Aims: To determine the prevalence and aetiological profiles of facial paralysis in Kano, Nigeria. Methods: This study involved three tertiary and health institutions in Kano, Nigeria between January 2006 and December 2010. Out of 11145 patients' records, 1003 cases had indication of facial nerve paralysis but 936 met the inclusion criteria. Data were extracted using research pro-forma. Data was analyzed using z-test for proportional significance, and Chi square test at 0.05 significant levels. Results: Prevalence rate of facial paralysis was 9.1% and mostly common (48.1%) between age of 20-38 years with males (52.8%) and the married (71.2%) more affected. Left side of the face was involved more frequently (53.0%) than the right side (46.4%) and bilateral (0.6%). Lower motor neuron lesion type (74.1%) was more common. Most common co-morbidity associated with facial paralysis was infections, closely followed by diabetes mellitus and pre-eclampsia. Highest incidence was in the year 2010, and the least was in 2006. z-values showed that minor difference in the prevalence exist between male and female. There was an association between each of age, occupation, comorbidities and place of residence and the aetiologic factors. However, the strength of relationships was weak and the degree of association is very weak as determined using Cramer V and Lambda. Conclusion: Prevalence of facial paralysis is relatively high in this region. It is affected by urban dwelling, being a fullhousewife and co-morbidity. Lower motor neuron type and sudden onset were predominant. This calls for greater awareness for preventive measures.


OBJECTIVE
To estimate the frequency of depressive symptoms and selected psychiatric disorders in the Women's Health Initiative Memory Study (WHIMS) cohort and related them to cognitive syndromes.

DESIGN
WHIMS was a randomized, double-blinded, placebo-controlled prevention clinical trial examining whether opposed and unopposed hormone therapy reduced the risk of dementia in healthy postmenopausal women. Participants scoring below a designated cutpoint on a cognitive screener received a comprehensive neuropsychiatric workup and adjudicated outcome of no cognitive impairment, mild cognitive impairment, or probable dementia.

PARTICIPANTS
Seven thousand four hundred seventy-nine WHIMS participants between age 65 and 79 years and free of dementia at the time of enrollment in WHIMS. Five hundred twenty-one unique participants contributed complete data required for these analyses.

MEASURES
Depressive symptoms were measured with the 15-item Geriatric Depression Scale and the presence of selected psychiatric disorders (major depression, generalized anxiety, and panic and alcohol abuse) was made using the PRIME-MD.

RESULTS
The 18% of women had at least one psychiatric disorder with depression being the most common (16%) followed by general anxiety or panic (6%) and alcohol abuse (1%). Depression and the presence of a psychiatric disorder were associated with impaired cognitive status. Participants having a psychiatric disorder were more than twice as likely to be diagnosed with cognitive impairment as those with no psychiatric disorder (odds ratio = 2.06, 95% confidence interval = 1.17-3.60). Older age, white race, and diabetes were also associated with cognitive impairment.

CONCLUSION
The frequency of a psychiatric disorder is associated with poorer cognitive functioning among older women enrolled in WHIMS. That approximately one in five women had a probable psychiatric disorder, most typically depression, highlights the need for greater detection and treatment efforts in this population.


People spend a lot of time in vehicles. Driving involves risks that are mitigated by passive and active safety systems. Active safety systems prevent accidents from happening in the first place. Human machine interfaces (HMI) are needed to monitor the driver's behavior and capture driver's input. This presents challenges based on environmental, vehicle interior, and user characteristics. Vehicles are directly exposed to the environment. Sensors have to cope with both rapid light changes and complete darkness. Vehicle interiors contain geometries that obscure parts of the human body. Sensors that require a line of sight may therefore be at a disadvantage. Sensor positioning is also limited by vehicle geometry. Sensors that require additional mounting impact the design and result in an obtrusive system. Systems that can be integrated invisibly into existing vehicle structures are less obtrusive and have less impact on the design. Parts of the user must also be monitored in free air, which makes contact-based scanning systems unsuitable. Some sensor systems are capable of monitoring the entire body, but still have to deal with the requirements of vehicle users. People will wear different clothing or glasses. User monitoring must be enabled regardless of this condition. People are also becoming sensitive to their personal data. This can be crucial for the acceptance of systems. Systems must also comply with regulations such as "Privacy by Design" which is required in the European Union. Privacy must therefore be preserved. I argue that capacitive proximity sensors are capable of dealing with the above challenges. Due to the physical principle, illumination changes are not an issue, and they can sense through insulators. Capacitive proximity sensors (CAPS) can therefore be used in existing vehicle structures, both in close proximity and without contact with the object to be monitored. In addition, they are often said to maintain privacy. Based on the challenges and capabilities of CAPS, three research questions emerge:

• RQ1: How can we use existing vehicle structures to enhance or substitute vehicular HMI using CAPS?
• RQ2: How can we use existing vehicle structures to provide new ways of human computer interaction using CAPS?
• RQ3: Can CAPS contribute to the acceptance of vehicular HMI with regard to privacy concerns?

To find evidence to support these research questions, I focused on systems that help users drive safely. Cameras are commonly used in HMI. Because they require line of sight, affect interior design, and capture data that creates privacy concerns, they may not be the best choice. CAPS are therefore an opportunity to change the modality. Several applications are developed that provide evidence that the use of CAPS is beneficial for vehicle HMI. Each application is developed following a common process with the goal of meaningful uses. Each application is based on accident statistics and related research, so that real-world problems are addressed. This entails analysis of driving issues, prototype implementations of sensor topologies, and algorithms for attention monitoring, child monitoring, authentication, and gesture recognition in vehicles. One will additionally receive best practices for CAPS data labeling, which is crucial for supervised learning methods that are considered helpful. Privacy compliant behavior is analyzed in this thesis. Vehicle HMI are therefore analyzed with regard to privacy concerns and regulations. The user's data protection perspective is also captured in a survey. This is necessary to find indications that CAPS is not only an alternative from a technical point of view. It is also an alternative that could be in the user's favor.


The paper describes some recent field test programmes performed across Europe. Given the increased need to develop alternative, clean energy sources the paper presents details of R&D programmes with a focus on reducing costs offshore developments and increases safety. Work on the development of design codes for large diameter piles is presented. New areas of research are highlighted in particular ongoing research is needed to look at effects such as cyclic loading and dynamic interaction. In the offshore field the use of piles that reduce environmental impact is an area of ongoing research that is addressed. Interesting full-scale field tests looking at the problem of negative skin friction are also considered.


The study of indefinite causal order has seen rapid development, both theoretically and experimentally, in recent years. While classically the causal order of two timelike separated events A and B is fixed - either A before B or B before A - this is no longer true in quantum theory. There, it is possible to encounter superpositions of causal orders. In light of recent work on quantum reference frames, which reveals that the superposition of locations, momenta, and other properties can depend on the choice of reference frame or coordinate system, the question arises whether this also holds true for superpositions of causal orders. Here, we provide a negative answer to this question for quantum diffeomorphisms. First, we provide an unambiguous definition of causal order between two events in terms of worldline coincidences and the proper time of a third particle. Then, we show that superpositions of causal order defined as such cannot be rendered definite even through the most general class of coordinate transformations - quantum-controlled, independent diffeomorphisms in each branch. Finally, based on our results, we connect the information theoretic and gravitational perspectives on indefinite causal order.


The SW Barents Sea was subjected to significant uplift and erosion during the Cenozoic, processes that are believed to have had a significant impact on hydrocarbon maturation and migration in the area. The current study uses compaction of shale- and sand-dominated layers to make a map of net apparent erosion throughout the SW Barents Sea. The map shows regional trends consistent with deep-seated isostatic uplift of the crust in combination with glacial erosion as a driving mechanism for the erosion. We find increased erosion towards the north and decreased erosion towards the west, in the western Barents Sea. The trend of highest erosion has an axis stretching in a SE–NW orientation towards Svalbard. This indicates a major change in the crustal uplift pattern in the transition from the Norwegian mainland to the Barents Sea. The velocity inversion method used in this study combined with a two-baseline normal compaction trend model demonstrates a reliable procedure for accurate erosion estimations. It allows erosion estimates from layers with different lithologies to be integrated into a common interpretation and differences to be interpreted geologically: for example, an apparent facies change to a mixed sand–shale lithology, possibly with reservoir quality sands developed, in the Cretaceous on the Bjarmeland Platform.


Three patients had pneumatosis intestinalis. The first suffered from recurrent intestinal obstruction; pneumatosis intestinalis developed with the deterioration of his condition. The second patient was admitted for abdominal pain; pneumoperitoneum was an incidental finding on routine x-ray films of the abdomen, and a diagnosis of pneumatosis intestinalis was made by excluding the possibility of the other disorders that cause pneumoperitoneum. In the third case the disease was diagnosed at autopsy. A mechanical factor alone does not seem sufficient to produce intestinal cysts and an additional factor, a mucosal permeability change, is apparently needed to cause appearance of the disease.


Shoulder pain is a common musculoskeletal complaint that if severe enough, can contribute significantly to morbidity due to its debilitating and often disabling nature which may leave patients unable to perform activities of daily living. Various etiologies of shoulder pain exist which present with clinical signs and symptoms based on the source of the pathology. Although most shoulder injuries can be diagnosed with a detailed history and physical exam, magnetic resonance imaging (MRI) has become a well-established technique for confirming pathology J Orthop Sports Med 2021; 3 (3): 102-115 DOI: 10.26502/josm.511500046 Journal of Orthopaedics and Sports Medicine 103 of the shoulder due to its high diagnostic accuracy. The ability to visualize soft tissue as well as bone morphology has allowed it to become widely utilized across all specialties that manage shoulder pathology; especially in orthopaedics. Radiologists that interpret MR images often describe changes to normal anatomy by utilizing terms that have been well studied and published throughout radiology literature. These terms are referred to as "signs" and are used to assist in diagnosis of a disease by correlation with clinical symptoms. These signs are a key component of the fundamental core of musculoskeletal radiology but are not often discussed or utilized in the field of orthopaedics to assist with a diagnosis. This manuscript will discuss and review the presentation of a selection of unique clinical signs of shoulder pathology that are identifiable with MRI as well as how they are described by musculoskeletal radiologists. The signs discussed within this manuscript are unique due to the fact that although they are more published throughout musculoskeletal radiology literature when compared to orthopaedic surgery and sports medicine literature.


