Disruption of the CHO1 gene encoding phosphatidylserine synthase in Saccharomyces cerevisiae.
A Saccharomyces cerevisiae mutant that lacked phosphatidylserine synthase [EC 18.104.22.168] (CDP-1,2-diacyl-sn-glycerol: L-serine O-phosphatidyltransferase) completely was constructed by disrupting its structural gene, CHO1. Over two-thirds of its coding region, from the starting to the 200th codon, was replaced with a LEU2 DNA fragment. This new cho1 mutant showed no detectable synthesis of phosphatidylserine but grew slowly in a medium that contained either ethanolamine or choline. These results indicate that phosphatidylserine synthase and most probably phosphatidylserine are dispensable in S. cerevisiae but necessary for its optimal growth. Additional supplementation with myo-inositol raised the cellular content of phosphatidylinositol and improved the growth of the mutant, suggesting the importance of the negative charges of the membrane surface. The CHO1-disrupted mutant, when grown on choline, accumulated phosphatidylethanolamine to a significant level even after extensive dilution of the initial culture. It segregated prototrophic revertants that could synthesize phosphatidylethanolamine without recovery of phosphatidylserine synthesis. These results imply the presence of a route(s) for the formation of ethanolamine or its phosphorylated derivative in S. cerevisiae.


Examining Care Assessment Scores of Community-Dwelling Adults in Flanders, Belgium: The Role of Socio-Psychological and Assessor-Related Factors.
One of the primary objectives of health systems is to provide a fair system by providing a comprehensive and holistic approach to caregiving rather than focusing on a single aspect of a person's care needs. This approach is often embodied by using standardized care assessments across health and social care settings. These assessments are completed by professional assessors and yield vital information regarding a person's health or contextual characteristics (e.g., civic engagement, psychosocial wellbeing, environmental characteristics, informal care). However, these scores may be subject to bias that endangers the fairness of the health system. In this study, we investigate to what extent socio-economic and psychological indicators and assessor-related indicators are associated with BelRAI Screener care assessment scores amongst 743 community-dwelling adults nested within 92 assessors in Flanders, Belgium. Findings indicate that there is significant variance in scores at the assessor-level. Socio-psychological characteristics of clients are associated with scores: being fluent in Dutch and providing informal care are associated with low care dependency, while living with children, feelings of depression, and the presence of an informal caregiver during assessment are associated with high care dependency. We discuss the importance of rigorous assessor training and the potential for socio-psychological factors to contribute to the allocation of welfare benefits in light of the Flemish home care system's potential (lack of) fairness.


Estrogen treatment and age effects on auditory brainstem responses in the post-breeding Long-Evans rat.
The auditory brainstem response (ABR) was recorded from 20-month-old Long Evans hooded female rats to determine if latency reductions occur from estrogen replacement. The ABR in these post-breeding age rats was also examined for reductions in response latencies as a function of adult age. Tone pip stimuli (8 and 40 kHz) were presented at 21, 51, or 81 s(-1). Aging control and ovariectomized animals showed slower response latencies for waves Ib-VI than young adults for 8 and 40 kHz stimulation at 21 s(-1). Increased stimulus rate resulted in longer latencies for all waves at 20 months. In contrast to hormone treatment effects in young adults, ABR latencies in post-breeding age estrogen-treated animals were not reduced, consistent with a general decrease in CNS responsiveness to estrogen steroids associated with age. The results also suggest that sensorineural modifications in the auditory system which prolong ABR latencies can occur early in the aging process of adult female subjects.


Characterization of MCSF-induced proliferation and subsequent osteoclast formation in murine marrow culture.
To clarify events involved in 1,25(OH)2D3-stimulated osteoclast-like cell (OCLC) formation in primary murine marrow culture, we have characterized kinetics of precursor proliferation and fusion and their dependence on macrophage colony-stimulating factor (MCSF). 3H-thymidine nuclear incorporation in tartrate-resistant acid phosphatase positive multinucleated cells (TRAP+ MNCs) was assessed: 3H-thymidine incorporation was greatest when tracer was added during day 4 or 5, with labeled nuclei in 81% (day 4) and 90% (day 5) of the TRAP+ MNCs counted at the end of day 7. The percentage of total nuclei labeled was highest when 3H-thymidine was dosed on day 4 (58%), decreasing to 2% by day 7. Final TRAP+ MNC numbers were depleted by 80% when treated for 24 h with hydroxyurea on either day 3 or 4; this inhibition dropped to 57% and 12% when hydroxyurea was pulsed during days 5 or 6, respectively. The absence of 1,25(OH)2D3 during days 1-4 caused 70% attenuation of TRAP+ MNC formation; however, exposure to 3H-thymidine during day 4 in this experiment resulted in subsequent labeling of 81% of the TRAP+ MNCs formed, indicating that precursor proliferation occurred in the absence of 1,25(OH)2D3. To demonstrate that proliferation required MCSF, cultures were exposed to a monoclonal anti-MCSF antibody during days 3, 4, 5, 6, or 7. Inhibition of TRAP+ MNC formation was 85% when antibody was added during day 3. Antibody treatment after day 5 had little effect on the OCLC number. Fusion of precursors showed steady progression with OCLCs containing 4.8 +/- 0.3 nuclei at the end of day 4, 8.3 +/- 0.5 nuclei after day 5, 12.0 +/- 1.3 after day 6, and 13.7 +/- 1.5 at the end of day 7. This steady accretion of nuclei was unaffected by doses of MCSF antibody which blocked proliferation. In conclusion, we have shown that OCLCs arise from an MCSF-dependent expansion of the precursor pool occurring during days 3 and 4. Fusion of these precursors, which begins as proliferation diminishes, is able to progress in the presence of anti-MCSF antibody. These results should help refine the analysis of factors affecting proliferation and fusion of osteoclasts in murine marrow culture.


Utilization trends of pedicle subtraction osteotomies compared to posterior spinal fusion for deformity: a national database analysis between 2008-2011.
Increased awareness regarding the importance of the sagittal spinal profile has led to more aggressive correction of sagittal malalignment. The utilization trends of pedicle subtraction osteotomy (PSO) for sagittal plane correction in spinal deformity surgery have not been well characterized. A commercially available database (PearlDiver, Inc) was queried for both Private Payor and 5 % Medicare claims from 2008 to 2011. Revision and clarification of the coding guidelines for PSO were introduced in 2008. Patients who had a thoracic and/or lumbar PSO were identified using CPT codes (22206-22208). In order to appropriately interpret trends in PSO use, three comparison groups were identified. Patients who had a diagnosis of adult spine deformity were identified using ICD-9 codes. Patients who had fusion for spine deformity or posterior spine fusion were identified using CPT codes. Differences in annual utilization and demographics between these four groups were then compared. From the Private Payor database, 199 PSOs were identified with the number of PSOs increasing from 33 in 2008, to 61 in 2011, representing a 185 % increase. From the Medicare data, 102 PSOs were identified, increasing from 13 in 2008 to 32 in 2011, a 246 % increase. In contrast, from both databases, there was minimal to no increase in the incidence of adult spine deformity, fusion for spine deformity or posterior spine fusion over the study time interval. Over the study time interval, there was up to a 3.2-fold increase in the utilization of PSOs while the diagnosis of adult spine deformity, fusion for spine deformity and posterior spine fusions had minimal to no increase.


Added dietary vegetables and fruits improved coat quality of capybara in Seoul Zoo, Republic of Korea: A case study.
Adequate levels of dietary vitamin C are necessary for capybaras (Hydrochoerus hydrocharis) because they cannot synthesize the vitamin endogenously. Beginning in 2013, hair and weight loss, as well as general dermatitis, were observed in all individual capybaras (n = 4) in a mixed exhibit at Seoul Zoo. Seven additional vegetables, leafy greens, and fruits that increased dietary vitamin C concentration from ∼300-400 to >600 mg/kg dry matter were added to the diet since January 2015. Within 6 months, capybaras' skin and coats improved considerably, with hair becoming thicker and glossier. Animals visually appeared healthier and gained weight. In conclusion, hair loss, dermatitis, and weight loss in capybara can be improved by feeding enough fresh green leaves, vegetables, and fruits. Although vitamin C is considered a major factor for alleviation of poor body condition observed, increased status of other nutrients (i.e., vitamin B6 ) provided by the diet change may also have contributed to the improvements seen in the capybara. Zoo Biol. 36:50-55, 2017. © 2016 Wiley Periodicals, Inc.


Ethical implications of implantable radiofrequency identification (RFID) tags in humans.
This article reviews the use of implantable radiofrequency identification (RFID) tags in humans, focusing on the VeriChip (VeriChip Corporation, Delray Beach, FL) and the associated VeriMed patient identification system. In addition, various nonmedical applications for implanted RFID tags in humans have been proposed. The technology offers important health and nonhealth benefits, but raises ethical concerns, including privacy and the potential for coercive implantation of RFID tags in individuals. A national discussion is needed to identify the limits of acceptable use of implantable RFID tags in humans before their use becomes widespread and it becomes too late to prevent misuse of this useful but ethically problematic technology.


Diversification of genes for carotenoid biosynthesis in aphids following an ancient transfer from a fungus.
The pea aphid genome was recently found to harbor genes for carotenoid biosynthesis, reflecting an ancestral transfer from a fungus. To explore the evolution of the carotene desaturase gene family within aphids, sequences were retrieved from a set of 34 aphid species representing numerous deeply diverging lineages of aphids and analyzed together with fungal sequences retrieved from databases. All aphids have at least one copy of this gene and some aphid species have up to seven, whereas fungal genomes consistently have a single copy. The closest relatives of aphids, adelgids, also have carotene desaturase; these sequences are most closely related to those from aphids, supporting a shared origin from a fungal to insect transfer predating the divergence of adelgids and aphids. Likewise, all aphids, and adelgids, have carotenoid profiles that are consistent with their biosynthesis using the acquired genes of fungal origin rather than derivation from food plants. The carotene desaturase was acquired from a fungal species outside of Ascomycota or Basidiomycota and closest to Mucoromycotina among sequences available in databases. In aphids, an ongoing pattern of gene duplication is indicated by the presence of both anciently and recently diverged paralogs within genomes and by the presence of a high frequency of pseudogenes that appear to be recently inactivated. Recombination among paralogs is evident, making analyses of patterns of selection difficult, but tests of selection for a nonrecombining region indicates that duplications tend to be followed by bouts of positive selection. Species of Macrosiphini, which often show color polymorphisms, typically have a larger number of desaturase copies relative to other species sampled in the study. These results indicate that aphid evolution has been accompanied by ongoing evolution of carotenogenic genes, which have undergone duplication, recombination, and occasional positive selection to yield a wide variety of carotenoid profiles in different aphid species.


