USING A BIOPSYCHOSOCIAL APPROACH WITHIN ACL REHABILITATION: AN EXPLORATION OF STUDENT PHYSIOTHERAPISTS` PERCEPTIONS AND EXPERIENCES.
Supporting the psychological needs of the patient during Anterior Cruciate Ligament Reconstruction (ACLR) rehabilitation is of paramount importance in order to optimize function and return to sport. Despite this, the amount of psychological training physiotherapists receive is inadequate. the central aim of this study was to gain valuable insight, through the lens of the student physiotherapist, in relation to biopsychosocial practices used within ACL rehabilitation. A phenomenological design using an inductive approach through purposive sampling was used. The study conducted semi-structured interviews, which involved ten undergraduate and postgraduate physiotherapy students from a UK University institution. The study identified perceptions, experiences and training surrounding a biopsychosocial approach within ACL rehabilitation. Data analysis included thematic analysis with triangulation and an audit trail to enhance confirmability and credibility. Participants demonstrated a superficial understanding of the biopsychosocial approach, psychological symptoms and the significance of applying a patient-centered approach. Nonetheless, participants consistently reported barriers to implementing this approach, including the application of theory to practice when working with patients following ACL surgery. Findings were consistent with previous research surrounding inadequate biopsychosocial education and training within ACL rehabilitation. The application of theory of the model to clinical practice was absent from the students' training. These findings suggest that student physiotherapists are aware of the possible benefits of incorporating psychological interventions but feel inadequately trained, highlighting a need for a review of the curriculum. Future research focusing on pedagogy-based strategies to effectively equip students to apply biopsychosocial theory to practice is of critical importance to prepare students for contemporary ACL rehabilitation and practice.


EFFECTS OF PROFESSIONAL ORAL HYGIENE AND TEETH WHITENING ON THE MICROELEMENT COMPOSITION OF ENAMEL.
Aim: The objective of this study is to investigate the impact of professional teeth cleaning and the substances used in modern dentistry for whitening on the microelement composition of tooth enamel. Materials and Methods: To study the morphology and microelement composition of the enamel, scanning electron microscopy was performed using the MiraLM microscope equipped with a Schottky field emission electron gun from Tescan. Results: A comparative analysis between the areas subjected to mechanical cleaning and those where it was not applied revealed a significant difference in the research results, particularly in carbon, which changed from 25.16±1.04 to 32.02±1.8. An analysis of the enamel's chemical composition before and after whitening revealed a decrease in carbon from 45.91±1.20 to 42.46±1.74. The change in phosphorus content was determined to be from 9.77±0.39 to 9.56±0.75. A decrease in calcium from 15.96±0.64 to 15.21±1.22 and magnesium from 0.07±0.01 to 0.01±0.01 was also observed. Conclusions: Professional dental hygiene does not have a direct impact on the microelement composition of enamel, such as the levels of calcium, phosphorus, fluoride, and other microelements. However, it can have an indirect and temporary influence due to the use of abrasive materials that affect dental deposits, pellicle, and the surface layer of enamel. Teeth whitening can affect the microelement composition of enamel, but these changes are mostly temporary and associated with processes of demineralization/ remineralization and oxygenation.


Cardiovascular effects of congenital infections.
In the course of gestation, many bacteria, parasites, and viruses may infect the pregnant woman, but few cross the placenta to affect the fetus and fewer still affect the fetal heart. Although the incidence of fetal cardiac infection is low, the effect on the fetus is major. In terms of frequency, rubella virus, Toxoplasma gondii, and Coxsackie virus B are the principal infectious agents affecting the fetal heart, but any number of organisms may cross the placenta to affect the fetus. The pathogenesis of infection of the fetal heart relates to the agent and to the time of gestation when the infection occurs. The agent affects the heart along one or more of three separate pathways: inhibition of cell growth, cytolysis, and interference with the blood supply. Most agents cause cytolysis, stimulating inflammation and scarring. Although several agents carry the suspicion of teratogenicity, only rubella virus has been incriminated with certainty as capable of functioning along each of the three pathways with the potential to serve as teratogen.