Pseudohypoparathyroidism type Ia (PHP type Ia) is associated with several endocrinopathies. We describe two siblings with PHP type Ia, hypothyroidism and growth hormone deficiency (GHD). To our knowledge, these patients are the first to have PHP type Ia and GHD. The defect which is most likely responsible for the three endocrinopathies is a deficiency of the stimulatory guanine nucleotide-binding regulatory protein, Gs.


Water, energy and food are the pillars upon which society can further advance. The lack of a secure and economical provision of one of these essentials could result in a breakdown of supply, affordability and accessibility of the two others, especially for the most vulnerable in society. Management of the nexus is of great concern, and the Water Science Forum of the Royal Society of Chemistry have created this brief which outlines some of the challenges and emerging solutions that our members have been focused on.


Brazil is the world leader in broiler production and export. It achieved this position mainly to its excellent supply chain structure and climate, which favor poultry and grain production throughout its territory. Although Brazilian egg production is not as important as broiler production, this segment presents great potential of increasing its share in the global market. However, as elsewhere in the world, Brazilian poultry production faces the challenge to balance two elements within its supply chain: cruelty and productivity. The consumers of the European Union (EU) are very concerned with animal welfare issues. In order to increase its share in the European market, and eventually in the world market, Brazilian poultry producers must understand the effects of production systems on poultry welfare, and try to develop systems that are suited for its climate and other production conditions. There is a consensus that the natural behaviors performed by poultry in intensive production systems allow better welfare. This objective of this review is to present scientific research studies that relate different behaviors to chicken welfare. Poultry behavior is a reflex of their welfare status at a particular moment, and it is related to internal (physiological) and external (environmental) factors. Several natural behaviors that favor welfare, as well as undesirable behaviors, may be stimulated by environmental enrichment. The correct interpretation of the behaviors expressed by poultry, including their frequency, duration, and sequence, may be used to estimate their welfare. Animal production is an import sector of Brazilian economy. It significantly contributes to the Gross Domestic Product (GDP), in terms of products destined both to domestic consumption and exports. New technologies applied to products and management practices have been developed for field application, aiming at improving producers' productivity and profitability. In order to comply with the European Union's (EU) guidelines for animal protein production, Brazilian poultry production needs to undergo a process of adaptation. In May, 2007, the EU Commission established its new guidelines for animal welfare in poultry production, pressured by consumer demand. In the EU, there is a growing concern among consumers as to how poultry are reared and slaughtered. European consumers are in the fore front of the demand of high quality products produced with under better welfare conditions, and have spread this concern throughout the world. Beaumont et al. (2010) mentioned that European consumers frequently perceive that standard commercial poultry production has poor animal welfare practices. According to Naas et al. (2008), Brazilian poultry production today needs to find a balance between cruelty and productivity. In fact, ensuring animal welfare may provide better financial results, as it increases the producer's profit margins and allows maintaining Brazilian chicken export quotas to the EU. Franca (2008) noted that biological studies that define ethical limits and guidelines for poultry production foster the development of new production practices that may ensure good product quality and productivity without putting bird welfare at risk. Gonyou (1994) states that, when animal welfare started to be studied, the only behavioral factors considered were those related to feeding and reproduction. These first studies used as indicators of animal welfare reduced life expectancy, impaired growth, impaired reproduction, body damage, disease, immunosuppression, adrenal activity, behavior anomalies, and self-narcotization (Broom, 1991). However, current studies evaluate additional indicators, such as natural behaviors, behavioral needs, preferences, behavioral problems, emotional state, cognitive abilities, etc. In the field of ethology, the expression of natural behavior is a frequently used tool used to estimate the welfare of poultry destined to human consumption. According to Bracke & Hopster (2006), natural behavior can be defined as the behavior the animal normally presents when exposed to conditions similar to its natural habitat. Natural behaviors are pleasurable and promote biological functions that are meaningful to the animal's welfare. The definition of natural behavior, though, does not include the bird's behavior when sick, in flight or during aggression, since these are not considered pleasurable situations. Considering layer behavioral needs in the design of housing facilities optimize their welfare. Mishra et al. (2005) verified that ISA Brown layers spent, during 24 hours, around 97% of the time in the nest, feeding, walking, resting, or dust bathing, and that 57% of these behaviors did not depend on environmental enrichment. It was also observed that hens had preferred behavioral sequences, which included foraging and comfort behaviors, such as wing-stretching and preening. The present review aims at discussing, albeit not exhaustively, scientific research studies on the behavior of Gallusgallus domesticus and its relationship to welfare. The following behaviors are reviewed: feather pecking, scratching, dust bathing, nesting, locomotion activities, and aggressive behaviors. These behaviors are the most frequently observed in commercial broiler, broiler breeder, and layer farming, and therefore, monitoring their incidence may contribute to measure poultry welfare.


Background: A better understanding of the context specific epidemiology, outcomes and risk factors for death of critically ill parturients in resource-poor hospitals is needed in order to tackle the still alarming in-hospital maternal mortality in African countries.Methods: One–year retrospective cohort in a referral maternity hospital in Freetown, Sierra Leone. Primary data source was the patient chart. The primary endpoint was the association between risk factors and HDU mortality. The study was registered on ClinicalTrials.gov (study identifier NCT04121234).Results: 523 patients (median age 25 years, IQR 21-30) were admitted to the HDU for a median of 2 (IQR 1-3) days. 65% were referred with a red obstetric early warning score (OEWS) code, representing 1.17 cases per HDU bed per week. 11% of patients died in HDU, mostly in the first 24 hours from admission. The factors independently associated with HDU mortality were: ward rather than post–operative referrals (odds ratio (OR), 3.21 [95%-confidence interval (CI) 1.48 to 7.01]; P = 0.003), admissions with a red vs. yellow/green OEWS (OR, 3.66 [95%-CI 1.15 to 16.96]; P = 0.04), responsiveness to pain or unresponsiveness on the AVPU scale (OR, 5.25 [95%-CI 2.64 to 10.94]; P =<0.0001), use of vasopressors (OR, 3.24 [95%-CI 1.32 to 7.66]; P =0.008). Higher SpO 2 was associated with improved survival (OR, 0.95 [95%-CI 0.91 to 0.98]; P =0.007).Conclusions: Critically ill parturients were predominantly referred with a red OEWS code and usually required intermediate care for 48 hours. Mortality is high and mostly occurs during first day. Medical admission, a red OEWS code, a poor neurological and hemodynamic status were independently associated with mortality, while adequate oxygenation was associated with survival.Trial Registration: The study was registered on ClinicalTrials.gov (study identifier NCT04121234).Plain English summarySierra Leone is one of the countries with the highest maternal mortality rate of the world. Understanding of critical care issues and potential interventions is lagging behind approaches in the primary care and obstetric domain. This study, reporting data from 525 patients admitted to an obstetric HDU, to date represents the largest cohort of critically–ill parturients from a low–income country. At multivariable analysis, being referred from the ward rather than being post–operative (OR 3.21, 95% CI 1.48 to 7.01), red OEWS code (OR 3.66, 95% CI 1.15 to 16.96), being responsive to pain or unresponsive on AVPU scale (OR 5.25, 95% CI 2.64 to 16.96) at admission, use of vasopressors at admission (OR 3.24, 95% CI 1.32 to 7.66) were independent risk factors for mortality, while higher SpO2 (OR 0.95, 95% CI 0.91 to 0.99) was associated with increased survival.The findings of this study can be summarized as follows (1) in a low–resource referral maternity hospital one out of 14 deliveries needed critical care attention, with a crude mortality rate of 10.5%; (2) independent predictors of mortality were poor neurological status, a red OEWS code at admission to HDU and the use of vasopressors during the stay; (3) higher oxygenation was associated with survival. Clinicians and policy makers may use these findings to prioritize simple critical care interventions to address maternal mortality in a high burden scenario.


Promotion is a process of altering and giving information toward public
that there is product which being offered for sale in a persuasively in order that
people are aiming to buy the product. According to the tourist's data in Semarang
City since 2010, tourist were increased but the amount of visitors in some tourist
attraction have no stability. Through one of the promotion, to keep increasing
number of tourists, the department of culture and tourism semarang city were
participated in tourism exhibition at Jogja Expo Centre. Methodology in
conducting this research is using descriptive qualitative and also by doing
interview toward the employee of Culture and Tourism Department of Semarang
City and the stand's visitor of Semarang City.
Research results refer that tourism exhibition of department of culture and
tourism semarang city at jogja expo centre were through several stages, that is
research-listening from public hearing with the tourism stakeholder, the result,
even the visitors in some tourists attraction did not stable but overall the visitors
of semarang city were increased in every year. Next, planning-decision, like
things that need to be prepared in the exhibition based on standard, job decision
and coordination of several parties. The next stage is communication-action that
refers to activitiesand altering information which persuade the visitors so that they
are interest in visiting tourist destination in Semarang City. Then the result
response of the visitors were quite good, they've became interest, because so far
they only know popular places, after getting the information it becomes clearer
that there so many tourists attractions that hasn't been visited yet, they even want
to looking for more information about the tour.