Challenges of the Immunotherapy: Perspectives and Limitations of the Immune Checkpoint Inhibitor Treatment.
Immunotherapy is a quickly developing type of treatment and the future of therapy in oncology. This paper is a review of recent findings in the field of immunotherapy with an emphasis on immune checkpoint inhibitors. The challenges that immunotherapy might face in near future, such as primary and acquired resistance and the irAEs, are described in this article, as well as the perspectives such as identification of environmental modifiers of immunity and development of anti-cancer vaccines and combined therapies. There are multiple factors that may be responsible for immunoresistance, such as genomic factors, factors related to the immune system cells or to the cancer microenvironment, factors emerging from the host cells, as well as other factors such as advanced age, biological sex, diet, many hormones, existing comorbidities, and the gut microbiome.


Morphological, chemical and structural characterisation of deciduous enamel: SEM, EDS, XRD, FTIR and XPS analysis.
The purpose of this study was to characterise the enamel surface of sound deciduous teeth in terms of morphology, chemical composition, structure and crystalline phases. The enamel of 30 human deciduous teeth was examined by: Scanning Electron Microscopy (SEM), Energy Dispersive X-Ray Spectroscopy (EDS), X-ray Powder Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), and X-ray Photoelectron Spectroscopy (XPS). Chemical differences between incisors and canines were statistically evaluated using the Mann-Whitney U test (p ≤ 0.05). Three enamel patterns were observed by SEM: 'mostly smooth with some groves', 'abundant microporosities' and 'exposed prisms'. The average Ca/P molar ratios were 1.37 and 1.03 by EDS and XPS, respectively. The crystallite size determined by XRD was 210.82 ± 16.78 Å. The mean ratio between Ca bonded to phosphate and Ca bonded to hydroxyl was approximately 10:1. The enamel of sound deciduous teeth showed two main patterns: 'mostly smooth with some groves' and 'abundant microporosities'. 'Exposed prisms' was a secondary pattern. There were slight variations among the Ca/P molar ratios found by EDS and XPS, suggesting differences in the mineral content from the enamel surface to the interior. The crystalline phases found in enamel were hydroxyapatite and carbonate apatite, with major type B than type A carbonate incorporation.


Syntheses of Z-Iodovinylfurans and 2-Acyl Furans via Controllable Cyclization of Ynenones.
A divergent synthesis of Z-iodovinylfurans and 2-acyl furans promoted by NIS via controllable cyclization of ynenones is reported. The reaction proceeded by sequential 5-exo-dig electrophilic cyclization to intermediate 2-(iodomethylene)-2H-furanium cation D, providing a range of synthetically valuable and useful trisubstituted furan derivatives 2 and 3 in moderate to excellent yields. This approach is metal-free, mild, and atom-economic, with good selectivity and high stereoselectivity.


A survey of women who continue to smoke during pregnancy in Slovenia.
Smoking in pregnancy is unhealthy and can also have negative effects on the foetus. However, there are still some women who do not quit smoking during pregnancy. The aim of the study was to identify Slovenian women at risk who smoke during pregnancy. A quantative approach using an online survey was adopted. The study was conducted in May and June 2017, in Slovenia. A snowball sample was used. Participation in the survey was anonymous and voluntary, and 118 women who identified themselves as smokers participated in the study. Descriptive statistics was used to analyse the data. More than half (66%) did not quit smoking during pregnancy. Women who continued to smoke during pregnancy were usually younger, less educated with a partner who smoked. Women who smoked more cigarettes per day before conception were less likely to refrain from smoking during pregnancy. The most common reason for not quitting smoking during pregnancy was failure in attempts to quit (37%). Women who smoke need support to stop smoking before pregnancy or, at least, in the first trimester. Special groups for smoking cessation need to be created. Further and more extensive research is warranted in Slovenia to assess this issue.


Exploiting supramolecular synthons in designing gelators derived from multiple drugs.
A simple strategy for designing salt-based supramolecular gelators comprised of various nonsteroidal anti-inflammatory drugs (NSAIDs) and amantadine (AMN) (an antiviral drug) has been demonstrated using a supramolecular synthon approach. Single-crystal and powder X-ray diffraction established the existence of the well-studied gel-forming 1D supramolecular synthon, namely, primary ammonium monocarboxylate (PAM) synthon in all the salts. Remarkably five out of six salts were found to be capable of gelling methyl salicylate (MS)-an important ingredient in commercially available topical gels; one such selected biocompatible salt displayed an anti-inflammatory response in prostaglandin E2 (PGE2 ) assay, thereby indicating their plausible biomedical applications.


[Multimodal treatment of pancreatic cancer].
The experience with combined treatment of 122 patients with pancreatic cancer in the clinic of the Institute of Clinical & Experimental Surgery for the period of from 1988 to 1990 is summarized. Radical operations were performed in 54 patients, the palliative ones--in 68. After performance of a palliative operation, the patients underwent polychemotherapy, 5--in combination with UHF-hyperthermia. To study the effect of chemotherapy on the immune system, the immunologic monitoring was carried out. It was established that under the influence of chemotherapy and hyperthermia, the indices of immunity in patients with pancreatic cancer improved. In cancer of the pancreatic head with involvement of pancreatic body, the performance of subtotal pancreatoduodenal resection with subsequent regional chemotherapy is expedient. Chemotherapy and hyperthermia in combination with creation of a shunt permit to improve the results of treatment of inoperable tumors. The use of regional chemotherapy in subtotal resection contributed to increase in 2-year survival of the patients.


Breast Cancer: Influence of Taxanes on Response Assessment with Dynamic Contrast-enhanced MR Imaging.
To prospectively investigate the influence of taxane-containing neoadjuvant chemotherapy (T-NACT) versus non-taxane-containing NACT (NT-NACT) on the contrast material enhancement of breast cancers, benign enhancing lesions (BELs), and background parenchymal enhancement (BPE) at dynamic contrast-enhanced magnetic resonance (MR) imaging. This institutional review board-approved study was performed in 62 patients with invasive breast cancer who underwent multiagent NACT with (n = 49) or without (n = 13) taxanes between 2008 and 2011. Written informed consent was obtained. Patients underwent dynamic contrast-enhanced MR imaging according to a standardized protocol before and 2 weeks after completing NACT. The percentage reduction of enhancement of breast cancers, BELs, and BPEs was calculated for patients undergoing NT-NACT versus those undergoing T-NACT. Final surgical pathologic results served as standard of reference. Changes in mean enhancement of breast cancers, BELs, and BPEs between the regimens were compared by using the Student t test for unpaired samples; for intraindividual comparison, the Student t test for paired samples was used. Similar rates of complete pathologic response were observed after T-NACT and NT-NACT (28 [57.2%] of 49 vs eight [61.5%] of 13). T-NACT was associated with an almost complete suppression of enhancement in not only breast cancers but also BELs and BPE in the same patients, with an average reduction of enhancement of -89.9% ± 9.3, -90.2% ± 11.8, and -91.2% ± 7.5, respectively. After T-NACT, cancers with partial (n = 21) or complete (n = 28) pathologic response exhibited a similar reduction of enhancement (-81.8% ± 17.5 vs -93.9% ± 2.3; P = .22). The reduction of enhancement of cancers after NT-NACT was significantly less pronounced than that after T-NACT (-41.1% ± 22.8 vs 88.1% ± 13.9; P < .0001), and effects on enhancement of BELs and BPE were significantly less pronounced compared with effects on enhancement of cancers in the same women (P < .0001). MR imaging led to an overestimation of response (yielded false-negative results for residual disease) in 66.7% (14 of 21) of patients after T-NACT, versus in 20% (one of five) of patients after NT-NACT. The reduction of enhancement observed in breast cancers after T-NACT is, in part, unrelated to their oncologic response. MR imaging-detectable effects of taxanes represent a combination of specific antimitotic and nonspecific antiangiogenic effects. This impacts the accuracy with which dynamic contrast-enhanced MR imaging helps predict complete pathologic response to T-NACT. (©) RSNA, 2015 Online supplemental material is available for this article.


Plasminogen promotes influenza A virus replication through an annexin 2-dependent pathway in the absence of neuraminidase.
Proteolytic cleavage of haemagglutinin (HA) is essential for the infectivity of influenza A viruses (IAVs). This is usually mediated by trypsin-like proteases present in the respiratory tract. However, the ability to use plasminogen (PLG) as an alternative protease may contribute to pathogenesis of IAV infections and virus replication outside the respiratory tract. It was demonstrated previously that neuraminidase (NA) of the IAV strain A/WSN/33 can sequester PLG, allowing this virus to replicate in a PLG-dependent fashion. However, PLG also promotes replication of other IAVs, although its mode of action is poorly understood. Here, using NA-deficient viruses, we demonstrate that NA is not required for the binding of PLG and subsequent cleavage of HA. However, we demonstrate that the cellular protein annexin 2 (A2) can bind PLG and contributes to PLG-dependent cleavage of HA and subsequent IAV replication. Collectively, these results indicate that PLG promotes IAV replication in an A2-dependent fashion in the absence of NA.


Retinal blood flow during hyperoxia in humans revisited: concerted results using different measurement techniques.
Retinal vasculature shows pronounced vasoconstriction in response to hyperoxia, which appears to be related to the constant oxygen demand of the retina. However, the exact amount of blood flow reduction and the exact time course of this phenomenon are still a matter of debate. We set out to investigate the retinal response to hyperoxia using innovative techniques for the assessment of retinal hemodynamics. In a total of 48 healthy volunteers we studied the effect of 100% O(2) breathing on retinal blood flow using two methods. Red blood cell movement in larger retinal veins was quantified with combined laser Doppler velocimetry and retinal vessel size measurement. Retinal white blood cell movement was quantified with the blue field entoptic technique. The time course of retinal vasoconstriction in response to hyperoxia was assessed by continuous vessel size determination using the Zeiss retinal vessel analyzer. The response to hyperoxia as measured with combined laser Doppler velocimetry and vessel size measurement was almost twice as high as that observed with the blue field technique. Vasoconstriction in response to 100% O(2) breathing occurred within the first 5 min and no counterregulatory or adaptive mechanisms were observed. Based on these results we hypothesize that hyperoxia-induced vasoconstriction differentially affects red and white blood cell movement in the human retina. This hypothesis is based on the complex interactions between red and white blood cells in microcirculation, which have been described in detail for other vascular beds.