Chamber-dependent expression of brain natriuretic peptide and its mRNA in normal and diabetic pig heart.
Brain natriuretic peptide (BNP) is produced in cardiac myocytes, and increased secretion is closely associated with cardiac dysfunction. However, several fundamental aspects of BNP expression in the myocardium have not yet been resolved. In the present study, we report the presence of a precursor BNP mRNA transcript and a mature BNP mRNA transcript in normal porcine hearts. In normal pigs, the amount of precursor BNP mRNA was similar in atrial and ventricular myocardium, whereas the mature BNP transcript was 10- to 50-fold more abundant in atrial than in ventricular myocardium. Quantitation of proBNP in normal porcine hearts by radioimmunoassay disclosed abundant proBNP in the atria, whereas proBNP was undetectable in the ventricles. Laser confocal microscopy revealed proBNP in secretory granules of atrial but not in the ventricular myocardium of normal pigs. Mild streptozotocin-induced diabetes doubled the expression of BNP mRNA in porcine atrial myocardium (P=0.03), but was without effect on BNP mRNA in the ventricular myocardium. The data suggest that BNP mRNA processing and proBNP storage differ between the atrial and ventricular myocardium. The results also imply that diabetes increases cardiac BNP expression in a chamber-dependent manner.


Clinical characteristics of nonneoplastic cavernomatous transformation of the portal vein at a Gastroenterology Service in Spain.
To identify predisposing factors, clinical characteristics and effective treatment in patients with nonneoplastic cavernomatous transformation of the portal vein in our gastroenterology service. We retrospectively reviewed the clinical records of 2,201 patients diagnosed as having portal hypertension (2,165 with cirrhosis and 36 with noncirrhotic portal vein hypertension) during the period from 1977 to 1998. The diagnosis of cavernomatous transformation was confirmed with angiographic or Doppler echographic studies, or both. Thirteen patients (6 males, 7 females, age range 8 to 69 years) with cavernomatous transformation were found. Predisposing factors were omphalitis (1), echinococcal cyst (1), major abdominal surgery (3), liver cirrhosis (3), Sjögren syndrome (1), and no apparent cause (4). Eleven of the 13 patients had upper digestive tract bleeding from varices, 9 had splenomegaly, and 2 had cirrhotic decompensation. Splenectomy was done in 3 patients on admission, and in 5 patient shunts were used (splenorenal in 4, mesenteroatrial in 1) because of repeated bleeding. Of the patients with noncirrhotic portal hypertension, 27.7% had nontumoral cavernomatous transformation of the portal vein. Previous abdominal surgery was the most frequent predisposing factor; the 2 cases of echinococcal liver disease and Sjögren disease were exceptional. Age younger than 30 years, bleeding esophageal varices and splenomegaly were the most frequent clinical features. Portosystemic shunt was the only effective treatment alternative in these patients.


Urban population exposure to lead and cadmium in east and south-east Asia.
Information is still scarce for many Asian countries on general population exposure to two potentially toxic heavy metals of lead (Pb) and cadmium (Cd). The present review on publications from this study group is intended to provide an overview of the non-occupational exposure to Pb and Cd among general populations in east and south-east Asia. During the period of 1991-1998, surveys were conducted in four cities in south-east Asia, five cities in mainland China, and two cities each in Japan and Korea. Peripheral blood, morning spot urine and 24-h food duplicate samples were collected from 20-50 non-smoking adult women in each survey site. The samples were digested by heating in the presence of mineral acids, and then analyzed by inductively-coupled plasma mass spectrometry for the metals in blood (Pb-B and Cd-B), in urine (Pb-U and Cd-U), and in food duplicate (Pb-F and Cd-F). Measures were subjected to statistical analysis with an assumption of log-normal distribution. Pb-B, Pb-U and Pb-F levels varied substantially among the 11 urban sites; GM distributed in ranges of 32-65 microg/l for Pb-B, 2.1-7.5 microg/g cr (creatinine) for Pb-U, and 7-32 microg/day for Pb-F. The same was also the case for Cd exposure parameters, the distribution ranges being 0.5-1.8 microg/l for Cd-B, 1.2-3.1 microg/g cr for Cd-U, and 5-32 microg/day for Cd-F. It appeared that the exposure to Pb and Cd was highest in Kuala Lumpur, and Tokyo + Kyoto, respectively, and lowest in Tokyo + Kyoto and in Manila. Additional surveys in Japan showed that Pb exposure was even lower in rural areas than in Tokyo + Kyoto. When compared with the values reported in the literature, Pb exposure levels among Asian populations appear to be similar to the levels in Europe and in the United States, whereas Cd exposure seems to be higher in Asia than in Europe. The contribution of the dietary route in Pb absorption was variable and was inversely related to the extent of air pollution, whereas Cd uptake was almost exclusively via the dietary route with little contribution of the respiratory route.