Accumulation of unfolded proteins in the endoplasmic occurs when the cell is subject to stress caused by various pathological conditions such as hypoxia, viral infection, and glucose depravation. Under such stress the cell will initiate an unfolded protein response (UPR), a protective mechanism that is specifically designed to re‐establish homeostasis and normal endoplasmic reticulum (ER) function. This adaptive mechanism inhibits overall protein translation, but enhances the translation of a small number of key stress response proteins that will clear the ER of unfolded proteins and send them to the cytoplasm for degradation. The UPR is initiated by several proteins such as IRE1a, ATF6a and PERK, the later being a key Ser/Thr protein kinase in UPR signaling. In response to inducers of ER stress, BiP (GRP78) dissociates from the luminal ER domain of PERK, resulting in the oligomerization, autophosphorylation, and activation of PERK which in turn phosphorylates eIF‐2a on Ser51 and Nrf2 (unknown site of phosphorylation). In order to further identify potential substrates for PERK, this enzyme was tested against large protein and peptide microarrays. A significant number of proteins and peptides in the microarrays were found to be phosphorylated by PERK. After additional selection, several of these substrates were further characterized using a microfluidic mobility‐shift assay and submitted to LC/MS analysis to identify the site of phosphorylation by PERK. These newly identified peptide substrates were used to develop a robust biochemical assay for the testing of small molecule inhibitors of PERK activity. A limited SAR was established for a set of compounds against PERK and two other related protein kinases, GCN2 and PKR. One of the most potent and selective PERK inhibitors was found to modulate PERK cellular signaling as evidenced by blocking the phosphorylation of (Ser51)eIF‐2a as judged by Elisa and Western blot analysis. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B258.


"Criminal careers" denotes ways in which offenders develop specialisms and versatility, but studies linking delinquency to social skills deficits have not attempted to explore cognitive, internalised processes by which such "careers" might be chosen. This study investigated criminal minds via script theory: "internal" scripts are used to guide behaviour, "situational" scripts are knowledge of everyday events, and "personal" scripts are a sequence of actions towards a desired goal. This research investigated whether criminal career offenders develop situational scripts for offending and whether such situational scripts express an internalised identity, which manifests as a personal script. Thematic analysis of data derived from "criminal career offenders" supports the notion of criminal situational scripts, with emergent themes considered evidence of personal scripts.


The synthesis of branched copolymers with precise composition, specifically the ratio of methacrylic acid (MAA) to ethylene glycol (EG) has been demonstrated. These polymers were used to stabilise dodecane oil-in-water emulsion droplets. It was demonstrated in the literature that branched copolymers containing a 1:1 ratio of MAA:EG formed pH-responsive emulsions, capable of triggered inter-droplet hydrogen bonding to form engineered emulsions (EE). The effect of varying this ratio on the rate of engineered emulsion formation, and the resulting strength and stiffness of the emulsion droplet aggregates was investigated. This control over systems is exemplified by the demonstration of selective acid-triggered assembly of binary mixtures of droplets stabilised by polymer containing only EG functionality with droplets stabilised by polymers containing only MAA functionality. EEs stabilised using a branched copolymer containing a 1:1 ratio of MAA:EG were produced and allowed to dehydrate, leading to the removal of water from droplet interstitial sites. The resulting single-phase materials are known as polymer-structured oils (PSOs), held structurally by the inter-droplet polymer-polymer interactions. These polymer boundaries provide enough of a barrier between droplets to prevent coalescence upon the removal of water, allowing reversible hydration of PSOs to reform EEs. The production of large volume, well-defined EEs produced via the hydrolysis of glucono-δ-lactone (GδL) to gluconic acid in an emulsion's water phase was investigated. This process provides a homogeneous pH trigger for the formation of EEs, eliminating the slow diffusion of HCl. A homogeneous pH trigger also allows the formation of EEs to be studied in situ using rheology. A comparison between GδL and a conventional HCl trigger is presented. Branched copolymer-stabilised ethyl acetate o/w emulsions were used as templates in the production of both pH-responsive, surface-functionalised poly(methyl methacrylate) (PMMA) colloidal nanoparticles and non-responsive PMMA particles via an emulsion-solvent-evaporation technique. Lowering of the solution pH can trigger the reversible aggregation of these highly dispersed pH-responsive colloids into 3D structures with internal macroporosities dictated by the method of dehydration employed. The colloids can also co-encapsulate various hydrophobic molecules without any effect on particle stability and pH-responsiveness. The production of multi-responsive emulsion droplets via the encapsulation of oleophilic, magnetic Fe3O4 nanoparticles within a stable, surface-functionalised dodecane o/w emulsion was investigated. Droplet surface functionality allowed the formation of EE on lowering the pH, and encapsulated nanoparticles gave both the free-flowing and aggregated emulsions magnetic-responsiveness. The rate of aggregation and gel strength of multi-responsive EEs is compared to that of a standard pH-responsive emulsion.


Hajnal, Rado, Partition relations for cardinal numbers, Acta mathematica, vol. 16 (1965), pp. 93-196. The authors conclude II with several problems concerning the classes E = {K: K -y (K)£ »} and E' a , where E' a = {«: K -> (a)a a }. These classes of Erdos cardinals are of foundational signifi cance. On the consistency of the generalized continuum hypothesis. pp. This paper gives a reformulation of GQdel's consistency proof for the generalized continuum hypothesis (G.C.H.) (VI 112). The changes are not very far-reaching; the eight fundamental operations which GQdel used are changed slightly by removing the relativizing factor from F 4 — F B ; and some changes are made in the construction of L and the proof of the Godel axioms, the axiom of choice, and the G.C.H. in L. But the proofs are still very close in spirit to the Godel proofs; thus no attempt is made to give a proof as indicated in Godel's 1939 paper V 117, and nothing is proved beyond what is proved in his monograph VI 112. Some insight is given into the meaning of V = L, in terms of the "progenitors" of a set (i.e., the arguments of the fundamental operation used to construct the set); and some of the proper ties of the segments of the constructible hierarchy (in Gfidel's terms, F"a for regular cardinals a) are pointed out.


Aims Young people (YP) have the right to be involved in decisions regarding their healthcare and may be able to offer a unique perspective in the selection and recruitment of medical professionals. We aimed to explore the involvement of young people in selection of candidates to Paediatric Specialty Training. In addition to investigating agreement between consultant and YP scores, we also aimed to evaluate feedback from candidates, YP and consultants on the interview participation process. Methods We conducted this pilot service evaluation exercise at our regional interviews for entry to run-through training. Local YP were invited to take part and informed consent was obtained from YP and their parents. YP participated in the structured presentation station, with scoring of 31 candidates by panels of two consultants and two YP. For this pilot exercise YP's scores were not included for ranking and appointment. We conducted agreement analysis of scores (Bland Altman) and collated feedback from 5-level Likert scale questionnaires. Results There was reasonable agreement between consultants and YP with a mean difference of 0.9 (range ±5 points) for presentation scores out of 20. If current consultant scoring were replaced by equally weighted consultant and YP scoring for a single station, 61% (16) of ranked candidates would have seen a change in their ranking. Candidates were deemed unappointable if a minimum score was not achieved; no candidates would have crossed this threshold by the inclusion of YP's scores. Median total score was 117/160 (IQR 23). 83% (43) of feedback respondents believed that YP should be involved in the recruitment of all paediatric trainees. Conclusions YP were motivated to partake in this participation project and could feasibly be involved in the recruitment and selection process. Consultant colleagues were enthusiastic and positive about YP participation. There was reasonable, but not absolute, agreement between consultant and young interviewers such that ranking but not appointability would be affected in this scenario. We intend to extend training for YP with potential involvement in the communication skills station in future. There is genuine potential to implement YP participation widely throughout medical recruitment and selection processes.


Mammography has been one of the most reliable methods for early detection of breast carcinomas. The main objective of this paper is to detect and segment the tumor from mammogram images that helps to provide support for the clinical decision to perform biopsy of the breast. In this paper, there are two aspects to segmentation in mammography. First is to separate out the mammogram from the background and the identification of putative masses and the pectoral muscle. The extraction approach is done using basic region growing method to identify the tumor. Second is to extract the features from segmented masses and classifies the masses by case base reasoning method. The experimental results are shown in this paper till the first phase of mass segmentation.


The purpose of the study was to examine the anti-malodor, anti-gingivitis, and plaque reducing properties of a 2 phase oil:water mouthrinse compared with a control mouthrinse. Fifty subjects rinsed with one of the two rinses for 30 seconds twice a day over 6 weeks, while continuing their normal oral hygiene habits. Measurements were made at time zero (prior to beginning the rinsing regimen), and > or = 9 hours following rinsing, at intervals of 1, 3, and 6 weeks. Malodor of whole mouth, as well as tongue dorsum anterior and posterior, was assessed on a 0 to 5 semi-integer scale by two odor judges. Volatile sulphide compounds (VSC) were determined using a sulphide monitor. Gingival, plaque, and bleeding indices were recorded for Ramfjord teeth. Oral microbial levels were assessed using the oratest. Salivary levels of diamines (putrescine and cadaverine) were analyzed by HPLC. Results were analyzed by 2-tailed covariant ANOVA, with the time zero value as covariant. Dramatic improvements were observed in parameters associated with malodor, periodontal health, plaque accumulation, and microbial levels in both groups. As compared to time zero scores, whole mouth odor, tongue dorsum anterior and posterior odors decreased continuously over time, attaining 80%, 79% and 70%, reductions, respectively following 6 weeks, in the 2-phase mouthrinse group, versus 70%, 77% and 59% for the control group. For whole mouth and tongue dorsum posterior, the reductions observed in the 2-phase mouthrinse group were significantly greater than those obtained with the control mouthrinse (P = 0.026 and P = 0.025, respectively), suggesting that the 2-phase mouthrinse is superior to the control mouthrinse in long-term reduction of oral malodor. For bleeding index, gingival index, oral microbial levels, and VSC, differences between the groups were not significant. Diamine levels were not significantly reduced in either group. The control mouthrinse reduced plaque index more significantly than the 2-phase mouthrinse (P < 0.005). The results of this randomized clinical trial suggest that the 2-phase oil:water mouthrinse formulation is superior to the control mouthrinse in long-term reduction of oral malodor.