Mitochondrial targeting adaptation of the hominoid-specific glutamate dehydrogenase driven by positive Darwinian selection.
Many new gene copies emerged by gene duplication in hominoids, but little is known with respect to their functional evolution. Glutamate dehydrogenase (GLUD) is an enzyme central to the glutamate and energy metabolism of the cell. In addition to the single, GLUD-encoding gene present in all mammals (GLUD1), humans and apes acquired a second GLUD gene (GLUD2) through retroduplication of GLUD1, which codes for an enzyme with unique, potentially brain-adapted properties. Here we show that whereas the GLUD1 parental protein localizes to mitochondria and the cytoplasm, GLUD2 is specifically targeted to mitochondria. Using evolutionary analysis and resurrected ancestral protein variants, we demonstrate that the enhanced mitochondrial targeting specificity of GLUD2 is due to a single positively selected glutamic acid-to-lysine substitution, which was fixed in the N-terminal mitochondrial targeting sequence (MTS) of GLUD2 soon after the duplication event in the hominoid ancestor approximately 18-25 million years ago. This MTS substitution arose in parallel with two crucial adaptive amino acid changes in the enzyme and likely contributed to the functional adaptation of GLUD2 to the glutamate metabolism of the hominoid brain and other tissues. We suggest that rapid, selectively driven subcellular adaptation, as exemplified by GLUD2, represents a common route underlying the emergence of new gene functions.


Epidemiology of accidents among users of two-wheeled motor vehicles. A surveillance study in two Italian cities.
This paper describes a study on the epidemiology of accidents among users of two-wheeled motor vehicles in two Italian cities, Rome and Naples. A surveillance study was conducted, recruiting the victims of accidents among users of two-wheeled motor vehicles, visiting the emergency departments of two Italian hospitals. The registration form includes personal data of the involved person, circumstances of the accident, means of arrival at the hospital, type of vehicles involved, helmet use, and eventually third parties involved, and data on the specific injury diagnosis. 736 injured drivers of two-wheeled motor vehicles were investigated for the study (65.1% males, 34.9% females). The mean age of the victims was 22.92 years; 42.9% of the injuries were the result of a single accident. In 35.5% of the injuries cars were involved and in 8.6% of the cases there was a passenger included. Only 12% of the injured people were wearing a helmet. Most of the lesions concerns the knee or lower leg (27.5%), followed by the head (17.5%), elbow and forearm (8.8%), wrist and hand (8.6%), shoulder and upper arm (8.4%) and ankle and foot (6.9%). Helmet use has a protective effect (OR = 0.23), whereas accidents in Naples and during dark hours are associated with an increased risk of head injury (respectively OR = 1.93, and OR = 1.46). In this study the lower injury risk due to the use of the helmet on the frequency and severity of head trauma was confirmed. Moreover, the results confirm that Emergency Departments can provide essential epidemiological information, and they have already provided clear arguments in favour of extending the compulsory use of helmets to people above 18 years in Italy.


[Voluntary wheel running enhances cell proliferation and expression levels of BDNF, IGF1 and WNT4 in dentate gyrus of adult mice].
Adult hippocampal neurogenesis plays important roles in learning, memory and mood regulation. External factors, such as physical exercise, have been found to modulate adult hippocampal neurogenesis. Voluntary running enhances cell proliferation in subgranular zone (SGZ) and increases the number of new born neurons in rodents, but underlying mechanisms are not fully understood. In this study, we used BrdU assay to identify proliferating cells in 2-month-old C57BL/6 mice after 15 days of voluntary wheel running test. mRNA and protein levels for several neural factors in dentate gyrus, Ammon's horn, and cortex were also analyzed by RT-qPCR and Western blot assay after 15 days of voluntary wheel running. Our data show that voluntary wheel running for 15 days elevated the number of proliferation cells in dentate gyrus and significantly up-regulated the mRNA levels of Bdnf, Igf1 and Wnt4. The protein levels of BDNF and IGF1 in dentate gyrus were also increased after voluntary wheel running. These results indicate that the increase of adult hippocampal neurogenesis caused by voluntary wheel running for 15 days might be through up-regulating BDNF, IGF1 and WNT4 in dentate gyrus.


Moxifloxacin increases anti-tumor and anti-angiogenic activity of irinotecan in human xenograft tumors.
Camptothecins (CPTs) are topoisomerase I inhibitors chemotherapeutic agents used in combination chemotherapy. We showed previously that combination of moxifloxacin (MXF) and CPT induced inhibitory effects on topoisomerase I activity, on proliferation of HT-29 cells in vitro and enhanced apoptosis, compared to CPT alone. Analysis of secretion of the pro-angiogenic factors IL-8 and VEGF showed significant reduction by MXF. Using a murine model of human colon carcinoma xenograft, we compared the effects of MXF/CPT in vitro to MXF/irinotecan combination in vivo. We show that the MXF/CPT inhibitory effects observed in vitro are reflected in the inhibition of the progressive growth of HT-29 cells implanted in SCID mice. Using caliper measurements, Doppler ultrasonography, image analyses and immunohistochemistry of nuclear proteins (Ki-67) and vascular endothelial cells (CD-31) we show that addition of MXF (45mg/kg) to a relatively ineffective dose of irinotecan (20mg/kg), results in a 50% and 30% decrease, respectively, in tumor size and a decrease in Ki-67 staining. Power Doppler Ultrasound showed a significant, pronounced decrease in the number of blood vessels, as did CD-31 staining, indicating decreased blood flow in tumors in mice treated with MXF alone or MXF/irinotecan compared to irinotecan. These results suggest that the combination of MXF/irinotecan may result in enhanced anti-neoplastic/anti-angiogenic activity.


Ergonomics in laparoscopic surgery.
Laparoscopic surgery provides patients with less painful surgery but is more demanding for the surgeon. The increased technological complexity and sometimes poorly adapted equipment have led to increased complaints of surgeon fatigue and discomfort during laparoscopic surgery. Ergonomic integration and suitable laparoscopic operating room environment are essential to improve efficiency, safety, and comfort for the operating team. Understanding ergonomics can not only make life of surgeon comfortable in the operating room but also reduce physical strains on surgeon.


Maintenance and turnover of Sox2+ adult stem cells in the gustatory epithelium.
Continuous turnover of taste bud cells in the oral cavity underlies the homeostasis of taste tissues. Previous studies have demonstrated that Sox2+ stem cells give rise to all types of epithelial cells including taste bud cells and non-gustatory epithelial cells in the oral epithelium, and Sox2 is required for generating taste bud cells. Here, we show the dynamism of single stem cells through multicolor lineage tracing analyses in Sox2-CreERT2; Rosa26-Confetti mice. In the non-gustatory epithelium, unicolored areas populated by a cluster of cells expressing the same fluorescent protein grew over time, while epithelial cells were randomly labeled with multiple fluorescent proteins by short-term tracing. Similar phenomena were observed in gustatory epithelia. These results suggest that the Sox2+ stem cell population is maintained by balancing the increase of certain stem cells with the reduction of the others. In the gustatory epithelia, many single taste buds contained cells labeled with different fluorescent proteins, indicating that a single taste bud is composed of cells derived from multiple Sox2+ stem cells. Our results reveal the characteristics of Sox2+ stem cells underlying the turnover of taste bud cells and the homeostasis of taste tissues.


[Dynamics of microtubular cytoskeleton in higher plant meiosis. IX. The cycle accomplishment. Transition from phragmoplast to radial microtubule system].
In this study we analysed the terminal step of cytoskeleton cycle in higher plant meiosis: transition from phragmoplast to radial interphase configuration. Wild type meiosis in a range of mono- and dicotyledonous species was studied. A number of cytoskeleton abnormalities on this stage was described in meiotic mutants, haploids and wide hybrids of various species. We described processes of cytoskeleton rearrangements on this stage: disjunction of phragmoplast MTs, their shortening and the role of daughter cell membranes. The independence of the interphase radial MT system formation from the previous steps of cytoskeleton cycle and from nuclear envelope cycle is proposed.


[Acceptability of auto-injection of vasoactive drugs in the treatment of erectile dysfunction].
To study the utility of the PenInject 2.25 (SHL Medical AB), an instrument for intracavernous auto-injection of vasoactive drugs. 61 males, aged 30-70 years, with erectile dysfunction were studied. The study comprised two groups: group A consisted of 26 patients previously treated with intracavernous injections using a syringe that were started on treatment with the self-injector, and group B consisted of 35 previously untreated patients that started treatment directly with the self-injector. Different data and questions on the facility of use and acceptance of the instrument were analyzed. Data evaluation were plotted on visual analog scales of 10 cm. A score of 5 or more showed good results and less than 5 was considered unfavorable. The positive aspects were facility of use, comfort, design of the self-injector, which scored higher than 7. The negative aspects were pain, fear, discomfort intensity, which scored below 4. The use of the PenInject self-injector in this group of patients improved the acceptability of intracavernous therapy for erectile dysfunction in comparison to the classical syringe.


Cost-effectiveness of prophylactic cranial irradiation in stage III non-small cell lung cancer.
In stage III non-small cell lung cancer (NSCLC), prophylactic cranial irradiation (PCI) reduces the brain metastases incidence and prolongs the progression-free survival without improving overall survival. PCI increases the risk of toxicity and is currently not adopted in routine care. Our objective was to assess the cost-effectiveness of PCI compared with no PCI in stage III NSCLC from a Dutch societal perspective. A cohort partitioned survival model was developed based on individual patient data from three randomized phase III trials (N = 670). Quality-adjusted life years (QALYs) and costs were estimated over a lifetime time horizon. A willingness-to-pay (WTP) threshold of €80,000 per QALY was adopted. Sensitivity and scenario analyses were performed to address parameter uncertainty and to explore what parameters had the greatest impact on the cost-effectiveness results. PCI was more effective and costly (0.443 QALYs, €10,123) than no PCI, resulting in an incremental cost-effectiveness ratio (ICER) of €22,843 per QALY gained. The probability of PCI being cost-effective at a WTP threshold of €80,000 per QALY was 93%. The probability of PCI gaining three and six additional months of life were 76% and 56%. The scenario analysis adding durvalumab increased the ICER to €35,159 per QALY gained. Using alternative survival distributions had little impact on the ICER. Assuming fewer PCI fractions and excluding indirect costs decreased the ICER to €18,263 and €5554 per QALY gained. PCI is cost-effective compared to no PCI in stage III NSCLC, and could therefore, from a cost-effectiveness perspective, be considered in routine care.