Structural basis for clonal diversity of the human T-cell response to a dominant influenza virus epitope.
Influenza A virus (IAV) causes an acute infection in humans that is normally eliminated by CD8+ cytotoxic T lymphocytes. Individuals expressing the MHC class I molecule HLA-A2 produce cytotoxic T lymphocytes bearing T-cell receptors (TCRs) that recognize the immunodominant IAV epitope GILGFVFTL (GIL). Most GIL-specific TCRs utilize α/β chain pairs encoded by the TRAV27/TRBV19 gene combination to recognize this relatively featureless peptide epitope (canonical TCRs). However, ∼40% of GIL-specific TCRs express a wide variety of other TRAV/TRBV combinations (non-canonical TCRs). To investigate the structural underpinnings of this remarkable diversity, we determined the crystal structure of a non-canonical GIL-specific TCR (F50) expressing the TRAV13-1/TRBV27 gene combination bound to GIL-HLA-A2 to 1.7 Å resolution. Comparison of the F50-GIL-HLA-A2 complex with the previously published complex formed by a canonical TCR (JM22) revealed that F50 and JM22 engage GIL-HLA-A2 in markedly different orientations. These orientations are distinguished by crossing angles of TCR to peptide-MHC of 29° for F50 versus 69° for JM22 and by a focus by F50 on the C terminus rather than the center of the MHC α1 helix for JM22. In addition, F50, unlike JM22, uses a tryptophan instead of an arginine to fill a critical notch between GIL and the HLA-A2 α2 helix. The F50-GIL-HLA-A2 complex shows that there are multiple structurally distinct solutions to recognizing an identical peptide-MHC ligand with sufficient affinity to elicit a broad anti-IAV response that protects against viral escape and T-cell clonal loss.


Determining motion parameters for scenes with translation and rotation.
A study of methods that determine the rotation parameters of a camera moving through synthetic and real scenes is conducted. Algorithms that combine ideas of Jain and Prazdny, using hypothesizeand-verify paradigm, are developed to find translational and rotational parameters. An argument is made for using hypothesized motion parameters rather than relaxation labeling to find correspondence. Some work with real scenes shows the difficulties introduced by noise, the lack of resolution, and the need for better low-level techniques.


The Influence of Fluid Intelligence, Executive Functions and Premorbid Intelligence on Memory in Frontal Patients.
Objective: It is commonly thought that memory deficits in frontal patients are a result of impairments in executive functions which impact upon storage and retrieval processes. Yet, few studies have specifically examined the relationship between memory performance and executive functions in frontal patients. Furthermore, the contribution of more general cognitive processes such as fluid intelligence and demographic factors such as age, education, and premorbid intelligence has not been considered. Method: Our study examined the relationship between recall and recognition memory and performance on measures of fluid intelligence, executive functions and premorbid intelligence in 39 frontal patients and 46 healthy controls. Results: Recall memory impairments in frontal patients were strongly correlated with fluid intelligence, executive functions and premorbid intelligence. These factors were all found to be independent predictors of recall performance, with fluid intelligence being the strongest predictor. In contrast, recognition memory impairments were not related to any of these factors. Furthermore, age and education were not significantly correlated with either recall or recognition memory measures. Conclusion: Our findings show that recall memory in frontal patients was related to fluid intelligence, executive functions and premorbid intelligence. In contrast, recognition memory was not. These findings suggest that recall and recognition memory deficits following frontal injury arise from separable cognitive factors. Recognition memory tests may be more useful when assessing memory functions in frontal patients.