e-mail: firstname.lastname@example.com Despite the apprehension of certain parties, the demand for maritime emergency logistics has emerged following the occurrence of maritime accidents around the world while trading activities are performed. The requirement of Emergency Logistics Centre (ELC) is crucial as part of the maritime disaster preparedness at the Straits of Malacca (SOM). The ELC prevents massive losses, should any disaster occur in the rough ocean. Based on unforeseen situations at sea, this paper explores the contributing factors of the ELC in proposing and improving strategies for Kuala Linggi seaport as an ELC. The Exploratory Factor Analysis (EFA) has been employed to achieve the objectives of this paper. The outcome of this paper indicates that resource availability, risk management, and geographical factors are the three key attributes that are substantially required to transform Kuala Linggi seaport into an ELC. Furthermore, disaster preparedness, ELC supply-chain management system, and safety procedures are the crucial components to enhance the operational efficacy at this seaport as an ELC. The findings of this research may contribute to the safety of the maritime route and disaster preparedness at the SOM. Emergence of Emergency Logistics Centre (ELC): Humanitarian Logistics Operations at the Straits of Malacca


The variation of power system parameters causes modal interaction within the power system modes and leads to strong resonance. The effect of this dynamic modal interaction on the oscillatory modes can affect the system stability. This paper examines the performance of these power system modes in the presence of PSS and FACTS controllers, and also provides solution to mitigate this problem. The significant modes of interest are identified using the methods of participation factors and isolated using the multi-modal decomposition. Then strong resonance is observed in complete and reduced system, during the simultaneous tuning of PSS and FACTS controllers. The reduced system is obtained by the method of perturbations, proposed by Seiranyan. The case studies are presented for the New England 10-machine 39 bus system.


Costal cartilage activity ([35S]sulphate and [3H]thymidine incorporation) and somatomedin (SM) activity in normal Snell-mice and dwarfmice before and during treatment with human growth hormone (hGH), porcine growth hormone (pGH) and L-thyroxine (T4) were studied, in order to obtain more insight in the interrelationship of these parameters with growth velocity. In normal mice endogenous (21 h incubation in medium with label) and plasma stimulated cartilage activity (21 h pre-incubation in medium, 48 h incubation with 20% human plasma, supplemented for the last 24 h with label) slows down immediately after birth, whereas the length velocity has a peak at 1 1/2 week of age and diminishes gradually thereafter. The endogenous activity of dwarfmice between the ages of 7 and 17 weeks is comparable with 3 weeks old normals, however plasma stimulated activity is much higher indicating a discrepancy between growth capacity of the cartilage and chronological age. Cartilage of dwarfmice recognizes growth hormone dependent differences in human plasma. The SM content of mouse serum using homologous cartilage turned out to be low for dwarfs, reaching subnormal values during hGH treatment. Three days after initiation of treatment with hGH endogenous sulphate and thymidine incorporation in costal cartilage is increased compared to saline treated dwarfmice. The effect is age-dependent and a combination of GH and T4 shows an effect equal to the sum of the effects of hormones given separately. After treatment for 5 weeks with hGH no differences between treated and untreated animals could be observed anymore, although the length velocity did not change throughout the 10 weeks of treatment. A difference of the cartilage sensitivity to human plasma between hGH treated and untreated mice is noted one week after treatment and a small difference remains after 5 weeks of treatment.


This paper proposes a set of novel pricing factors for currency returns that are motivated by microstructure models. In so doing, we bring two strands of the exchange rate literature, namely market-microstructure and risk-based models, closer together. Our novel factors use order flow data to provide direct measures of buying and selling pressure related to carry trading and momentum strategies. We find that they appear to be good proxies for currency crash risk. Additionally, we show that the association between our order-flow factors and currency returns differs according to the customer segment of the foreign exchange market. In particular, it appears that financial customers are risk takers in the market, while non-financial customers serve as liquidity providers.


Union of the Pharmacists Employees of the Republic of Poland in the Pomeranian Voivodeship (1919–1939) The Union of Pharmacists Employees of the Polish Republic (1919–1939) was a nationwide organization representing pharmaceutical staff employed primarily in private pharmacies. Its statutory objectives were: defense of material, moral and low interests of pharmacists working in pharmacies, laboratories, chemical and pharmaceutical factories, and institutions of a similar type, striving to achieve better working conditions, and improving the whole affairs of the pharmaceutical profession. In the interwar period, in Pomorskie voivodship existed local branches of this organization: Branch of Wloclawek, Branch of Pomerania, Branch of Bydgoszcz and Branch of Gdynia. Forms of their activities were: lectures and discussions about labor rights and of scientific issues, financial support for the poor people (mainly for pharmacists), and other social affairs, assistance in finding employment for pharmacists, and also striving for respected and improvement of working conditions in pharmacies. These branches, despite the limited funds, exerted constant pressure on the owners of pharmacies, react in cases of violations of labor rights. The Union of Pharmacists Employees of the Polish Republic in autumn 1939 was liquidated by the German authorities.


The miniature cultivar Micro-Tom has attracted much attention as a model of tomato (Solanum lycopersicum) because it has small size (10-20 cm in height), a short life cycle (70- 90 days), and grows well in ordinary laboratory spaces. Recently, expressed sequence tag data and full-length cDNA sequences have been accumulated for Micro-Tom. To provide genomic information resource for Micro-Tom, we constructed the MiBASE database, which can be access via the Internet at http://www.kazusa.or.jp/jsol/microtom/. In addition to sequence information, this database contains information on simple sequence repeats, single nucleotide polymorphisms between other tomato inbred lines, nonredundant sequence sets, gene ontology terms, metabolic pathway names, and gene expression data.


The cytosolic factor p47-phox (NCF1) is a key component of the phagocyte NADPH-oxidase system, critical for microbicidal activity. The human p47-phox gene has been well characterized and resides on chromosome 7q11. Here we describe the molecular characterization of the mouse ortholog (Ncf1), which maps to distal chromosome 5, and compare the structure of the genes, commenting on the degree of homology. The mouse and human genes contain the same number of exons and introns, but the mouse gene is more compact (7.8 kb versus 15.2 kb). A percentage identity plot analysis comparing the human and mouse genes indicates that sequence homology is generally restricted to exons and does not include any large segment of introns or the 5' flanking sequence. The mouse gene also contains notably fewer repetitive elements than its human counterpart (34% versus 50%). The start of transcription of the mouse gene has been localized to within 12 nucleotides of the translation start site, similar to the human ortholog. Our findings provide an important foundation for investigating the evolutionary history of the p47-phox gene, particularly as it relates to understanding the molecular basis of the p47-phox-deficient autosomal recessive form of chronic granulomatous disease.


The ligand [{Me3SiC[triple bond, length as m-dash]CC(NDipp)2}Li(thf)3] (Dipp = 2,6-diisopropylphenyl) was used for salt metathesis reactions with [AuCl(tht)] (tht = tetrahydrothiophene) to obtain the dinuclear alkyne functionalized bisamidinate [{Me3SiC[triple bond, length as m-dash]CC(NDipp)2}2Au2]. This compound serves as a building block for the polynuclear carbide bridged gold(i) amidinate complex [Au8{μ3-(η1:η2-C[triple bond, length as m-dash]C)}2(Me3SiC[triple bond, length as m-dash]CC(NDipp)2)4(tht)2], which is the first gold(i) complex with a μ3-η1:η2 carbide coordination. Both gold(i) compounds show distinct aurophilic interactions and are remarkably stable at ambient conditions. Photophysical investigations revealed intense luminescence with notable high quantum yields both in the solid state and in solution.


The way design problems are presented may influence an engineer's ideation process, and eventually, the design outcomes. We aimed to explore the ways in which pre-engineering students shift their design ideas based on different framings of design problems. We evaluated ideas with respect to the metric of paradigm-relatedness, which refers to the extent to which an idea works within the explicitly stated and commonly understood bounds of a problem, versus moves beyond those bounds. Thirteen prospective engineering students participated in the study. Students were first given a problem statement framed in a way that didn't encourage any particular type of solution. The students were asked to generate solutions to the problem using visual and verbal depictions. Subsequently, they were given a second problem framed either to encourage practical solutions based on pre-existing designs or framed to encourage radical solutions not based on pre-existing designs. Ideas were coded as either paradigm-preserving or paradigm-modifying. We identified students whose ideas shifted from more of one type to more of another from their first ideation session to their second, as well as students whose ideas remained consistent. We analyzed their generated idea sets and reflection questionnaires to describe the influence of the framed design problem statements on their ideation approaches. The findings illustrate that problem framing can influence the paradigm-relatedness of ideas generated in a design tasks, both in more adaptive directions and in more innovative directions. However, our findings also illustrate that problem framing is not always successful in causing an individual to shift in their ideation approach, and so additional factors such as individuals' cognitive styles should also be taken into account.