[Myocardial Infarction in Women of Reproductive age: Risk Factors, Clinical Picture, Prognosis].
Aim To study risk factors (RF) and clinical and anamnestic features of the course and prediction in women with a preserved menstrual cycle and postmenopausal women after ST segment elevation (STEMI) and non-ST elevation myocardial infarction (NSTEMI).Material and methods This study included 121 women aged 32 to 55 years diagnosed with MI. The patients were divided into two groups, group 1 (study group) consisting of 60 women with preserved menstrual function (1А, STEMI; n=38; age, 48.3±5.7 years and 1B, NSTEMI; n=22; age. 49.0±4.8 years), and group 2 (control) consisting of 61 postmenopausal women (2А, STEMI; n=43; age, 49.05±4.9 years; 2B, NSTEMI; n=18; age, 49.9±3.5 years). Beside the analysis of RF and clinical features, a prediction was produced for each subgroup at one year after discharge from the hospital based on the following indexes: hospitalization for unstable angina, non-fatal MI, revascularization, cardiovascular (CV) death, and major adverse cardiac events (MACE), which included all these outcomes.Results In all subgroups, the most frequent RFs were arterial hypertension (AH), overweight and obesity, family history, smoking, and type 2 diabetes mellitus (DM2). Among patients with STEMI, smoking was significantly more frequently observed in the group with preserved menstrual function. Oral contraceptives were used by 3 and 6 women of reproductive age in the STEMI and NSTEMI subgroups, respectively. Incidence of STEMI as the onset of ischemic heart disease (IHD, 46.7%) was higher than in subgroup 2A (27.9 %; р=0.003). Early postinfarction angina was a more frequent complication of MI in subgroup 1A than in 2A (р=0.02).Conclusion The incidence rate of RFs, including AH, overweight and obesity, dyslipidemia, family history, and DM2, was similar in both STEMI and NSTEMI groups. Incidence rate of smoking was statistically significantly higher in subgroup 1A. One-year prediction for women with STEMI and NSTEMI was comparable irrespective of the presence or absence of the menstrual function.


[A case of adult T-cell leukemia responding to recombinant interferon-beta (GKT-beta)].
Interferon-beta (GKT-beta) was administered to a patient with adult T-cell leukemia (ATL), presumably of acute type, with a marked organ infiltration and increases in serum calcium, LDH and bilirubin. The therapy produced a fall in the number of peripheral blood abnormal lymphocytes, disappearance of jaundice, reduction in the degree of hepatomegaly and splenomegaly and a remarkable improvement of general condition with a performance status of grade 3 improving to grade 1. The response has been maintained for more than seven months. Dose, schedule and criteria for drug discontinuation are matters for further investigation.


Contrast-enhanced ultrasonography of the placental barrier; the protective umbrella of the fetus during pregnancy.
Ultrasonography is the preferred technique to evaluate the status of maternal and fetal health during pregnancy. Non-obstetric acute or chronic conditions occurring during pregnancy must be diagnosed as early as possible to permit timely and necessary treatment for the sake of maternal and fetal health. The purpose of this study was to evaluate the safety and value of contrast-enhanced ultrasonography (CEUS) during pregnancy. This prospective study included 14 pregnant women requiring pregnancy termination and six healthy pregnant women. The 14 pregnant women requiring pregnancy termination underwent CEUS prior to surgery to investigate the pattern of contrast agent diffusion. The six healthy pregnant women did not undergo CEUS. The structure of placentae with and without contrast agent injection were also compared by light microscopy. CEUS analysis failed to identify any signs of contrast agents in the umbilical cord blood and fetus. There were no obvious changes in the morphology of placentae with and without contrast agent injection under light microscope. CEUS identified the need for early treatment in one pregnant woman with an ovarian tumor. Due to the protective effect of the placental barrier on the fetus, CEUS during pregnancy may represent a safe form of imaging technology that can provide valuable information for the diagnosis of non-obstetric acute or chronic disorders and to guide thefuture treatment of pregnant women.


Pediatric pharmacists' perspectives on essential skills and activities for community pharmacists caring for pediatric patients: A mixed-methods study.
Provision of care to pediatric patients represents a set of unique challenges for pharmacists. Pharmacists practising in pediatric-specialty areas (acute care or ambulatory) have unique perspectives on approaches to pediatric care that can be shared to support pharmacists less familiar with this group of patients in providing effective, patient-centred care. This was a mixed-methods study using data from pharmacist interviews to quantify and qualitatively describe the approaches to care most commonly reported by pediatric-specialty pharmacists when asked to provide advice to pharmacists on providing pharmaceutical care to infants and children. Data were coded in duplicate using an inductive approach, and discrepancies were resolved by consensus. The number of times a theme (or subtheme) was mentioned and the number of pharmacists who mentioned it were used as markers of the relative importance of the content. The themes (and subthemes) that emerged as most important were clinical activities (dose checks, considering indication, using up-to-date height/weight), caregiver counselling (demonstrating measurement, discussing administration), medication safety (using consistent concentrations of liquids), compounded medications (risks of, use of caution), adherence (formulation considerations, palatability), avoiding use of over-the counter products (except analgesics/antipyretics) and use of external supports (colleagues, caregivers, resources). We present a collated and prioritized list of practical approaches for pharmacists to use when caring for pediatric patients across the spectrum of practice. Can Pharm J (Ott) 2020;153:xx-xx.


Differences in acoustic features of vocalizations produced by killer whales cross-socialized with bottlenose dolphins.
Limited previous evidence suggests that killer whales (Orcinus orca) are capable of vocal production learning. However, vocal contextual learning has not been studied, nor the factors promoting learning. Vocalizations were collected from three killer whales with a history of exposure to bottlenose dolphins (Tursiops truncatus) and compared with data from seven killer whales held with conspecifics and nine bottlenose dolphins. The three whales' repertoires were distinguishable by a higher proportion of click trains and whistles. Time-domain features of click trains were intermediate between those of whales held with conspecifics and dolphins. These differences provided evidence for contextual learning. One killer whale spontaneously learned to produce artificial chirps taught to dolphins; acoustic features fell within the range of inter-individual differences among the dolphins. This whale also produced whistles similar to a stereotyped whistle produced by one dolphin. Thus, results provide further support for vocal production learning and show that killer whales are capable of contextual learning. That killer whales produce similar repertoires when associated with another species suggests substantial vocal plasticity and motivation for vocal conformity with social associates.


Glomerular malondialdehyde levels in patients with focal and segmental glomerulosclerosis and minimal change disease.
Minimal change disease (MCD) and focal and segmental glomerulosclerosis (FSGS) are often studied together, because both present with heavy proteinuria and the nephrotic syndrome. The precise distinction between MCD and FSGS is sometimes difficult because of inadequate number of glomeruli for definite diagnosis. Some evidence suggests that markers of lipid peroxidation, such as malondialdehyde (MDA) is an index of free radical mediated injury and may be involved in the pathogenesis of FSGS. In this study, we assessed the immunoreactivity of MDA, the end product of lipid peroxidation in glomeruli of patients with idiopathic FSGS, MCD as well as normal controls (NC). Our results showed that the immunostaining level of MDA was significantly higher in patients with FSGS (mean = 1.5) than in either patients with MCD (mean = 0.16) or normal controls (mean = 0.11) with P value < 0.001. Glomerular MDA level correlated well with the degree of glomerulosclerosis in patients with idiopathic FSGS. Our data demonstrates that the glomerular level of MDA is higher in idiopathic FSGS than MCD. We suggest that MDA immunostaining can be helpful in differentiating between FSGS and MCD in problematic cases and when we do not have enough glomeruli for definite and correct diagnosis.


Nanoscale Electrochemical Sensor Arrays: Redox Cycling Amplification in Dual-Electrode Systems.
Micro- and nanofabriation technologies have a tremendous potential for the development of powerful sensor array platforms for electrochemical detection. The ability to integrate electrochemical sensor arrays with microfluidic devices nowadays provides possibilities for advanced lab-on-a-chip technology for the detection or quantification of multiple targets in a high-throughput approach. In particular, this is interesting for applications outside of analytical laboratories, such as point-of-care (POC) or on-site water screening where cost, measurement time, and the size of individual sensor devices are important factors to be considered. In addition, electrochemical sensor arrays can monitor biological processes in emerging cell-analysis platforms. Here, recent progress in the design of disease model systems and organ-on-a-chip technologies still needs to be matched by appropriate functionalities for application of external stimuli and read-out of cellular activity in long-term experiments. Preferably, data can be gathered not only at a singular location but at different spatial scales across a whole cell network, calling for new sensor array technologies. In this Account, we describe the evolution of chip-based nanoscale electrochemical sensor arrays, which have been developed and investigated in our group. Focusing on design and fabrication strategies that facilitate applications for the investigation of cellular networks, we emphasize the sensing of redox-active neurotransmitters on a chip. To this end, we address the impact of the device architecture on sensitivity, selectivity as well as on spatial and temporal resolution. Specifically, we highlight recent work on redox-cycling concepts using nanocavity sensor arrays, which provide an efficient amplification strategy for spatiotemporal detection of redox-active molecules. As redox-cycling electrochemistry critically depends on the ability to miniaturize and integrate closely spaced electrode systems, the fabrication of suitable nanoscale devices is of utmost importance for the development of this advanced sensor technology. Here, we address current challenges and limitations, which are associated with different redox cycling sensor array concepts and fabrication approaches. State-of-the-art micro- and nanofabrication technologies based on optical and electron-beam lithography allow precise control of the device layout and have led to a new generation of electrochemical sensor architectures for highly sensitive detection. Yet, these approaches are often expensive and limited to clean-room compatible materials. In consequence, they lack possibilities for upscaling to high-throughput fabrication at moderate costs. In this respect, self-assembly techniques can open new routes for electrochemical sensor design. This is true in particular for nanoporous redox cycling sensor arrays that have been developed in recent years and provide interesting alternatives to clean-room fabricated nanofluidic redox cycling devices. We conclude this Account with a discussion of emerging fabrication technologies based on printed electronics that we believe have the potential of transforming current redox cycling concepts from laboratory tools for fundamental studies and proof-of-principle analytical demonstrations into high-throughput devices for rapid screening applications.