Current status of circulatory support with an intra-aortic balloon pump.
Although the initial clinical application of IABP was for the purpose of support of circulation in cardiogenic shock, its indications have expanded and include prophylactic use, especially in patients with ischemic heart disease. Controversy exists regarding the efficacy of this device in these conditions. Prolonged balloon support for periods of more than 5 days is presently employed in patients with chronic heart failure undergoing cardiac surgery, without concern for so-called "balloon dependence." In recent years, the incidence of use of IABP has declined markedly mainly because of comparable effects obtained by hemodynamic treatment with various drugs aimed at altering a specific parameter of cardiac function. Percutaneous application of an intra-aortic balloon catheter, although associated with a higher complication rate, has brought to clinical practice a rapid method for utilization of this device under fluoroscopic control. Because of an appreciable number of complications, however, balloon assist should be used for very specific clinical conditions.


The use of preferred social stimuli as rewards for rhesus macaques in behavioural neuroscience.
Macaques are often motivated to perform in neuroscientific experiments by implementing fluid restriction protocols. Daily access to water is controlled and the monkeys are rewarded with droplets of fluid for performing correct trials in the laboratory. Although these protocols are widely used and highly effective, it is important from a 3Rs perspective to investigate refinements that may help to lessen the severity of the fluid restriction applied. We assessed the use of social stimuli (images of conspecifics) as rewards for four rhesus macaques performing simple cognitive tasks. We found that individual preferences for images of male faces, female perinea and control stimuli could be identified in each monkey. However, using preferred images did not translate into effective motivators on a trial-by-trial basis: animals preferred fluid rewards, even when fluid restriction was relaxed. There was no difference in the monkeys' performance of a task when using greyscale versus colour images. Based on our findings, we cannot recommend the use of social stimuli, in this form, as a refinement to current fluid restriction protocols. We discuss the potential alternatives and possibilities for future research.


[Role of estrogen-related receptor alpha in adipocyes lipolysis].
Estrogen-related receptor a (ERRalpha) is a key regulator for energy metabolism and adipogenesis. However, its role in lipolysis is unknown. To study the function of ERRalpha in lipolysis, primary cultured differentiated porcine adipocytes were treated by a specific inverse agonist XCT790 or infected with adenoviral vector expressed ERRalpha for 48 h, in the absence and/or presence of specific protein kinase A (PKA) inhibitor or extracellular signal-related kinase (ERK) inhibitor. Then, we measured the triglyceride (TG) content and the glycerol release into the culture media to analysis the effect of ERRalpha on lipolysis; Further, we analyzed the expression of PPARgamma, perilipin A, p-perilipin A, HSL and ATGL with Western blotting. Here, we found that ERRalpha significantly increased adipocytes differentiation, TG accumulation and glycerol release. Separately or simultaneously block the PKA and ERK pathway do not significantly altered the effect of ERRalpha on glycerol release. ERRalpha significantly up-regulated the proteins expression of PPARgamma, perilipin A, HSL and ATGL, while the p-perilipin A protein level was not significantly changed. These findings imply that ERRalpha could increase lipolysis via up-regulating HSL and ATGL, thereby to supply more FFA as substrate for a larger turnover of cellular triglyceride pool during adipocytes differentiation.


Effectiveness of flipped classroom combined with team-, case-, lecture- and evidence-based learning on ophthalmology teaching for eight-year program students.
This study aimed to investigate the benefits and challenges of the flipped classroom combined with team-, case-, lecture- and evidence-based learning (FC-TCLEBL) for ophthalmology teaching for eight-year program students. FC-TCLEBL and the traditional lecture-based classroom (LBC) were compared based on student and teacher feedback questionnaires, student learning burden, and scores on standardized tests as well as their effects on the abilities of clinical thinking, scientific research, active-learning, practical application, humanistic care and communication with patients. Both the students and teachers were more satisfied with the FC-TCLEBL model. More students in the FC-TCLEBL group agreed that the course helped them to develop skills in creative thinking, problem solving, and teamwork. Students in the FC-TCLEBL group spent significantly more time preparing for class than those in the LBC group, but the time spent on review was significantly lower in the FC-TCLEBL group. The students from the FC-TCLEBL group performed better in a post-test on diabetic retinopathy (DR) as compared to the LBC group. FC-TCLEBL teaching model is effective and suitable for ophthalmology teaching.