Whole plasma infusion, in our experience, has been highly effective in the management of patients with thrombotic thrombocytopenic purpura. The effectiveness of plasma infusion in the treatment of this severe disorder implies the deficiency of a factor in the patient's plasma. Furthermore, we have observed that when platelets are suspended in plasma obtained during active, untreated thrombotic purpura, aggregation occurs. This effect is neutralized by preincubation of the thrombotic thrombocytopenic purpura plasma with normal plasma. Thus, there is both a correlation with the clinical pathogenic mechanism, disseminated platelet aggregation, and with the therapeutic response to plasma infusion. Based upon our experience and the concept that thrombotic thrombocytopenic purpura is a plasma factor deficiency state, we recommend initial infusion of a full plasma volume equivalent over the first 24 hours. This should be done under an intensive care setting. After this initial plasma infusion, we advise the infusion of 3 units of plasma daily until a full remission is obtained. When the clinical situation has stabilized, we stop the daily plasma infusions and cautiously observe for recurrence of the manifestations of thrombotic thrombocytopenic purpura. If there is a recurrence, plasma is again infused in substantial quantity during the first 24 hours and then 3 units daily until a full remission is again evident. Whether the plasma requirement might be attenuated or the course of the disease shortened by the concomitant use of antiplatelet agents, corticosteroids or other means remains to be determined.


s 1st NATO Medical Conference S31 A Model of Major Trauma Audit to Improve Clinical Effectiveness in Both Civilian and Military Field Hospital Environments Col. Timothy John Hodgetts, MMEd, MB, BS, FRCP, FRCSEd, FFAEM, FIMCRCSEd, FRGS, L/RAMC Defence Consultant Adviser and Professor, Emergency Medicine and Trauma, Royal Centre for Defence Medicine, Birmingham, UK The management of severely injured patients is a core business of military medical services on operations. The Major Trauma Clinical Effectiveness project was started in 1997, to improve the outcome of severely injured victims treated in a combined civilian-military hospital in the UK (Ministry of Defence Hospital Unit, Frimley Park). A fulltime, military Trauma Nurse Coordinator (TNC) was responsible for collating data from point of injury to discharge, and for monitoring 40 clinical performance indicators in four areas (prehospital care, resuscitation, definitive care, and documentation). In 1999, the same model was implemented in 22 field hospitals in Kosovo, allowing direct comparison of standards of care in the civilian and military environments. In 2001, the project was transferred to the new Royal Centre for Defence Medicine in Birmingham, UK, and a course was developed to train military TNCs for all future deployments. This has allowed the collection and analysis of data from the war in Iraq in 2003, with TNCs placed in all British Army field hospitals and onboard the hospital ship. An analysis of the trauma data is presented.


The Fram Strait separates Northeast Greenland from the Svalbard Archipelago, and is the only deep connection to the Arctic Ocean. Therefore, this strait is the only gateway for direct exchange of intermediate and deep waters between the Arctic Ocean and the North Atlantic. Two main currents influence the exchanges: i) the West Spitsbergen Current, bringing Atlantic waters northwards, and ii) the East Greenland Current, which carries cold Arctic waters and ice southwards. These two currents consist of water masses with different origin, generate distinct physical and chemical conditions between the eastern and western parts of the strait, which effects the biological characteristics in this region. Oceanographic observations in the Fram Strait have been carried out for ~15 years with microbial research in the water column focusing mainly on eukaryotes, while very little exploratory work was conducted on pelagic Bacteria and Archaea. Here we present a preliminary report of the first extensive survey across the waters of the Fram Strait focused on Bacterial and Archaeal domains, conducted as part of the Arctic long-term observatory HAUSGARTEN annual expedition in summer 2016. Besides the investigation of "who is out there", the observations gained in this survey will be integrated with other biological and physical data of the long-term observatory framework and will provide an essential step towards the understanding of the biochemical dynamics in the Fram Strait. In addition, on a long-term plan this project will contribute to the microbial observatory work as part of the FRAM Helmholtz research infrastructure and EU AtlantOS program.


The incidence of agenesis of inferior vena cava in the general population was estimated at 0.6 - 0.8%. In patients with deep vein thrombosis the frequency of agenesis was estimated between 5 and 6.7% in young people. In this pictorial essay, we present the ultrasound findings obtained in 8 patients with high deep venous thrombosis and inferior vena cava anomaly (absence of a segment), compared with images obtained by angio-computed tomography or magnetic resonance imaging. At the end we discuss the place of abdominal ultrasound in the evaluation of these patients.


Brucella infection is often an occupational disease of veterinarians, agricultural workers, and slaughterhouse workers. The infection is generally spread by contact of broken skin (open cuts or wounds) with infected animal tissues or by ingesting unpasteurized milk and dairy products from the infected animals. Brucellosis, which can have many different clinical presentations, may rarely cause joint prosthesis infection. There is not enough literature about the treatment of such infection which should be kept in the differential diagnosis, especially in endemic regions. We aim to present diagnostic and treatment approach of Brucella prosthetic infection in a 70-year woman with total knee arthroplasty. Key Words: Brucella, Prosthesis, Infection, Total knee arthroplasty.


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Introduction: Central serous chorioretinopathy (CSC) has the main symptoms of choroidal thickening, detachment of retinal pigment epithelium (RPE), and presence of subretinal fluid. Treatment of CSC is indicated for cases with SRF persisting for more than 4 months, decreased visual acuity, history of recurrence, or history of previous CSC in other eyes with poor visual outcome. This case report aims to describe the management of CSC using focal laser photocoagulation.
Case presentation: A man, 41 years old, living in the city, came with complaints of sudden blurred vision in his left eye when he woke up 3 months ago. This complaint is accompanied by a decrease in the ability to see in the middle. There are no vision complaints such as flashes of light, no blurred vision such as tunnels or closed curtains, no red eyes, pain, or eye discharge. On ophthalmological examination, there was a decrease in visual acuity oculi sinistra (OS) 6/12, intraocular pressure within normal limits, and orthophoria. On examination of the posterior segment of the OS, a decreased positive foveal reflex was found. Fluorescent angiography fundus photo examination showed central serous chorioretinopathy OS. This patient was diagnosed with central serous chorioretinopathy oculi sinistra. Management is given to patients in the form of disease-related education, laser focal photocoagulation OS, clobazam 10 mg/24 hours, eye drops oxymetazoline HCl 1 drop in the left eye/8 hours.
Conclusion: Treatment with laser focal photocoagulation is beneficial in the clinical improvement of cases of central serous chorioretinopathy.


The multiferroic material YbMnO_3 has been reported to exhibit both ferroelectric and antiferromagnetic orders in the ground state. Of these two orders, the ferroelectric order is associated with the P6_3/mmc-to-P6_3cm structural transition, which occurs around 1270 K. The interesting feature of the ferroelectric state is that a cloverleaf domain structure with a pseudo-six-fold symmetry is observed in transmission electron microscopy images with the beam incidence parallel to the hexagonal axis. To understand the origin of the formation of the cloverleaf domain structure, we have examined the crystallographic features of the ferroelectric state in YbMnO_3 by transmission electron microscopy. In this study, particularly, we adopted the experimental condition that electron beam incidences are perpendicular to the hexagonal axis. It was, as a result, found that there existed various ferroelectric domain structures including the cloverleaf domain structure under the present condition. The notable feature of domain structures found in this study is that each domain structure basically consists of six domains, whose domain boundaries are terminated at one point. Because this feature makes us reminiscent of a discommensurate structure in an incommensurate state, we took high-resolution electron micrographs of areas including domain boundaries. Their analysis indicated that a domain boundary could be identified as a discommensuration with a phase slip of π/3. It is thus understood that the cloverleaf domain structure should be one of domain morphologies for a discommensurate structure, which is related to the break of the translational symmetry.


Applying a constitutive rhetorical framework to public speeches and letters circulated transnationally from 1859–1866 by the leadership of the revolutionary Irish nationalist Fenian movement, this essay argues that constitutive rhetorical theory's assumed ideological effects must be modified to account for the transnational rhetorical practices of movements like the Fenians. The essay first traces how Fenian identification practices seek to fix the entire diaspora as the "Irish people" and Ireland as the true homeland. It then examines how the movement transcodes its constitutive rhetoric to better fit the separate national constraints operating in the United States and Ireland, and how these strategies hamper the organization's ability to sustain the unity required for success. While the constituted Irish Revolutionary remained in each national context, their strategies for fulfilling the constitutive narrative had splintered, helping to doom the cause. The Fenian case demonstrates the need to render constitutive rhetorical theory in more dialogic terms, especially for transnational audiences.


Abstract. The quantification of the amount of anthropogenic carbon (Cant) that the ocean has taken up from the atmosphere since pre-industrial times is a challenging task because of the need to deconvolute this signal from the natural, unperturbed concentration of dissolved inorganic carbon (DIC). Nonetheless, a range of techniques have been devised that perform this separation using the information implicit in other physical, biogeochemical, and man-made ocean tracers. One such method is the TrOCA approach, which belongs to a group of back-calculation techniques, but relative to other methods employs a simple parameterization for estimating the preformed, pre-industrial concentration, the key quantity needed to determine Cant. Here we examine the theoretical foundation of the TrOCA approach and test its accuracy by deconvoluting the known distribution of Cant from an ocean general circulation model (OGCM) simulation of the industrial period (1864–2004). We reveal that the TrOCA tracer reflects the air-sea exchange of both natural and anthropogenic CO2 as well as that of O2. Consequently, the determination of the anthropogenic CO2 flux component requires an accurate determination not only of the contribution of the natural (pre-industrial) CO2 flux component, but also of the O2 flux component. The TrOCA method attempts to achieve this by assuming that the concentration changes invoked by these two air-sea flux components scale with temperature and alkalinity. While observations support a strong exponential scaling of the oxygen flux component with temperature, there exists no simple relationship of the natural CO2 flux component with temperature and/or alkalinity. This raises doubts whether the sum of these two components can be adequately parameterized with a single function. The analyses of the model support this conclusion, even when Cant is deconvoluted using parameter values that were optimized on the basis of the synthetic dataset from the model. Application of an optimal, but globally uniform set of parameters for the estimation of Cant results in a global positive bias in the inventory of more than a factor of two, suggesting that a "universal" TrOCA parameterisation is not achieveable. Even the application of regionally specific sets of parameters causes, on average, a global positive bias of more than 50%. This is substantially larger than the potential positive bias of 7% identified for the ΔC* method using a similar model-based assessment method.