[Odontogenic sinusitis with cutaneous fistulization. A case report].
A 70-year-old male patient presenting with a cutaneous node of the genal region that was first diagnosed as basal cell carcinoma is described. Owing to the following observation, the authors were prompted to a diagnosis of cutaneous odontogenic sinusitis: a) examination of the lesion which emitted pus upon gentle squeezing; b) presence in the vestibular fornix of a large fibrous cord; c) the serious conditions of the mouth and the radiologic results of homolateral sinusitis. The importance of the sinusitis picture, and the necessity to completely remove all bacteria foci prior to surgery on the abdominal aorta the patient was scheduled to undergo, prompted the authors to avulse the cutaneous lesion with tooth extraction, after a "Caldwell-Luc" operation of the homolateral paranasal sinus. Full restitutio ad integrum was achieved.


Neoadjuvant gemcitabine therapy for breast cancer.
Neoadjuvant chemotherapy has become a standard treatment in the management of locally advanced breast cancer. Patients with earlier-stage disease may also benefit from neoadjuvant treatment in terms of improved rates of breast-conserving surgery and thus better quality of life. Gemcitabine is a pyrimidine analogue that has shown activity in a variety of solid tumors, a good toxicity profile, and nonoverlapping toxicity with other chemotherapeutic agents. Several phase II/III studies are assessing gemcitabine combined with anthracyclines, taxanes, and/or vinorelbine both in the neoadjuvant and metastatic disease settings. This article reviews developments in neoadjuvant use of gemcitabine in combination with anthracyclines and taxanes. Several phase II trials of gemcitabine combined with doxorubicin/epirubicin or with doxorubicin/paclitaxel have been carried out. Preliminary findings demonstrate increased complete response rates and good tolerability of these regimens in patients with breast cancer.


Relations between GPR4 expression, microvascular density (MVD) and clinical pathological characteristics of patients with epithelial ovarian carcinoma (EOC).
G-protein coupled receptor 4 (GPR4) is a G protein-coupled receptor (GPCR) activated by sphingosylphosphorylcholine (SPC) and lysophosphatidylcholine (LPC). Later studies indicated that GPR4 can serve as a proton sensor. GPR4 has been known to play a critical role in the tube formation of vascular endothelial cells, and GPR4 overexpression is observed in various types of malignancies, suggesting its involvement in the cancer-related angiogenesis. In this study, we examined the GPR4 expression levels in blood vessels of ovarian cancer, and analyzed the relationship between GPR4 expression and the clinical and pathological characteristics of patients with epithelial ovarian carcinomas (EOC). Results from immunohistochemistry showed that GPR4 is detectable in the endothelium of vessels of both EOC and benign ovarian tumor tissue, but the expression levels were significantly increased in EOC. Moreover the increased expression is accompanied by a higher microvascular density (MVD) in EOC compared to that in the benign ovarian tumors. We demonstrated a positive correlation between GPR4 expression density and MVD in EOC, but not benign ovarian tumor tissues. Further analyses indicated that GPR4 expression and MVD in EOC were correlated to the status of lymph node metastasis and clinical stage, but not significantly correlated to the pathological classifications, histopathological grades, the amounts of ascites, status of peritoneal cytology, tumor sizes, or patients' ages. These results suggested that GPR4 may play an important role in the development of EOC, and its overexpression might be required for the angiogenesis, tumor growth, and metastasis of EOC.


Clinical and genetic investigations of three Moroccan families with retinitis pigmentosa phenotypes.
Progressive inherited retinal dystrophies, characterized by degeneration of rod photoreceptors and then cone photoreceptors, are known as retinitis pigmentosa (RP), for which 89 genes have been identified. Today, only five Moroccan families with RP with a genetic diagnosis have been reported, justifying our investment in providing further clinical and genetic investigations of families with RP in Morocco. The clinical diagnosis based on a combination of a history of night blindness, abnormal rod or rod-cone responses in electroretinography (ERG), and constricted visual field or difficulty perceiving side objects identified three Moroccan families with an RP phenotype. Probands of these families underwent whole exome sequencing (WES), and candidate variants were evaluated for their segregation within family members. All patients had a history of night blindness and unrecordable rod and cone ERG traces. In addition, one patient had cystoid macular edema, and another had discrete autofluorescence abnormalities, in addition to ellipsoid zone disorganization and narrowed retinal vessels. WES sequencing revealed heterozygous compound mutations in CRB1:c.1690G>T//c.1913C>T and in ABCA4:c.5908C>T//c.6148G>C and a homozygous PDE6B splice mutation c.1920+2T>C. We provide the first description of Moroccan patients with the RP phenotype harboring pathogenic mutations in the CRB1 and ABCA4 genes and the second description of an individual with RP with a PDE6B mutation, associated with cystoid macular edema. These data contribute to expand the genetic diagnosis of RP phenotypes in Morocco.


Spontaneous and glucocorticoid-induced apoptosis in human mature T lymphocytes.
Glucocorticoid (GC)-induced apoptosis is a well-recognized physiologic regulator of murine T-cell number and function. We have analyzed its mechanisms in human mature T cells, which have been thought to be insensitive until recently. Peripheral blood T cells showed sensitivity to GC-induced apoptosis soon after the proliferative response to a mitogenic stimulation, and were also sensitive to spontaneous (ie, growth factor deprivation-dependent) apoptosis. CD8+ T cells were more sensitive to both forms than CD4+ T cells. Acquisition of sensitivity to GC-induced apoptosis was not associated with any change in number or affinity of GC receptors. Both spontaneous and GC-induced apoptosis were increased by the macromolecular synthesis inhibitors, cycloheximide (CHX) and puromycin. A positive correlation between the degree of protein synthesis inhibition and the extent of apoptosis was observed. Interleukin-2 (IL-2) IL-4, and IL-10 protected (IL-2 > IL-10 > IL-4) T cells from both forms of apoptosis in a dose-dependent manner. Our data suggest that spontaneous and GC-induced apoptosis regulate the human mature T-cell repertoire by acting early after the immune response and differentially affecting T-cell subsets.


Global health indicators and maternal health futures: The case of Intrauterine Growth Restriction.
Public health indicators generally operate in the world as credible, apolitical and authoritative. But indicators are less stable than they appear. Clinical critiques of Intrauterine Growth Restriction (IUGR) criteria have been forthcoming for decades. This article, though, takes up the measuring and calculation gradients of IUGR in the ultrasound machine itself, including the software algorithms that identify IUGR. One hospital where research was conducted incorrectly predicted pathological birth outcomes 14 of 14 times. We are at a historical moment when the global use of prenatal diagnostic ultrasound for the express purpose of assessing IUGR is set to escalate. Medical imaging device corporations like Siemens, Toshiba, General Electric and Phillips are quite literally banking on it, and new forms of ultrasound technology and diagnostic software are increasingly available on smartphones, tablets and laptops. Clinical guidelines for IUGR--assumed to be authoritative and evidence-based--are evolving right along with the installation throughout the world of the technology capable of diagnosing it. Maternal malnutrition remains the single strongest predictive factor for IUGR, regardless of the technological investments currently amassing to identify the indicator, which is cause for a reassessment of priority spending and investment.


ST/b and DBA/2 mice differ in brain alpha-bungarotoxin binding and alpha 7 nicotinic receptor subunit mRNA levels: a quantitative autoradiographic analysis.
Inbred mouse strains vary in sensitivity to a number of behavioral and physiological effects produced by nicotine. Differences in sensitivity to nicotine are correlated with variance in the number of brain nicotinic receptors as measured in regionally dissected brain tissue. The studies reported here used quantitative autoradiography and in-situ hybridization methods to measure regional levels of alpha-bungarotoxin (alpha BTX) binding and alpha 7 mRNA levels. Two inbred mouse strains, ST/b and DBA/2, were compared because these strains differ maximally in sensitivity to nicotine-induced seizures and in alpha BTX binding measured in regional brain homogenates. The binding of alpha BTX was significantly greater in the St/b strain in 42 of 127 brain regions that were analyzed, and a trend towards increased binding was seen in many additional brain regions. The most consistent strain differences were found in hippocampal, thalamic and pontine nuclei. Strain differences in alpha 7 mRNA levels were also detected, but these were not as widespread as were the alpha BTX binding differences. The alpha 7 mRNA levels were significantly correlated with alpha BTX binding in both mouse strains which suggests that the strain differences in binding are related, in part, to the levels of alpha 7 mRNA.


Statistically designing microarrays and microarray experiments to enhance sensitivity and specificity.
Gene expression signatures from microarray experiments promise to provide important prognostic tools for predicting disease outcome or response to treatment. A number of microarray studies in various cancers have reported such gene signatures. However, the overlap of gene signatures in the same disease has been limited so far, and some reported signatures have not been reproduced in other populations. Clearly, the methods used for verifying novel gene signatures need improvement. In this article, we describe an experiment in which microarrays and sample hybridization are designed according to the statistical principles of randomization, replication and blocking. Our results show that such designs provide unbiased estimation of differential expression levels as well as powerful tests for them.


On the ecology of Cystophora spp. forests.
Cystophora is the second largest genus of fucoids worldwide and, like many other forest-forming macroalgae, is increasingly threatened by a range of anthropogenic impacts including ocean warming. Yet, limited ecological information is available from the warm portion of their range (SW Western Australia), where severe range contractions are predicted to occur. Here, we provide the first insights on the abundance, diversity, productivity, and stand structure of Cystophora forests in this region. Forests were ubiquitous over more than 800 km of coastline and dominated sheltered and moderately-exposed reefs. Stand biomass and productivity were similar or greater than that of kelp forests in the temperate reef communities examined, suggesting that Cystophora spp. play a similarly important ecological role. The stand structure of Cystophora forests was, however, different than those of kelp forests, with most stands featuring an abundant bank of sub-canopy juveniles and only a few plants forming the canopy layer. Stand productivity followed an opposite seasonal pattern than that of kelps, with maximal growth in late autumn through early winter and net biomass loss in summer. Annually, stands contributed between 2.2 and 5.7 kg · m-2 (fresh biomass) to reef productivity depending on the dominant stand species. We propose that Cystophora forests play an important and unique role in supporting subtidal temperate diversity and productivity throughout temperate Australia, and urge a better understanding of their ecology and responses to anthropogenic threats.