AlphaII-spectrin is an in vitro target for caspase-2, and its cleavage is regulated by calmodulin binding.
The spectrin-actin scaffold underlying the lipid bilayer is considered to participate in cell-shape stabilization and in the organization of specialized membrane subdomains. These structures are dynamic and likely to undergo frequent remodelling during changes in cell shape. Proteolysis of spectrin, which occurs during apoptosis, leads to destabilization of the scaffold. It is also one of the major processes involved in membrane remodelling. Spectrins, the main components of the membrane skeleton, are the targets for two important protease systems: m- and micro-calpains (Ca2+-activated proteases) and caspase-3 (activated during apoptosis). In this paper, we show that caspase-2 also targets spectrin in vitro, and we characterize Ca2+/calmodulin-dependent regulation of spectrin cleavage by caspases. Yeast two-hybrid screening reveals that the large isoform (1/L) of procaspase-2 specifically binds to alphaII-spectrin, while the short isoform does not. Like caspase-3, caspase-2 cleaves alphaII-spectrin in vitro at residue Asp-1185. This study emphasizes a role of executioner caspase for caspase-2. We also demonstrated that the executioner caspase-7 but not caspase-6 cleaves spectrin at residue Asp-1185 in vitro. This spectrin cleavage by caspases 2, 3 and 7 is inhibited by the Ca2+-dependent binding of calmodulin to spectrin. In contrast, calmodulin binding enhances spectrin cleavage by calpain at residue Tyr-1176. These results indicate that alphaII-spectrin cleavage is highly influenced by Ca2+ homoeostasis and calmodulin, which therefore represent potential regulators of the stability and the plasticity of the spectrin-based skeleton.


Anti-inflammatory and anti-tumor-promoting effects of triterpene acids and sterols from the fungus Ganoderma lucidum.
A series of lanostane-type triterpene acids, including eleven lucidenic acids (3, 4, 9, 10, 13-19) and six ganoderic acids (20-22, 24, 26, 27), as well as six sterols (28-33), all isolated from the fruiting bodies of the fungus Ganoderma lucidum, were examined for their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, a known primary screening test for anti-tumor promoters. All of the compounds tested, except for ganolactone (27) and three sterols (29-31), showed potent inhibitory effects on EBV-EA induction, with IC(50) values of 235-370 mol ratio/32 pmol TPA. In addition, nine lucidenic acids (1, 2, 5-8, 11, 12, 18) and four ganoderic acids (20, 23-25) were found to inhibit TPA-induced inflammation (1 microg/ear) in mice, with ID(50) values of 0.07-0.39 mg per ear. Further, 20-hydroxylucidenic acid N (18) exhibited inhibitory effects on skin-tumor promotion in an in vivo two-stage mouse-skin carcinogenesis test based on 7,12-dimethylbenz[a]anthracene (DMBA) as initiator, and with TPA as promoter.


Molecular diagnosis of a laboratory mouse papillomavirus (MusPV).
MusPV, a novel papillomavirus (PV) that naturally infects laboratory mice, was isolated and characterized from a colony of NMRI-Foxn1(nu)/Foxn1(nu) (nude) mice in India. Because MusPV may have been missed during routine pathogen screening of mice in colonies worldwide, a variety of detection methods are described to detect MusPV. The clinical and histologic lesions of productive MusPV infections fit PV-associated features, including papillomas, koilocytes within the stratum granulosum of the hyperplastic/acanthotic papillomatous epithelium, and the presence of intranuclear virus particles in koilocytotic cells visualized by electron microscopy. Antiserum against disrupted PV virions, isolated from another species (canine), identified conserved viral antigens in productively infected cells by immunohistochemistry. A rolling circle technique was used to amplify viral circular DNAs followed by endonuclease restriction enzyme digestion to determine the correct size of PV DNA. Consensus PV degenerative primers, My09/11, commonly used to detect many different types of PVs by polymerase chain reaction (PCR), particularly mucosotropic HPVs, also identified MusPV and all rodent PVs tested. Since there was one nucleotide mismatch between the My09/11 primer set and the MusPV template, a new primer set, MusPV-My09/11, was designed to specifically detect MusPV in latent infections and spontaneous MusPV-induced papillomas. Southern blot analysis verified the presence of full size PV DNA in infected tissues. Virus-like particles (VLPs), generated from MusPV L1 genes, provided a substrate for serological testing of naturally and experimentally infected mice. In summary, a series of diagnostic assays were developed and validated to detect MusPV infection in skin tumors and serological response in laboratory mice.