The current research explores the potential to develop a cherry-apple hard cider market as a potential means to increase demand for and the value of Michigan fruit grower's product. Factors affecting both the development of hard cider markets in Michigan and cherry-apple hard cider were explored. Research results show that the potential value of Michigan hard cider market is relatively small but significant, estimated at ranging between $580,000 and $2,900,000 per year. Microbrews would be primary actors to promote HC market. They are willing and able to dabble in it, promote it. But they are constrained by need for license and this impedes participation of many who would be otherwise interested. Some microbrews uninterested in state-wide push because they feel it will focus on sweet product that they are uninterested in producing. This position is reflective of a seeming contraction inherent in current enthusiasm over the potential of the market, as figures recent market growth is largely fueled by the current trendiness of "malternatives" as a beverage category, while the maintenance of the market, and the interests of some microbrewers and other purveyors is primarily derived from the traditional image of hard cider, with "traditional" vs. "trendy" hard cider products reflecting significant taste differences. Hard cider is also potentially an important product for wineries. There is a high sales potential for a Michigan-brewed hard cider product, however producing a hard cider that is produced exclusively from Michigan-grown fruit could be more difficult due to supply limitations, logistical constraints, and cost. Constraints to growth of hard cider industry include licensing requirements, taxation issues, primary ingredient sourcing and transport, and fluctuating prices, particularly for cherry juice. The research showed high potential for hard cider that blends cherries (and many other fruits) with apple, however such a product would be rotated with current hard cider, not added as a new product in most cases. Its demand increasing potential still exists, however, even if offered as a substitute to hard cider, due to its novelty and variety.


In this thesis, methods to study gene and protein expression in cells and tissues were developed and utilized in combination with protein-specific antibodies, with the overall objective to attain greater understanding of protein function.To analyze protein expression in in vitro cultured cell lines, a cell microarray (CMA) was developed, facilitating antibody-based protein profiling of cell lines using immunohistochemistry (IHC). Staining patterns in cell lines were analyzed using image analysis, developed to automatically identify cells and immunohistochemical staining, providing qualitative and quantitative measurements of protein expression. Quantitative IHC data from CMAs stained with nearly 3000 antibodies was used to evaluate the adequacy of using cell lines as models for cancer tissue. We found that cell lines are homogenous with respect to protein expression profiles, and generally more alike each other, than corresponding cancer cells in vivo. However, we found variability between cell lines in regards to the level of retained tumor phenotypic traits, and identified cell lines with a preserved link to corresponding cancer, suggesting that some cell lines are appropriate model systems for specific tumor types. Specific gene expression patterns were analyzed in vitiligo vulgaris and malignant melanoma. Transcriptional profiling of vitiligo melanocytes revealed dysregulation of genes involved in melanin biosynthesis and melanosome function, thus highlighting some mechanisms possibly involved in the pathogenesis of vitiligo. Two new potential markers for infiltrating malignant melanoma, Syntaxin-7 and Discs large homolog 5, were identified using antibody-based protein profiling of melanoma in a tissue microarray format. Both proteins were expressed with high specificity in melanocytic lesions, and loss of Syntaxin-7 expression was associated with more high-grade malignant melanomas.In conclusion, the combination of antibody-based proteomics and microarray technology provided valuable information of expression patterns in cells and tissues, which can be used to better understand associations between protein signatures and disease.


Submitted: 15 May 2019 Accepted: 14 Aug 2019 Abstract Despite the increasing number of diabetic patients, self-care plays an important role in the prevention and detection of various complications such as neurological disorders. The aim of this experiment was to investigate the main factors affecting diabetes type 1 and self-care. For this purpose, six volunteer subjects with diabetes type 1 were included. Their glucose levels together with the carbohydrate intake and other factors were recorded four times a day for 30 days. In order to perform statistical analysis, the one-way variance analysis, Pearson correlation coefficient, time series analysis, and the combined time series (panel) analysis were applied. The findings of this study demonstrated that the alteration in blood glucose levels was strongly influenced by carbohydrate intake, physical activity, stress level, amount of sleep, and insulin; while slightly influenced by pills and supplements use, hypoglycemia, insulin sensitivity , alcohol and cigarette use, and comorbidity. In four patients, the self-care score was normal, one patient exhibited high level and the reaming showed low level. For each patient, the error rate was as follows: 6.451, 6.095, 8.819, 7.368, 6.05, 5.856. Regarding to the loss of HbA1c rate after our study, people are advised to control their blood glucose levels based on individual preferences, conditions, lifestyle, and physiology for preventing severe diabetes type 1 conditions and extra cost.


Humanization of decision support using knowledge acquired from simulation simulation of biological processes mathematical techniques in biological simulation integrating spatial and temporal aspects of a simulation - an energy example modelling processes and operation with linear programming expert systems for self-adjusting process simulation evaporation models use of crop simulation in management GOSSYM/COMAX integrated methods and models for deficit irrigation planning GRAZE - a beef-forage model of selective grazing dynamical models and their application to optimizing grazing management modelling and simulation in applied livestock production science the plant-animal interface in models of grazing systems field machinery selection using simulation and optimization whole-farm simulation of field operations fundamentals of neural networks artificial intelligence-based optimization using agents simulation of crop growth - CROPGRO.


Annual precipitation and river water volumes and chemistry were measured from 1995 to 1998 in a mesoscale agricultural area of southeast Brazil. Precipitation was mildly acidic and solute concentrations were higher in the west than in the east of the basin. Combustion products from biomass burning, automobile exhaust, and industry typically accumulate in the atmosphere from March until October and are responsible for seasonal differences observed in precipitation chemistry. In river waters, the volume-weighted mean (VWM) concentrations of major solutes at 10 sites across the basin were generally lower at upriver than at downriver sampling sites for most solutes. Mass balances for major solutes indicate that, as a regional entity, the Piracicaba River basin was a net sink of H+, PO4(3-), and NH4+, and a net source of other solutes. The main stem of the Piracicaba River had a general increase in solute concentrations from upriver to downriver sampling sites. In contrast, NO3- and NH4+ concentrations increased in the mid-reach sampling sites and decreased due to immobilization or utilization in the mid-reach reservoir, and there was denitrification immediately downriver of this reservoir. Compared with tributaries of the Chesapeake Bay estuary, the Piracicaba River is affected more by point-source inputs of raw sewage and industrial wastes than nonpoint agricultural runoff high in N and P. Inputs of N and C are responsible for a degradation of water quality at downriver sampling sites of the Piracicaba River drainage, and water quality could be considerably improved by augmenting sewage treatment.


In the course of molecular studies on Japanese glucose-6-phosphate dehydrogenase (G6PD) variants using single-strand conformation polymorphisms (SSCP) analysis, we found an unusual class 1 G6PD variant that had nucleotide deletion in exon 9. The patient showed chronic nonspherocytic hemolytic anemia associated with frequent episodes of severe hemolytic attack. The hemolysate exhibited no measurable activity. Although the partially purified enzyme had detectable activity, we could not perform kinetic studies because of its extreme instability. Nucleotide sequencing showed a unique 24 bp deletion at nucleotide 953-976 that predicts an eight amino acid deletion of TKGYLDDP at residue 319-326. While this is one of the most drastic structural alterations found in G6PD variants, the region with the amino acid deletion was distant from both the G6P and NADP+ binding sites and was located in a domain with low sequence homology among species. The comparatively low functional importance of the deleted region may have saved the patient from lethal tissue dysfunction.


Simple Summary The use of cannabinoids containing plant extracts as herbal medicine can be traced back to as early as 500 BC. In recent years, the medical and health-related applications of one of the non-psychotic cannabinoids, cannabidiol or CBD, has garnered tremendous attention. In this review, we will discuss the most recent findings that strongly support the further development of CBD as a promising anti-cancer drug. Abstract Recently, cannabinoids, such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), have been the subject of intensive research and heavy scrutiny. Cannabinoids encompass a wide array of organic molecules, including those that are physiologically produced in humans, synthesized in laboratories, and extracted primarily from the Cannabis sativa plant. These organic molecules share similarities in their chemical structures as well as in their protein binding profiles. However, pronounced differences do exist in their mechanisms of action and clinical applications, which will be briefly compared and contrasted in this review. The mechanism of action of CBD and its potential applications in cancer therapy will be the major focus of this review article.


A coherent software environment simplifies maintenance - and using the same terminology facilitates communication and learning within the IT department. Having a mixed and complex software environment could put strain on the IT department. Applications and databases needs to be somehow cataloged in case of system failure. While mapping applications to databases using a unified terminology might seem to be a good idea from the start, but when it comes to generating a data model of interconnections based on terminology - confusion will arise. This confusion could lead to misinterpretations, which in turn could lead to incidents.


In this paper, we show a formal equivalence between histogram equalization and distribution-preserving quantization. We use this equivalence to connect histogram equalization to quantization for preserving anonymity under the k-anonymity metric, while maintaining distributional properties for data analytics applications. Finally, we make connections to mismatched quantization. These relationships allow us to characterize the loss in mean-squared error (MSE) performance of privacy-preserving quantizers that must meet distribution-preservation constraints as compared to MSE-optimal quantizers in the high-rate regime. Thus, we obtain a formal characterization of the cost of anonymity.


From the beginning of his career, Marty Redish has been something of a bomb thrower, repeatedly challenging legal orthodoxy. During the last decade, democratic theory has been at the center of many of his challenges to widely accepted procedural rules. Meanwhile, American proceduralists are gradually waking up to the reality that the rest of the world handles procedure quite differently. Redish's theoretical challenge to U.S. procedure - premised on political theory - therefore also corresponds to efforts to harmonize American procedure more closely with that of the rest of the world. But the United States remains stubbornly resistant to that harmonization, and even limited shifts in the direction Redish endorses excite very vigorous opposition. This Article recognizes the ways in which Redish's democratic theory could lead to greater harmonization with the rest of the world, but contrasts several other political theory explanations for American exceptionalism that support retaining our current methods. It concludes by recognizing that this tension presents considerable challenges to American rulemakers.


