focus will be on how the landscape of mutations evolves during disease progression considering therapy. It will focus on a select group of early and late mutations and utilize SPOP mutations to illustrate recurrent alterations that may have clinical implications.


Parkinson's disease alpha-synuclein mutations exhibit defective axonal transport in cultured neurons.
Alpha-synuclein is a major protein constituent of Lewy bodies and mutations in alpha-synuclein cause familial autosomal dominant Parkinson's disease. One explanation for the formation of perikaryal and neuritic aggregates of alpha-synuclein, which is a presynaptic protein, is that the mutations disrupt alpha-synuclein transport and lead to its proximal accumulation. We found that mutant forms of alpha-synuclein, either associated with Parkinson's disease (A30P or A53T) or mimicking defined serine, but not tyrosine, phosphorylation states exhibit reduced axonal transport following transfection into cultured neurons. Furthermore, transfection of A30P, but not wild-type, alpha-synuclein results in accumulation of the protein proximal to the cell body. We propose that the reduced axonal transport exhibited by the Parkinson's disease-associated alpha-synuclein mutants examined in this study might contribute to perikaryal accumulation of alpha-synuclein and hence Lewy body formation and neuritic abnormalities in diseased brain.


GABA release provoked by disturbed Na(+), K(+) and Ca(2+) homeostasis in cerebellar nerve endings: roles of Ca(2+) channels, Na(+)/Ca(2+) exchangers and GAT1 transporter reversal.
GABA release provoked by ion dysregulations typical of some neuropathological conditions was analyzed in purified cerebellar synaptosomes pre-labeled with [(3)H]GABA and exposed in superfusion to KCl, 4-aminopyridine (4-AP) or veratridine. The overflows caused by relatively low concentrations of the releasers were almost totally external Ca(2+)-dependent. Higher concentrations of KCl or veratridine, but not 4-AP, involved also external Ca(2+)-independent mechanisms. The GABA overflows evoked by veratridine and, less so, the overflow evoked by high K(+), occurred in part by reversal of the GAT1 transporter. None of the depolarizing agents activated store-operated or transient receptor potential or L-type Ca(2+) channels. Only the overflow caused by 4-AP occurred in part by N- and P/Q-type voltage-sensitive calcium channel-dependent exocytosis. Significant portions of the external Ca(2+)-dependent overflows evoked by the three releasers involved reversal of plasmalemmal Na(+)/Ca(2+) exchangers. The overflows evoked by high K(+) or veratridine, but not by 4-AP were evoked by Ca(2+) originated through mitochondrial Na(+)/Ca(2+) exchangers. Ca(2+)-induced Ca(2+) release mediated by inositoltrisphosphate receptors participated exclusively in the GABA release stimulated by high KCl which also occurred in a modest portion through anion channels. Important differences could be observed between the release mechanisms of GABA here described and those previously reported for glycine, in spite of the abundant vesicular co-localization of the two transmitters in cerebellar interneurons.


Spontaneous allocation of visual attention: dominant role of uniqueness.
Common sense suggests that unique or abruptly changing (transient) elements in a visual scene often draw attention involuntarily. Visual search studies paint a seemingly different picture, however Unique items usually draw attention involuntarily only when observers seek a unique target. One type of transient--abrupt onsets--draws attention involuntarily, but only when the observer is seeking an onset (Folk, Remington, & Johnston, 1992). One way of reconciling common-sense with these findings is to suppose that when people view a scene with no specific goal or task, they adopt a default set, which might prioritize novelty and/or transients. In two experiments, 336 subjects saw a single display of six items for 900 msec, expecting to have to describe it (Experiment 1) or make an aesthetic judgment about it (Experiment 2). One item in the display was either uniquely flashing (surrounded by static items) or uniquely static (surrounded by flashing items). In both studies, the unique item, even if static, was more often reported than the non-unique item, with flashing items enjoying an additional advantage.


High frequency of spontaneous Minute mutations detected in the F1 progeny of interstrain matings between a recombination-defective mei-9L1 and the y w m f/sc8(y+) Y BS; dp strain of Drosophila melanogaster.
The yield of spontaneous Minute mutations was recorded in the F1 progeny of interstrain (reciprocal) and intrastrain matings between a recombination- and excision repair-defective mei-9L1 (mei-9) strain and the y w m f/sc8(y+) Y BS; dp (ywmf-2) strain of Drosophila melanogaster. As a comparison, interstrain matings between a postreplication repair-defective st mus(3)302D1 (mus(3)) strain and the ywmf-2 strain were also studied for Minute mutations. The results show that: (1) a strikingly high frequency of Minute mutations is observed in the progeny of mei-9 female X ywmf-2 male crosses, but not in that of ywmf-2 females X mei-9 males; (2) no such difference exists in the progeny of intrastrain matings; and (3) there exists no marked inequality of Minute frequencies in the progeny of reciprocal crosses of mus(3) and ywmf-2 strains.


Single and tandem stents in sheep iliac arteries: is there a difference in patency?
To compare patency and neointima formation of single and tandem arterial stents. In each of six sheep, two Memotherm nitinol stents (tandem stents) were inserted into the external iliac artery on one side and a single stent into the artery on the opposite side. The size of the iliac lumen was assessed in the proximal, middle, and distal segments of the stents by intravascular ultrasound (IVUS) before, immediately after, and 1 month after implantation when the sheep were killed. Neointimal thickness was determined in the proximal, middle, and distal segments of each stent by light microscopy. All stents remained patent. There was no significant difference in lumen and neointimal thickness between single and tandem stents. Cranial tandem stents showed a significantly wider lumen and smaller neointimal thickness than caudal tandem stents. In the proximal and distal segments, the lumen of the stents was significantly smaller and the neointimal thickness greater than in the middle segment; differences in neointimal thickness were significant only between the proximal and the middle segment. In an experimental setting, tandem stents did not interfere with one another with regard to patency and neointima formation when compared with a single contralateral stent. Neointimal thickening after stent insertion seems to be inversely related to the original arterial diameter.