Comparative demographic effects of Canadian-U.S. immigration flows.
"A joint study by Statistics Canada and the U.S. Bureau of the Census examines special tabulations of U.S. residents born in Canada from the 1980 census of the United States and compares them with matching tabulations of Canadian residents born in the United States from the 1981 census of Canada. As might be expected, the two populations are remarkably similar and the preponderance of the migration flow is from Canada to the United States. The comparative social and economic characteristics of the two migrant stocks show the effects of increasing legal restrictions on migration between the two countries in the last two decades. The characteristics of the migrant flows have changed from large, unregulated population movements responding to economic motivations similar to internal migration flows to a much smaller, highly controlled movement more typical of long-distance international migration flows." This is a revised version of a paper originally presented at the 1987 Annual Meeting of the Population Association of America.


[Evaluation of ambulatory anesthesia at CHU, Brest].
Outpatient anaesthesia was investigated for a two-month period by means of a questionnaire filled from the preoperative anaesthesia consultation to the surgical procedure and the discharge of the patient. 868 consultations led to schedule 260 ambulatory procedures. ENT (88 patients), paediatric surgery (73 patients) and gynaecology (63 patients) were most frequently concerned. Indications of ambulatory practice could probably be enlarged provided that recovery rooms and surgical schedules were fully adapted.


Mathematical biology modules based on modern molecular biology and modern discrete mathematics.
We describe an ongoing collaborative curriculum materials development project between Sweet Briar College and Western Michigan University, with support from the National Science Foundation. We present a collection of modules under development that can be used in existing mathematics and biology courses, and we address a critical national need to introduce students to mathematical methods beyond the interface of biology with calculus. Based on ongoing research, and designed to use the project-based-learning approach, the modules highlight applications of modern discrete mathematics and algebraic statistics to pressing problems in molecular biology. For the majority of projects, calculus is not a required prerequisite and, due to the modest amount of mathematical background needed for some of the modules, the materials can be used for an early introduction to mathematical modeling. At the same time, most modules are connected with topics in linear and abstract algebra, algebraic geometry, and probability, and they can be used as meaningful applied introductions into the relevant advanced-level mathematics courses. Open-source software is used to facilitate the relevant computations. As a detailed example, we outline a module that focuses on Boolean models of the lac operon network.


Reduced thalamocortical functional connectivity in temporal lobe epilepsy.
In temporal lobe epilepsy (TLE), the thalamus is well known for its role in the propagation and spread of epileptiform activity. However, the integrity of thalamocortical functional connectivity (FC) in TLE and its relation to specific seizure patterns have not yet been determined. We address these issues with resting-state functional magnetic resonance imaging (fMRI). Resting-state fMRI was performed on two groups of unilateral TLE patients: those with focal seizures only (16 left TLE, 16 right TLE) and those with additional generalized seizures (16 left TLE, 10 right TLE), and 16 matched controls. A thalamic parcellation based on FC between five nonoverlapping cortical seeds (prefrontal, motor, somatosensory, parietal-occipital, and temporal) and the ipsilateral thalamus was carried out to parcel each thalamus into five corresponding segments. FCs between each segment and its ipsilateral cortical seed were extracted and compared across groups using analyses of variance (ANOVAs). Compared to healthy controls, patients with TLE displayed decreased thalamocortical FC in multiple posterior and ventromedial thalamic segments of both the ictal and nonictal hemispheres. Our parcellation analysis revealed that these thalamic regions were functionally connected to the parietal/occipital and temporal lobes. In patients with TLE with focal seizures these regional thalamocortical FC decreases were limited to the ictal hemisphere. In contrast, TLE patients with both focal and generalized epileptiform activity displayed FC decreases in both the ictal and nonictal thalamus involving the dorsolateral pulvinar, a region preferentially connected to the parietal and occipital lobes. Our data provide the first evidence of regional specific thalamocortical FC decreases in patients with unilateral TLE. Furthermore, our results demonstrate that patients with different seizure types present different thalamoparietal/occipital FC decrease patterns. While patients with focal seizures present thalamocortical FC decreases in the ictal hemisphere only, patients with additional generalized seizure activity also show thalamocortical FC decreases involving the thalamus in the nonictal hemisphere.


Cloud point extraction and spectrophotometric determination of mercury species at trace levels in environmental samples.
A new micelle-mediated separation and preconcentration method was developed for ultra-trace quantities of mercury ions prior to spectrophotometric determination. The method is based on cloud point extraction (CPE) of Hg(II) ions with polyethylene glycol tert-octylphenyl ether (Triton X-114) in the presence of chelating agents such as 1-(2-pyridylazo)-2-naphthol (PAN) and 4-(2-thiazolylazo) resorcinol (TAR). Hg(II) ions react with both PAN and TAR in a surfactant solution yielding a hydrophobic complex at pH 9.0 and 8.0, respectively. The phase separation was accomplished by centrifugation for 5 min at 3500 rpm. The calibration graphs obtained from Hg(II)-PAN and Hg(II)-TAR complexes were linear in the concentration ranges of 10-1000 μg L(-1) and 50-2500 μg L(-1) with detection limits of 1.65 and 14.5 μg L(-1), respectively. The relative standard deviations (RSDs) were 1.85% and 2.35% in determinations of 25 and 250 μg L(-1) Hg(II), respectively. The interference effect of several ions were studied and seen commonly present ions in water samples had no significantly effect on determination of Hg(II). The developed methods were successfully applied to determine mercury concentrations in environmental water samples. The accuracy and validity of the proposed methods were tested by means of five replicate analyses of the certified standard materials such as QC Metal LL3 (VWR, drinking water) and IAEA W-4 (NIST, simulated fresh water).


Long-term preservation of left ventricular function in medically treated patients with coronary artery disease and persistent exercise-induced ischemia.
Little information is available on the long-term evolution of left ventricular function of medically treated patients with coronary artery disease and gross limitation of coronary flow reserve. The aim of this study was to assess the long-term evolution of effort tolerance and left ventricular function and their relation to the control of ischemic events in patients with coronary artery disease and prolonged inducible exercise-induced myocardial dysfunction who either declined or were ineligible for cardiac revascularization.


Glomerella truncata: another Glomerella species with an atypical mating system.
In the genus Glomerella all species studied to date do not fit the usual mating system of heterothallic ascomycetes. This study investigated the mating system of G. truncata (anamorph Colletotrichum truncatum), a pathogen responsible for lentil anthracnose. Twenty-two field isolates from the Canadian prairies were crossed in all possible combinations, including selfings. All isolates also were screened for the presence of the MAT1-1 and MAT1-2 idiomorphs by targeting small conserved areas of the MAT genes (the alpha domain and the high mobility group HMG box) with degenerate primers, and a pair of G. truncata-specific HMG primers (CT21HMG) were designed. The results of the classical mating study suggested that G. truncata is heterothallic. Isolates fell into two incompatibility groups, which is consistent with a bipolar mating system but different from what has been described in other Glomerella species. Molecular screening showed that the HMG box used as a marker for the MAT1-2 idiomorph was present in both partners of fertile crosses in G. truncata, unlike in the typical ascomycete system, but as previously described for two other Glomerella species. G. truncata therefore appears to share unusual mating system characteristics with the other Glomerella species studied to date.


Role of impulsivity and reward in the anti-obesity actions of 5-HT2C receptor agonists.
The selective 5-HT2C receptor agonist lorcaserin entered clinical obesity trials with the prevalent view that satiety was a primary mechanism of action. Subsequent Phase II and III trials demonstrated efficacy in terms of weight loss, although the overall effect size (~3% placebo-corrected change) is considered modest. Lorcaserin has been approved by the FDA for the treatment of obesity with lifestyle modification, but since its introduction in 2013 its sales are in decline, probably due to its overall modest effect. However, in some individuals, lorcaserin has a much more clinically significant effect (i.e. >10% placebo-corrected change), although what common features, if any, define these high responders is presently unknown. In the present article we highlight the evidence that alternative mechanisms to satiety may contribute to the anti-obesity effect of lorcaserin, namely effects on constructs of primary and conditioned reward and impulsivity. This may better inform the clinical evaluation of lorcaserin (and any future 5-HT2C receptor agonists) to subgroups of obese subjects characterized by overeating due to maladaptive impulsivity and reward mechanisms. One such population might be individuals diagnosed with binge eating disorder.


Bullying among adolescents in North Cyprus and Turkey: testing a multifactor model.
Peer bullying has been studied since the 1970s. Therefore, a vast literature has accumulated about the various predictors of bullying. However, to date there has been no study which has combined individual-, peer-, parental-, teacher-, and school-related predictors of bullying within a model. In this sense, the main aim of this study was to test a multifactor model of bullying among adolescents in North Cyprus and Turkey. A total of 1,052 adolescents (554 girls, 498 boys) aged between 13 and 18 (M = 14.7, SD = 1.17) were recruited from North Cyprus and Turkey. Before testing the multifactor models, the measurement models were tested according to structural equation modeling propositions. Both models indicated that the psychological climate of the school, teacher attitudes within classroom, peer relationships, parental acceptance-rejection, and individual social competence factors had significant direct effects on bullying behaviors. Goodness-of-fit indexes indicated that the proposed multifactor model fitted both data well. The strongest predictors of bullying were the psychological climate of the school following individual social competence factors and teacher attitudes within classroom in both samples. All of the latent variables explained 44% and 51% of the variance in bullying in North Cyprus and Turkey, respectively.