Involving older adults in technology research and development discussions through dialogue cafés.
Citizen involvement is important for ensuring the relevance and quality of many research and innovation efforts. Literature shows that inadequate citizen involvement poses an obstacle during the research, development, and implementation of assistive technology. Previous studies have addressed the advantages and disadvantages of citizen engagement in health research and technology development, and there is concern about how to ensure valuable engagement to avoid situations where they don't have influence. Frail older adults are often excluded from being active partners in research projects. The overall objective of this commentary is to describe a case where dialogue cafés was used as a method for involving assisted living residents in technology discussions, elaborating on the following research question: In what ways are dialogue cafés useful for directing research and development and for engaging residents in assisted living facilities in assistive technology discussions? Six dialogue cafés with assisted living residents as participants were carried out over a period of 3 years (2016-19). Reports that were written after each café by the group leaders and rapporteurs provide the material for the analyses in this paper. This study demonstrates an example of facilitating user involvement where the participants felt useful by contributing to research and discussions on assistive technology and where this contribution in fact directed the research and development in the overall Assisted Living Project. This study demonstrated that dialogue cafés enable older residents at an assisted living facility to contribute with opinions about their needs and perspectives on assistive technologies. This negates the view of older adults as too frail to participate and demonstrates the importance of including and collaborating with older adults in research.


Hypocapnia induced by involuntary hyperventilation during mental arithmetic reduces cerebral blood flow velocity.
Functional neuroimaging studies have shown that cognitive processes increase regional cerebral blood flow in relation with enhanced neuronal activity. However, cognition induces elevation of blood pressure, heart rate and respiratory rate, each of which also affects cerebral circulation. For proper interpretation of functional neuroimaging data, it is necessary to dissociate the effects of systemic and local metabolic reactions on regional cerebral circulation. To elucidate this interaction, we examined the changes in cerebral blood flow velocity, which were caused by voluntary hyperventilation-induced hypocapnia without cognitive effort and hypocapnia evolving during mental arithmetic task. The cerebral blood flow velocity was recorded in the middle cerebral arteries, using transcranial Doppler sonography. Respiratory rate, end-tidal partial pressure of CO(2), heart rate and arterial blood pressure were simultaneously monitored. Data were statistically evaluated. Hypocapnia induced by voluntary hyperventilation without cognition decreased the cerebral blood flow velocity. During mental arithmetic, the cerebral blood flow velocity first increased, but the hypocapnia, which was induced by involuntary hyperventilation related to cognitive effort, reduced it. This implies temporary vasoconstriction of cerebral microvessels, and the increase in cerebral vascular resistance index supports this finding. These results suggest that hypocapnia, which develops during cognition, may decrease blood flow velocity in the middle cerebral arteries, which interferes with the neuronal activity-driven regulation of cerebral circulation. In conclusion, when interpreting the results of functional neuroimaging studies on cognitive mechanisms, the tight coupling of the effects of mental processes and autonomic/metabolic reactions should be considered.


Progression of aging in Mexico: the Mexican Health and Aging Study (MHAS) 2012.
To describe the third wave of the Mexican Health and Aging Study (MHAS), completed in 2012, and present preliminary results. Descriptive analyses by gender and age group of demographic and socioeconomic characteristics, health conditions and health behaviors, as well as social support and life satisfaction measures are presented. In addition, external validations are presented by comparing MHAS 2012 indicators with other national data sources. For the panel of older adults in the sample, the rate of health care insurance coverage increased greatly between 2001 and 2012, a significantly higher change in rural compared to urban areas. The results for 2012 are consistent with the previous two waves for the main indicators of health and physical disability prevalence, risk factors,and behaviors. The MHAS offers a unique opportunity to study aging in Mexico, as well as to complete cross-national comparisons. The cumulative number of deaths in the cohort should support the study of mortality and its association with health outcomes and behaviors over the life cycle. In addition, the sub-samples of objective markers will enable methodological research on self-reports and associations of biomarkers in old age with similar health outcomes and behaviors.