In this study, the effective patch radius expression for the circular microstrip antennas is improved by means of several manipulations. Departing from previously proposed equations in the literature, one of the most accurate equations is picked up, and this equation is fine-tuned by means of Particle Swarm Optimization technique. Throughout the study, impacts of other parameters (such as the definition of the fitness/objective function, the degree-of-freedom in the proposed effective patch radius expression, the number of measured resonant frequency values) are observed in a controlled manner. Finally, about 3% additional improvement is achieved over a very accurate formula, which was proposed earlier.


As first shown in Clarke (2011), Word Bank's Enterprise Surveys data suggest that the magnitude of bribery estimated by firm owners and managers in Africa is considerably higher when estimates are formulated as a percentage of turnover rather than in monetary value. This working paper confirms these findings with a randomized experiment carried out in Madagascar with 436 firm owners and managers and provides additional evidence that the observed gap in estimates between these two answer formats is caused by a measurement error on the part of survey respondents. Experience in running a business appears to mitigate error but without eliminating it completely.


Diabetes is a significant complication of b-thalassaemia major. The aetiology includes iron overload causing b-cell destruction, autoimmunity, insulin resistance secondary to liver disease and development of type 1 or 2 diabetes. There are specific issues for patients with diabetes and thalassaemia which will be discussed here. Impaired carbohydrate metabolism must be detected early, to allow intensification of iron chelation. As life expectancy in thalassaemia rises, diabetic complications are seen. Optimising blood glucose and cardiovascular risk factor control is essential. Insulin remains critical for severely symptomatic patients. With milder hyperglycaemia, oral antidiabetic drugs are increasingly used. At Whittington Hospital, we wanted to address these issues. In 2005, we developed a unique Joint Diabetes Thalassaemia Clinic, where patients are reviewed jointly by specialist teams, including Consultant Diabetologist and Haematologist. The Joint Clinic aims to optimise diabetes, endocrine and thalassaemia care, while supporting patient self-management. A retrospective audit of the Joint Clinic (2005-09), showed improvement in glycaemic control, (Fructosamine falling from 344 umol/l to 319 umol/l). We compared our cohort to the National Diabetes Audit for England (2007-08). Patients attending the Joint Clinic achieved better glycaemic control (target reached: 73% Joint Clinic vs. 63% Nationally), blood pressure control (target reached: 58% Joint Clinic vs. 30% Nationally) and cholesterol control (target reached: 81% Joint Clinic vs. 78% Nationally). 22.7% of our patients had ≥1 microvascular complication. A significant proportion had endocrinopathies (86% hypogonadism, 23% hypoparathyroidism, 18% hypothyroidism). Managing diabetes is one of the greatest challenges a person with thalassaemia can face. Training people to self-manage their diabetes and providing support from specialist teams working together are critical. The unique partnership working of our Joint Diabetes Thalassaemia Clinic allows these very complex patients to be managed effectively.


The viral E2 gene product plays a crucial role in the human papillomavirus (HPV) vegetative cycle by regulating both transcription and replication of the viral genome. E2 is a transcriptional repressor of the E6 and E7 viral oncogenes for HPV types 16 and 18, which are involved in cervical cancers. Using new polyclonal antibodies against the HPV16 E2 protein, we showed that E2 is expressed at various precursor stages of cervical carcinoma by immunohistochemistry on paraffin-embedded clinical samples. E2 was found to be highly expressed in the nuclei and cytoplasm of cells forming the intermediate and upper layers of cervical intraepithelial neoplasia (CIN). We could show that the expressions of E2 and p16(INK4a) (surrogate marker for oncogenic E7 expression) were exclusive in most of the cases, thus implying that E2 is not expressed together with high levels of E7. Moreover, we found that E2 is expressed in a subset of columnar cells adjacent to the CIN. We could show that expression of E2 is topologically distinct from the proliferation markers p63 and Ki67, whereas it coincides with the expression of cytokeratin K13, a marker of squamous cell differentiation. Expression of E2 also topologically coincides with episomal amplification of viral genomes in the upper layers of CIN1. These in vivo data thus validate previous assumptions of the crucial role of E2 in the early steps of HPV infection and of its negative link with expression of the viral E6 and E7 oncogenes.


: Venereal spirochetosis of rabbits, caused by Treponema cuniculi, have been observed since the 1940's in the rabbit colony maintained at The Jackson Laboratory. Treatment of individual rabbits with obvious clinical lesions using a product containing crystalline penicillin and dihydrostreptomycin caused lesions to heal but venereal spirochetosis persisted in the colony. Clinical and serological responses of rabbits receiving three subcutaneous injections of benzathine penicillin G-procaine penicillin G (either 42,000 or 84,000 IU/kg body weight/week) at 7 day intervals were monitored. Both doses were effective. Lesions healed within 2 weeks of the first treatment. Rapid plasma reagin titers declined markedly or disappeared by the sixth week after the first treatment. Based upon the above findings and results of previous epizootiological studies, a program to eradicate venereal spirochetosis from this enzootically infected colony was successfully undertaken.


Intracerebroventricular infusions of an amiloride analog, benzamil, reduce blood pressure in several rat models of hypertension. This effect has been attributed to an inhibition of amiloride-sensitive Na+ channels in the brain. This study examines whether intracerebroventricular benzamil would prevent the onset of deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats and whether this effect correlates with an inhibition of ion transport through the known amiloride-sensitive cation channels at the blood-brain barrier. We also examine whether the effects of benzamil on blood pressure are mediated by a Na+ channel by comparing the effects of different amiloride analogs. Benzamil (0.15 and 0.5 microgram/h icv) did significantly attenuate the increase in blood pressure induced by DOCA treatment. This antihypertensive effect, however, was not associated with an alteration in a blood-brain barrier ion transport as assessed by measurements of blood-to-brain 22Na transport and cerebral spinal fluid Na+ and K+ concentrations. Indeed, intracerebroventricular infusion of dimethyl amiloride, an amiloride analog with low affinity for Na+ channels, also attenuated the increase in blood pressure induced by DOCA-salt treatment. Comparisons of the effects of benzamil, dimethyl amiloride, and 3,4-dichlorobenzamil, another amiloride analog, suggest that these antihypertensive effects are mediated by an inhibition of Na+/Ca2+ exchange in the brain.


In jurisdictions that subscribe to adversarial mode of litigation, burdens and standards of proof have significant roles in the adjudication and determination of criminal cases. The operation of the principle of presumption of innocence in such jurisdictions determines issues of who bears what burden and the extent thereof. The Ethiopian criminal procedure system predominantly exhibits adversarial features, and there is the need for the comprehension and enforcement of the respective burdens and standards of proof borne by litigants. The constraints in clarity are more pronounced in those criminal law provisions that embrace some form of presumptions such as provisions on corruption offences. This note highlights how issues of burden and standard of proof are allocated as between prosecuting authorities and accused persons. Apart from explaining the nexus between the principle of presumption of innocence, burdens of proof and standards of proof, it indicates the implications of the operation of the principle of presumption of innocence upon the allocation of evidential and persuasive burdens of proof as between the state and the accused. It further outlines the effects of the various forms of   presumptions upon the different kinds of burdens of proof. Key words : Burden of proof, standard of proof, easing of burden of proof, criminal cases, presumption of innocence


The context of the current research is the crisis of the multilateral framework, since scepticism of effective multilateralism has been growing in recent years. The thesis focuses on the particular situation of the Council of Europe, and intends to examine the correlation between the soft power human rights instruments, the "normative institutionalism" and the classical, "power" realism. The dissertation aims to present one political (suspension of voting rights of the Russian parliamentary delegation in the Parliamentary Assembly of the Council of Europe) and one legal case study (reluctant implementation of the judgement of the European Court of Human Rights) to illustrate the political and legal difficulties the Council of Europe faces. After a qualitative analysis I seek an answer to the question, how the organisation can solve the challenges resulting from the reappearance of power realism in an intergovernmental organisation with the protection of human rights as a core mission. How, in other words, to solve its own Copenhagen dilemma. The concrete research questions are as follows: 1) "Could the recent political and legal challenges to effective multilateralism endanger the functioning of the Council of Europe in the long run?" 2) Could normative institutionalism prevail over the great powers' geopolitical interests, and if so, to what extent?" The thesis also intends to examine the enlargement dilemma of the organisation in the mid-nineties, whether to invite the Eastern European countries to join before they were in compliance with the main standards or to delay their accession until their legal and institutional structures were closer to European standards. This Chapter is highly relevant for the initial hypothesis, which is that the Eastern enlargement with the accession of the Russian Federation as a great power largely contributed to the political and legal challenges of the Council of Europe. The way I intend to conduct the research is partly based on my personal experiences in 1999 and between 2011 and 2016 in the Council of Europe, when I served in Strasbourg, as deputy to the Permanent Representative of Hungary to the Council of Europe. In this capacity I actively participated in the work of four rapporteur groups preparing the decision-making process of the Committee of Ministers and in the Human Rights (DH) sessions of the Ministers' Deputies responsible for the supervision of the execution of the Strasbourg Court's judgements. I also followed the activity of the Parliamentary Assembly in recent years, between 2016 and 2020. In addition, I am currently the Hungarian delegate in two institutions of the Council of Europe, the Steering Committee on Anti-Discrimination, Diversity and Inclusion (CDADI) and in the Governing Board of the Observatory on History Teaching. I also build on the evaluations of the semi-structured interviews with high-ranking officials of the Council of Europe and of the Hungarian foreign service. As the sources are very limited, there is no academic literature analysing these developments, the interviews with competent officials are of utmost importance. The list of interviewees covers different nationals of the Council of Europe working in the structure of the Committee of Ministers and the Parliamentary Assembly on the one hand, politicians of the Parliamentary Assembly and high ranking diplomats of the Hungarian foreign service on the other. It should be also noted that the structure of the thesis was determined in 2020, long before the war between the Russian Federation and Ukraine. However, this war in a neighbouring state has had a major impact on this research, therefore the exclusion of the Russian Federation from the Council of Europe, and its assessment will form an integral part of this research. Based on the conclusions of the thesis, the followings could be the new scientific results: • • Contribution to the general literature focusing on the future role of multilateral organisations; • • Providing a comprehensive analysis of the impact of political developments in the Council of Europe to the scientific literature; • • Chance to be the first to analyse the new complementary joint procedure; • • Based on the findings concerning their efficiency and capacity, the thesis could contribute to evaluating the role and opportunities of multilateral organisations, especially the Council of Europe; • • The conclusions of the research could assist the actions of the diplomacy in multilateral frameworks, contribute to fine-tuning the general perception of manoeuvring room in multilateral diplomacy.