Impact of IVIg on the interaction between activated T cells and microglia.
When human microglia are co-cultured with activated human T lymphocytes, several cytokines become up-regulated in significant quantities. This condition can also occur at sites of inflammation in autoimmune inflammatory diseases of the central nervous system (CNS), including multiple sclerosis (MS), where T cells infiltrate the brain tissue and come in proximity to microglia. Therefore, T cell-microglia interaction is a potential avenue of drug therapy to decrease neuroinflammation. An immunomodulator used in autoimmune disorders is intravenous immunoglobulins (IVIg). The mechanisms of IVIg activity in diseases such as MS remain unclear. Here, we report that the application of IVIg to activated T cells leads to their decreased ability to engage microglia. As a result of IVIg treatment of T cells, there were reduced levels of tumor necrosis factor-alpha a and interleukin-10 in T cell-microglia co-culture. Our results add to the understanding of how IVIg may affect inflammation of the CNS.


[Clonning and expression of procalcitonin and preparation of its polyclonal antibody].
To clone, express the procalcitonin (PCT) and prepare its polyclonal antibody. We designed 10 DNA primers according to the encoding sequence of human PCT gene from GenBank, amplified PCT gene by PCR and constructed the recombinant vector pGEX-KG-PCT. Then the fusion protein, PCT-GST, was expressed in E.coli and purified by affinity chromatography. The corresponding polyclonal antibody was produced in the New Zealand white rabbits immunized with the fusion protein, and its biological activity was detected by Western blotting. The specificity and titer of the polyclonal antibody was identified by agar gel immunodiffusion test. We successfully obtained the full-length PCT gene and expressed the fusion PCT-GST in E.coli. SDS-PAGE showed that relative molecular mass (Mr;) was about 36 000. Agar gel immunodiffusion test revealed that the prepared polyclonal antibody could specially recognized PCT and its titer was 1:4. The PCT is successfully cloned, expressed and purified. The high specific polyclonal antibody of PCT is prepared.


Parallax attention stereo matching network based on the improved group-wise correlation stereo network.
Recent stereo matching methods, especially end-to-end deep stereo matching networks, have achieved remarkable performance in the fields of autonomous driving and depth sensing. However, state-of-the-art stereo algorithms, even with the deep neural network framework, still have difficulties at finding correct correspondences in near-range regions and object edge cues. To reinforce the precision of disparity prediction, in the present study, we propose a parallax attention stereo matching algorithm based on the improved group-wise correlation stereo network to learn the disparity content from a stereo correspondence, and it supports end-to-end predictions of both disparity map and edge map. Particular, we advocate for a parallax attention module in three-dimensional (disparity, height and width) level, which structure ensures high-precision estimation by improving feature expression in near-range regions. This is critical for computer vision tasks and can be utilized in several existing models to enhance their performance. Moreover, in order to making full use of the edge information learned by two-dimensional feature extraction network, we propose a novel edge detection branch and multi-featured integration cost volume. It is demonstrated that based on our model, edge detection project is conducive to improve the accuracy of disparity estimation. Our method achieves better results than previous works on both Scene Flow and KITTI datasets.


Infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromcyin: a case review and cohort study.
In February, 1999, a local US health department identified a cluster of pertussis cases among neonates born at a community hospital and recommended oral erythromycin for post-exposure prophylaxis for about 200 neonates born at that hospital between Feb 1 and Feb 24, 1999. We investigated a cluster of seven cases of infantile hypertrophic pyloric stenosis (IHPS) that occurred the following month among the neonates who had received erythromycin. We obtained a masked, independent review of the IHPS ultrasonography diagnoses, calculated the monthly IHPS incidence, and compared index and historical (1998-99) IHPS cases with respect to several characteristics including erythromycin exposure. We used a retrospective cohort of infants born in January and February, 1999, to investigate further erythromycin exposure and development of IHPS. An independent review confirmed the ultrasonographic diagnoses of all seven index IHPS cases. All index cases versus none of the historical IHPS cases had been given erythromycin for pertussis prophylaxis. The IHPS rate for infants born in the hospital in February, 1999, was 32.3 per 1000 liveborn infants, representing nearly a seven-fold increase over 1997-98 (relative risk 6.8 [95% CI 3.0-15.7]). Among infants born in January and February, 1999, erythromycin was associated with IHPS (absolute risk 4.5%, relative risk infinity [1.7-infinity]). Neonates receiving oral erythromycin may have an increased risk of IHPS. The risks and benefits of erythromycin for neonatal pertussis prophylaxis should be re-evaluated, and caution should be used in defining risk groups for prophylaxis.


Thrombocytopenia with absent radius in a boy and his uncle.
We report a boy and his maternal uncle who have Thrombocytopenia-Absent Radius (TAR) syndrome. The mother of the propositus is normal. A maternal aunt has mild radial hypoplasia, possibly representing partial expression of the syndrome. A review of the literature shows several pedigrees in which relatives other than sibs were affected with TAR. Thus, autosomal recessive inheritance may not account for all cases and alternate modes of transmission should be considered.


An analysis of thyroid function diagnosis using Bayesian-type and SOM-type neural networks.
Thyroid function diagnosis is an important classification problem, and we made reanalysis of the human thyroid data, which had been analyzed by the multivariate analysis, by the two notable neural networks. One is the self-organizing map approach which clusters the patients and displays visually a characteristic of the distribution according to laboratory tests. We found that self-organizing map (SOM) consists of three well separated clusters corresponding to hyperthyroid, hypothyroid and normal, and more detailed information for patients is obtained from the position in the map. Besides, the missing value SOM which we had introduced to investigate QSAR problem turned out to be also useful in treating such classification problem. We estimated the classification rates of thyroid disease using Bayesian regularized neural network (BRNN) and found that its prediction accuracy is better than multivariate analysis. Automatic relevance determination (ARD) method of BRNN was surely verified to be effective by the direct calculation of classification rates using BRNN without ARD for all possible combinations of laboratory tests.


Personalized Prediction of Cardiovascular Benefits and Bleeding Harms From Aspirin for Primary Prevention: A Benefit-Harm Analysis.
Whether the benefits of aspirin for the primary prevention of cardiovascular disease (CVD) outweigh its bleeding harms in some patients is unclear. To identify persons without CVD for whom aspirin would probably result in a net benefit. Individualized benefit-harm analysis based on sex-specific risk scores and estimates of the proportional effect of aspirin on CVD and major bleeding from a 2019 meta-analysis. New Zealand primary care. 245 028 persons (43.6% women) aged 30 to 79 years without established CVD who had their CVD risk assessed between 2012 and 2016. The net effect of aspirin was calculated for each participant by subtracting the number of CVD events likely to be prevented (CVD risk score × proportional effect of aspirin on CVD risk) from the number of major bleeds likely to be caused (major bleed risk score × proportional effect of aspirin on major bleeding risk) over 5 years. 2.5% of women and 12.1% of men were likely to have a net benefit from aspirin treatment for 5 years if 1 CVD event was assumed to be equivalent in severity to 1 major bleed, increasing to 21.4% of women and 40.7% of men if 1 CVD event was assumed to be equivalent to 2 major bleeds. Net benefit subgroups had higher baseline CVD risk, higher levels of most established CVD risk factors, and lower levels of bleeding-specific risk factors than net harm subgroups. Risk scores and effect estimates were uncertain. Effects of aspirin on cancer outcomes were not considered. Applicability to non-New Zealand populations was not assessed. For some persons without CVD, aspirin is likely to result in net benefit. Health Research Council of New Zealand.


Effect of the attachment system on the biomechanical and clinical performance of overdentures: A systematic review.
Overdentures can improve the quality of life of elderly patients compared with conventional complete dentures. Different attachment systems can be used to retain these prostheses, but which system results in better function, mechanical performance, and patient comfort is unclear. The purpose of this systematic review was to evaluate randomized clinical trials to compare overdentures supported by either bar and clip or ball and O-ring attachments for retention, masticatory efficiency, bone loss, and patient satisfaction. A literature search was conducted in the PubMed and Web of Science databases. From 163 studies, 16 randomized clinical trials were included in this systematic review based on the inclusion and exclusion criteria. The risk of bias was evaluated according to the RevMan software Risk of Bias Table (RoB Table), and only the studies with a low or intermediate risk of bias were included in the review. From the limited number of studies, the attachment type did not affect the masticatory quality of the patients, bone loss marginal to the implants, or the degree of patient satisfaction. However, overdentures with the bar and clip attachment tended to have higher initial retention than the ball and O-ring system. Both the bar and clip and ball and O-ring attachment systems presented similar clinical performance regarding mechanical and functional properties and patient satisfaction.


Presence of glucocorticoid responsive elements in the mitochondrial genome.
Glucocorticoids rapidly affect nuclear RNA synthesis by binding, as hormone-receptor complexes, to Glucocorticoid Responsive Elements (GRE), differently positioned in glucocorticoid inducible genes. Glucocorticoids also affect, within minutes, mitochondrial RNA synthesis. We therefore searched for GREs in the mitochondrial genome of human (H), rat (R) and mouse (M) and found a number of such potential elements as follows: one within the 12s - rRNA gene (H1, R1 and M1) one within (H2), or at the start (R2, M2), of the presumptive protein 1 gene and three within the mouse cytochrome oxidase subunit 1 gene (COX1, COX2 and COX3). The nucleotide sequence of H1, R1 and M1 reveals the possibility of the formation of hairpin structures, stabilized by hydrogen bond formation, between three or four consecutive bases. The presence of potential GREs in the mitochondrial genome suggests an adjustment of mitochondrial metabolic control to the general control mechanisms of the cell.


Sequential changes in bone biochemical parameters and bone mineral density after renal transplant.
To evaluate sequential changes in biochemical bone parameters, parathyroid hormone (iPTH), vitamin D levels and bone mineral density (BMD) over a period of 24 weeks after renal transplantation, we studied 75 patients (58 males, with a mean age of 35.4 years) who underwent their first renal transplantation without a past history of parathyroid surgery or fractures. Serum calcium, phosphorus and albumin were measured before transplant, then weekly for four weeks and monthly for the following 20 weeks. Serum iPTH and vitamin D levels and BMD were measured at baseline and 24 weeks after transplantation. After transplantation, there was a significant fall in serum calcium in the first week, followed by a gradual rise. At 12 and 24 weeks, respectively, 17.5% and 8% patients had hypercalcemia. Serum phosphorus decreased after transplant and at 24 weeks; 25% patients had hypophosphatemia. The iPTH levels declined significantly from 251 ± 218.2 pg/mL before transplant to 97 ± 142.8 pg/mL at the end of the study period. At 12 and 24 weeks, 42.7% and 51.3% patients, respectively, had persistent hyperparathyroidism (HPT). Elevated baseline iPTH levels and graft dysfunction were the risk factors for HPT at 12 weeks, while low vitamin D levels were the risk factor at 24 weeks. The BMD showed a significant decline of 2.7% after transplant, and it negatively correlated with the pre-transplant iPTH levels; the patients who received tacrolimus immunosuppression had a lower decline in BMD than the rest of the patients. No fractures were reported during the study period. We conclude that, after renal transplantation, hypercalcemia and hypophosphatemia are common, while a significant proportion of patients have persistent HPT and decline in bone mineral density.