The slipper snail, Crepidula: an emerging lophotrochozoan model system.
Recent developmental and genomic research focused on "slipper snails" in the genus Crepidula has positioned Crepidula fornicata as a de facto model system for lophotrochozoan development. Here we review recent developments, as well as earlier reports demonstrating the widespread use of this system in studies of development and life history. Recent studies have resulted in a well-resolved fate map of embryonic cell lineage, documented mechanisms for axis determination and D quadrant specification, preliminary gene expression patterns, and the successful application of loss- and gain-of-function assays. The recent development of expressed sequence tags and preliminary genomics work will promote the use of this system, particularly in the area of developmental biology. A wealth of comparative information on phylogenetic relationships, variation in mode of development within the family, and numerous studies on larval biology and metamorphosis, primarily in Crepidula fornicata, make these snails a powerful tool for studies of the evolution of the mechanisms of development in the Mollusca and Lophotrochozoa. By bringing a review of the current state of knowledge of Crepidula life histories and development together with some detailed experimental methods, we hope to encourage further use of this system in various fields of investigation.


Complete genome sequence and immunoproteomic analyses of the bacterial fish pathogen Streptococcus parauberis.
Although Streptococcus parauberis is known as a bacterial pathogen associated with bovine udder mastitis, it has recently become one of the major causative agents of olive flounder (Paralichthys olivaceus) streptococcosis in northeast Asia, causing massive mortality resulting in severe economic losses. S. parauberis contains two serotypes, and it is likely that capsular polysaccharide antigens serve to differentiate the serotypes. In the present study, the complete genome sequence of S. parauberis (serotype I) was determined using the GS-FLX system to investigate its phylogeny, virulence factors, and antigenic proteins. S. parauberis possesses a single chromosome of 2,143,887 bp containing 1,868 predicted coding sequences (CDSs), with an average GC content of 35.6%. Whole-genome dot plot analysis and phylogenetic analysis of a 60-kDa chaperonin-encoding gene and the glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-encoding gene showed that the strain was evolutionarily closely related to Streptococcus uberis. S. parauberis antigenic proteins were analyzed using an immunoproteomic technique. Twenty-one antigenic protein spots were identified in S. parauberis, by reaction with an antiserum obtained from S. parauberis-challenged olive flounder. This work provides the foundation needed to understand more clearly the relationship between pathogen and host and develops new approaches toward prophylactic and therapeutic strategies to deal with streptococcosis in fish. The work also provides a better understanding of the physiology and evolution of a significant representative of the Streptococcaceae.


PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.
Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible patients (18-80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2·6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4·1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918. Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4-65·1], monthly dose: 61·3% reduction [53·6-69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5-65·8] and 65·6% reduction [59·8-71·3]; both p<0·0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]). In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo. Amgen Inc.


Behavioral effects of brotizolam, a new thienotriazolodiazepine derivative.
The behavioral effect of brotizolam was investigated in mice and rats, in comparison with those of diazepam, nitrazepam and estazolam. Locomotor activity of rats in an open field situation was slightly increased with smaller doses of brotizolam and estazolam and with larger doses of nitrazepam, while it was decreased with large doses of brotizolam and estazolam. The anticonflict effect of brotizolam in rats was approximately as potent as that of diazepam and was augmented following chronic administration for 10 days. In suppressing hyperemotionality and muricide of olfactory bulbectomized rats, brotizolam was more potent than diazepam, being approximately equipotent to nitrazepam and estazolam. Brotizolam, diazepam, nitrazepam and estazolam prevented both maximal electroshock and pentetrazol convulsions in mice, the effects on the latter being much more potent than those on the former. In impairing rotarod performance, brotizolam was as potent as estazolam and nitrazepam and was much more potent than diazepam in mice, but was less potent than estazolam and nitrazepam in rats. These results indicate that brotizolam possesses pharmacological properties characteristic to benzodiazepines and that the activity is more potent than that of diazepam and approximately as potent as those of nitrazepam and estazolam.