Hospital as one of the possible causes of water pollutants containing infectious, pathogens, toxic, biodegradable, radioactive contaminants, pharmaceutical product that can be a hazard agent in the environment. Wastewater treatment plant owned hospitals generally have not been able to eliminate with either of these compounds. National estimates of production wastewater 48.985,70 tons/day, which the total of hospitals in Indonesia as 2.410 hospitals with beds 295.035. The focus of hospital wastewater treatment in Indonesia is basically accordance with government regulations for reducing the chemical, physical, biological and radioactive materials from the wastewater. Climate of Indonesia is located in tropical regions may be produce additional types and other characteristics of wastewater. The Objective of this study to give an overview study of the new pollutant types of contaminants that require special processing through a hybrid membrane technology. The method used in this research were study literature of any membrane process in other countries and investigation of secondary data from multiple hospitals in Indonesia to determine the wastewater characteristics with government regulation. The study of result showed the characteristics of hospital wastewater of tropical region to provide suggestions scientifically for improvements government regulations that are currently used in Indonesia. The other result of this study can provide a picture of hybrid membrane technology in reducing the special waste with optimum process.


A new kind of the micron-sized flaky silver-coated copper powder was prepared by electroless silver plating in this paper. Its plating structures were characterized by XRD, SEM and EDS. And a new kind of the electromagnetic shielding composite coatings containing 60 wt% the micron-sized flaky silver-coated copper powders and 40 wt% epoxy resin was prepared. Its electromagnetic shielding properties were analyzed by coaxial transmission line equipment. The study results show the micron-sized flaky silver-coated copper powders are composed of 91.35 wt% Cu and 8.65 wt% Ag and have high width-thickness ratio and crystal structure characteristics. In the frequency range of 0.3-1000 MHz, the shielding effectiveness of the coatings is up to 70.15-77.46 dB and increased an average of 22.18 dB compared with the coatings containing 60 wt% micron-sized flaky copper powders when the coating layer thickness is 300 μm. It is seen that the electroless silver plating method effectively improves the inoxidizability, conductivity and electromagnetic shielding properties of copper powders.


In 2013, Michael Gove, then Secretary of State for Education and Health in the UK coalition government, criticised social workers for laying insufficient emphasis on the 'agency' of individuals and for being too preoccupied with social and economic inequalities. Such a perspective, which is not unique to Gove, needs to be countered by reaffirming the significance of an expansively critical sociology for social work. In this context, the thematic concerns of the French theorist, Loic Wacquant, illuminates key aspects of social work engagement with clients which Gove and his ideological associates appear intent on ignoring. The issues raised have significant political resonances given the pending UK General Election taking place in May 2015.


Rice paddies are highly important agricultural soils in view of their relevance as major staple food provider in the world and their key role in the global carbon cycle, caused by special management practices. A soil chronosequence, consisting of paddy and upland soils, developed on reclaimed estuarine sediments in the Province of Zhejiang, China, was sampled to investigate the influence of duration of agricultural use (50 to 2000 yr) on soil composition. The uniform composition of the parent material provides the unique opportunity to compare the effects of different land management practices (paddy and non-paddy) on soil carbon dynamics and the origin of organic carbon (OC) in top- and subsoils, using 14C measurements by accelerator mass spectrometry (AMS). The total soil organic carbon (TOC) was split into chemically defined pools of different mobility, namely the acid- and water-soluble fulvic acids (FA), the alkali-soluble humic acids (HA), and insoluble humin fraction. The more mobile HA and FA fractions contain significantly more 14C than the corresponding TOC and humin, indicating a downward transport of OC in the subsoil. Plant roots with 14C concentrations up to 128% of the modern standard, found far below the plough pan, reveal plant roots and root exudates as other direct sources of subsoil OC in paddy soils.


Background The interactions of the voltage-gated Ca2+ channel (VGCC) with syntaxin 1A (Sx 1A), Synaptosome-associated protein of 25 kD (SNAP-25), and synaptotagmin, couple electrical excitation to evoked secretion. Two vicinal Cys residues, Cys 271 and Cys 272 in the Sx 1A transmembrane domain, are highly conserved and participate in modulating channel kinetics. Each of the Sx1A Cys mutants, differently modify the kinetics of Cav1.2, and neuronal Cav2.2 calcium channel. Methodology/Principle Findings We examined the effects of various Sx1A Cys mutants and the syntaxin isoforms 2, 3, and 4 each of which lack vicinal Cys residues, on evoked secretion, monitoring capacitance transients in a functional release assay. Membrane capacitance in Xenopus oocytes co-expressing Cav1.2, Sx1A, SNAP-25 and synaptotagmin, which is Bot C- and Bot A-sensitive, was elicited by a double 500 ms depolarizing pulse to 0 mV. The evoked-release was obliterated when a single Cys Sx1A mutant or either one of the Sx isoforms were substituted for Sx 1A, demonstrating the essential role of vicinal Cys residues in the depolarization mediated process. Protein expression and confocal imaging established the level of the mutated proteins in the cell and their targeting to the plasma membrane. Conclusions/Significance We propose a model whereby the two adjacent transmembranal Cys residues of Sx 1A, lash two calcium channels. Consistent with the necessity of a minimal fusion complex termed the excitosome, each Sx1A is in a complex with SNAP-25, Syt1, and the Ca2+ channel. A Hill coefficient >2 imply that at least three excitosome complexes are required for generating a secreting hetero-oligomer protein complex. This working model suggests that a fusion pore that opens during membrane depolarization could be lined by alternating transmembrane segments of Sx1A and VGCC. The functional coupling of distinct amino acids of Sx 1A with VGCC appears to be essential for depolarization-evoked secretion.


Abstract Maine stratus clouds were simultaneously observed by nadir Nd:YAG lidar measurements and in situ cloud physics measurements. A procedure was applied to derive the two-dimensional vertical cross section of the liquid water from within the cloud top lidar observations. A comparison to direct in-cloud liquid water observations gave good results. The liquid water retrieval was limited to an effective optical of 1.5. The true cloud optical thickness was also obtained from the retrieval procedure to a corresponding limit of 3.8. The optical thickness of the observed marine stratus clouds was predominantly below 3.0.


Background: Neuropathic pain is characterized by hyperalgesia, allodynia and spontaneous pain. It often occurs as a result of injury to peripheral nerves, dorsal root ganglions (DRG), spinal cord, or brain. Recent studies have suggested that Toll-like receptor 4 (TLR4) might play a role in neuropathic pain. Methodology/Principal Findings: In this study, we investigated the role of TLR4 in a rat chronic constriction injury (CCI) model and explored the feasibility of treating neuropathic pain by inhibiting TLR4. Our results demonstrated that intrathecal siRNA-mediated suppression of TLR4 attenuated CCI-induced mechanical allodynia and thermal hyperalgesia through inhibiting the activation of NF-κB p65 and production of proinflammatory cytokines (e.g., TNF-α and IL-1β). Conclusions/Significance: These findings suggest that suppression of TLR4 mediated by intrathecally administered siRNA may be a new strategy for the treatment of neuropathic pain.


Tumor cells normally depend on both glycolysis and oxidative phosphorylation (OXPHOS) to provide the energy and macromolecule building blocks needed to enable continued tumor cell growth. Genetic or epigenetic inactivation of one of these two redundant pathways represents a metabolic vulnerability that should be susceptible to an inhibitor of the other pathway. Through an extensive medicinal chemistry campaign, IACS-10759 was identified as a potent inhibitor of complex I of oxidative phosphorylation. In isolated mitochondria or permeabilized cells, ATP production or oxygen consumption was inhibited at single digit nM concentrations in the presence of malate/glutamate, but not succinate. More directly, IACS-10759 inhibited the conversion of NADH to NAD+ in an immunoprecipitated complex I assay at low nM concentrations. Using genetic and pharmacological approaches, the specific complex I subunit inhibited by IACS-10759 has been identified and the mechanism of complex I inhibition is being investigated. Importantly, IACS-10759 is orally bioavailable with excellent physicochemical properties in preclinical species and achieved significant in vivo efficacy with daily oral dosing of 10-25 mg/kg. Specifically, there was a >50 day extension of median survival in an orthotopic AML cell line xenograft and robust regression in DLBCL and GBM xenograft models. In light of these results, as well as its drug like profile IACS-10759 has entered IND enabling studies with first-in-human studies targeted for third quarter of 2015. Citation Format: Marina Protopopova, Madhavi Bandi, Jennifer Bardenhagen, Christopher Bristow, Christopher Carroll, Edward Chang, Ningping Feng, Jason Gay, Mary Geck Do, Jennifer Greer, Marina Konopleva, Polina Matre, Zhijun Kang, Gang Liu, Florian Muller, Timothy Lofton, Timothy McAfoos, Yuting Sun, Melinda Smith, Jay Theroff, Yuanqiang Wu, Lynda Chin, Giulio Draetta, Philip Jones, Carlo Toniatti, M. Emilia Di Francesco, Joseph R. Marszalek. IACS-10759: A novel OXPHOS inhibitor which selectively kill tumors with metabolic vulnerabilities. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4380. doi:10.1158/1538-7445.AM2015-4380