Modification of thiamine pyrophosphate dependent enzyme activity by oxythiamine in Saccharomyces cerevisiae cells.
Oxythiamine is an antivitamin derivative of thiamine that after phosphorylation to oxythiamine pyro phosphate can bind to the active centres of thiamine-dependent enzymes. In the present study, the effect of oxythiamine on the viability of Saccharomyces cerevisiae and the activity of thiamine pyrophosphate dependent enzymes in yeast cells has been investigated. We observed a decrease in pyruvate decarboxylase specific activity on both a control and an oxythiamine medium after the first 6 h of culture. The cytosolic enzymes transketolase and pyruvate decarboxylase decreased their specific activity in the presence of oxythiamine but only during the beginning of the cultivation. However, after 12 h of cultivation, oxythiamine-treated cells showed higher specific activity of cytosolic enzymes. More over, it was established by SDS-PAGE that the high specific activity of pyruvate decarboxylase was followed by an increase in the amount of the enzyme protein. In contrast, the mitochondrial enzymes, pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes, were inhibited by oxythiamine during the entire experiment. Our results suggest that the observed strong decrease in growth rate and viability of yeast on medium with oxythiamine may be due to stronger inhibition of mitochondrial pyruvate dehydrogenase than of cytosolic enzymes.


The Current Landscape of Veterinary Compounding in the Veterinary Setting.
Compounding for veterinarians is regulated by the U.S. Food and Drug Administration, but day-to-day regulation is deferred to the state authorities. Veterinarians must meet certain standards when prescribing or dispensing a compounded medication. Veterinarians are expected to maintain current knowledge of the benefit of compounded preparations and prescribe and dispense in keeping with the best evidence related to animal and human health. Whether veterinarians recognize or adhere to these standards is unknown. A self-administered survey was distributed electronically to 30,000 email addresses on record with the Veterinary International Network. The survey asked questions about the regulations and standards associated with the use of or prescription of compounded medications. Of the distributed surveys, 1,520 survey responses were received, for a 5.1% response rate. All surveys were included in the final analysis. Respondents with a higher training level in compounding had a greater perceived skill level regarding compounding of medications (r = 0.26, P<0.0001). Similarly, respondents with a higher training level had a greater knowledge of state laws and regulations (r = 0.14, P<0.0001). Those with formal training had better scores on the assessment questions than those with informal or no training (P=0.01). Approximately one-third of the respondents felt that they were not knowledgeable at all about compounding rules and regulations. The most common compounded medications used in practice by veterinarians are methimazole, metronidazole, and doxycycline. Veterinarians mostly recognized that compounding backordered, commercially available products is permitted. Formal training improves familiarity with compounding rules, regulations, and current practices. Therefore, efforts should be directed at improving veterinary knowledge of laws and regulations surrounding the practice of compounding medications.


[Detection of HPV infection in CIN and invasive cancers by in situ hybridization method--comparison with histopathology].
The causal association of human papilloma virus (HPV) with cervical cancer has been supported by multiple lines of evidence. Therefore, in the case of dysplasia, the presence of HPV-DNA should be detected and its subtypes identified. This is important in the determination of the prognosis for cervical disease. We reported a study in which the localization and types of HPV in cervical diseases was identified by in situ hybridization using biotin-labelled DNA probes. Seven types (3 basic forms) of HPV were used as DNA probes. HPV types used were following: 6/11, 16/18, 31/33/35. In this study, we introduced 7 new types (3 forms) of probes for a total of 14 types (6 forms). The new probes introduced were 42/43/45, 45/56, 51/52. Using these probes, the rate of detection HPV according to types was examined. In addition, localization of HPV infection and its relationship with histopathological findings of cervical disease were evaluated. 1) Types 6/11 and 45/56 were found in the lesions with less important histological findings (CIN I). Types 16/18, 31/33/35, 51/52 were found in the all lesions. Type 42/43/44 were not detected in this study. 2) The addition of 7 new types (3 new forms) of probes resulted in a 17% increase (16 cases) in the rate of detection of HPV compared to our previous study. 3) Localization and distribution pattern of the HPV is not, as has been reported so far, dependent on HPV type but rather on the histological characteristics, such as the degree of dysplasia.


Correction factors for boundary diffusion in reaction-diffusion master equations.
The reaction-diffusion master equation (RDME) has been widely used to model stochastic chemical kinetics in space and time. In recent years, RDME-based trajectorial approaches have become increasingly popular. They have been shown to capture spatial detail at moderate computational costs, as compared to fully resolved particle-based methods. However, finding an appropriate choice for the discretization length scale is essential for building a reasonable RDME model. Moreover, it has been recently shown [R. Erban and S. J. Chapman, Phys. Biol. 4, 16 (2007); R. Erban and S. J. Chapman, Phys. Biol. 6, 46001 (2009); D. Fange, O. G. Berg, P. Sjöberg, and J. Elf, Proc. Natl. Acad. Sci. U.S.A. 107, 46 (2010)] that the reaction rates commonly used in RDMEs have to be carefully reassessed when considering reactive boundary conditions or binary reactions, in order to avoid inaccurate--and possibly unphysical--results. In this paper, we present an alternative approach for deriving correction factors in RDME models with reactive or semi-permeable boundaries. Such a correction factor is obtained by solving a closed set of equations based on the moments at steady state, as opposed to modifying probabilities for absorption or reflection. Lastly, we briefly discuss existing correction mechanisms for bimolecular reaction rates both in the limit of fast and slow diffusion, and argue why our method could also be applied for such purpose.


Gain of function mutations in membrane region M2C2 of KtrB open a gate controlling K+ transport by the KtrAB system from Vibrio alginolyticus.
KtrB, the K(+)-translocating subunit of the Na(+)-dependent bacterial K(+) uptake system KtrAB, consists of four M(1)PM(2) domains, in which M(1) and M(2) are transmembrane helices and P indicates a p-loop that folds back from the external medium into the cell membrane. The transmembrane stretch M(2C) is, with its 40 residues, unusually long. It consists of three parts, the hydrophobic helices M(2C1) and M(2C3), which are connected by a nonhelical M(2C2) region, containing conserved glycine, alanine, serine, threonine, and lysine residues. Several point mutations in M(2C2) led to a huge gain of function of K(+) uptake by KtrB from the bacterium Vibrio alginolyticus. This effect was exclusively due to an increase in V(max) for K(+) transport. Na(+) translocation by KtrB was not affected. Partial to complete deletions of M(2C2) also led to enhanced V(max) values for K(+) uptake via KtrB. However, several deletion variants also exhibited higher K(m) values for K(+) uptake and at least one deletion variant, KtrB(Delta326-328), also transported Na(+) faster. The presence of KtrA did not suppress any of these effects. For the deletion variants, this was due to a diminished binding of KtrA to KtrB. PhoA studies indicated that M(2C2) forms a flexible structure within the membrane allowing M(2C3) to be directed either to the cytoplasm or (artificially) to the periplasm. These data are interpreted to mean (i) that region M(2C2) forms a flexible gate controlling K(+) translocation at the cytoplasmic side of KtrB, and (ii) that M(2C2) is required for the interaction between KtrA and KtrB.


A new dermatome for surgical treatment of rhinophyma.
A new instrument is suggested for surgical treatment of rhinophyma. It is an electrically driven dermatome that has been used beneficially in surgery on the palate. Its use offers several advantages over other instruments and methods currently used for the management of rhinophyma. It avoids the danger of shaving too deeply because the depth of each sweep is both predictable and constant. The size of the blade allows fine sculpturing even in narrow spaces.


Impact of non-invasive imaging techniques on the trend of pancreatic cancer mortality in Austria.
The introduction of non-invasive imaging techniques on a large scale may falsely suggest an increase in incidence of pancreatic cancer. In the present study, it was investigated whether the new diagnostic techniques have improved the documentation of deaths due to pancreatic cancer and thus have an influence on the trend of mortality. Age-standardized mortality rates for men and women were calculated covering the period 1970 to 1993. Using Spearman's correlation coefficient, the trends during 1970 to 1993 as well as during 1970 to 1978 and 1981 to 1993 were analyzed for statistical significance. Furthermore, the development of mortality during 1973 to 1993 was analyzed in 5-year intervals for various birth cohorts and age groups. Age-standardized mortality rates have increased significantly since 1970, i.e. by 17% in men (p = 0.0021) and by 20% in women (p = 0.001). The observed trend is not linear but characterized by a step-like rise in 1979/1980, coinciding with the introduction of non-invasive imaging techniques on a large scale. The risk to develop cancer of the pancreas has not significantly changed since 1970. Rather, the documentation of pancreatic cancer on death certificates has improved as a result of the higher diagnostic accuracy, which explains the observed step-like rise in death rates.


Review of the cervical cancer disease burden in mainland China.
Human papillomavirus (HPV) infection is a common sexually transmitted infection (STI) worldwide. HPV may cause several reproductive tract diseases and cervical cancer is the most serious health problem due to persistent high risk HPV infection. Although cervical cancer showed a declining trend over the past three decades in China, it remains a major health problem in Chinese women especially women living in rural China. The disease burden is believed to be underestimated given the relatively high HPV prevalence shown in recent studies. To date, prophylactic vaccination as a primary prevention of cervical cancer are available in many countries and regions of the world; yet, they are not yet accessible in mainland China. Before introduction of HPV vaccines, screening remains the predominant method of prevention. Selected population based screening sites are available in every province of China, yet, an organized screening program operating nationwide still does not exist. A better understanding of the disease burden is likely to help develop a comprehensive intervention policy for future management of cervical cancer in China. It is important to review the disease burden of cervical cancer and the current status of cervical cancer screening in mainland China.