Detection of chronic wasting disease prions in salivary, urinary, and intestinal tissues of deer: potential mechanisms of prion shedding and transmission.
Efficient horizontal transmission is a signature trait of chronic wasting disease (CWD) in cervids. Infectious prions shed into excreta appear to play a key role in this facile transmission, as has been demonstrated by bioassays of cervid and transgenic species and serial protein misfolding cyclic amplification (sPMCA). However, the source(s) of infectious prions in these body fluids has yet to be identified. In the present study, we analyzed tissues proximate to saliva, urine, and fecal production by sPMCA in an attempt to elucidate this unique aspect of CWD pathogenesis. Oropharyngeal, urogenital, and gastrointestinal tissues along with blood and obex from CWD-exposed cervids (comprising 27 animals and >350 individual samples) were analyzed and scored based on the apparent relative CWD burden. PrP(CWD)-generating activity was detected in a range of tissues and was highest in the salivary gland, urinary bladder, and distal intestinal tract. In the same assays, blood from the same animals and unseeded normal brain homogenate controls (n = 116 of 117) remained negative. The PrP-converting activity in peripheral tissues varied from 10(-11)- to 10(0)-fold of that found in brain of the same animal. Deer with highest levels of PrP(CWD) amplification in the brain had higher and more widely disseminated prion amplification in excretory tissues. Interestingly, PrP(CWD) was not demonstrable in these excretory tissues by conventional Western blotting, suggesting a low prion burden or the presence of protease-sensitive infectious prions destroyed by harsh proteolytic treatments. These findings offer unique insights into the transmission of CWD in particular and prion infection and trafficking overall.


Peripheral Lattice Degeneration Imaging with Ultra-Widefield Swept-Source Optical Coherence Tomography.
To investigate a series of peripheral lattice degeneration cases using an ultra-widefield (UWF) swept-source optical coherence tomography (SS-OCT) system. From August 1, 2022 to July 31, 2023, 19 eyes from 16 patients with peripheral lattice degeneration were included. They all underwent a UWF SS-OCT examination. Anatomy of retina, vitreous, and associated pathologic changes were assessed. UWF SS-OCT showed various anatomical changes of retina and vitreous in patients with lattice degeneration. Of 15 eyes from 12 patients whose UWF SS-OCT images were clearly obtained, eight eyes showed regional retinal thinning, seven eyes showed vitreous traction, two eyes showed detached vitreous, and three eyes showed retinal break. UWF SS-OCT can be a useful tool to understand anatomical changes and pathophysiology of peripheral lattice degeneration.


Molecular architecture of the SYCP3 fibre and its interaction with DNA.
The synaptonemal complex (SC) keeps homologous chromosomes in close alignment during meiotic recombination. A hallmark of the SC is the presence of its constituent protein SYCP3 on the chromosome axis. During SC assembly, SYCP3 is deposited on both axes of the homologue pair, forming axial elements that fuse into the lateral element (LE) in the tripartite structure of the mature SC. We have used cryo-electron tomography and atomic force microscopy to study the mechanism of assembly and DNA binding of the SYCP3 fibre. We find that the three-dimensional architecture of the fibre is built on a highly irregular arrangement of SYCP3 molecules displaying very limited local geometry. Interaction between SYCP3 molecules is driven by the intrinsically disordered tails of the protein, with no contact between the helical cores, resulting in a flexible fibre assembly. We demonstrate that the SYCP3 fibre can engage in extensive interactions with DNA, indicative of an efficient mechanism for incorporation of DNA within the fibre. Our findings suggest that SYCP3 deposition on the chromosome axis might take place by polymerization into a fibre that is fastened to the chromosome surface via DNA binding.


[Comparison of databases of the medical profession: an example in anatomy and pathological cytology].
Medical demographic regulation policy is supported by statistical descriptive and prospective studies on the actual and future supply of medical practitioners. Two main data bases are available in France for these analyses one at the Ministry of Health and the other at the French Medical Council. While both are supposed to be exhaustive and reliable, the official publications of the two institutions provide different data. It is difficult to assess the actual number of French doctors. The task is even more problematic for each individual medical or surgical specialty. Using the medical specialty Pathology as an example, this article compares the quality of the different data bases and underlines some of the structural and dynamic problems which could interfere with the validity of the information. Better cooperation between the different institutions involved would be helpful to contribute to the quality of the data bases and the organization of the medical specialty.


Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study.
This study presents the results of a multicenter investigation of the efficacy of acamprosate in the treatment of patients with chronic or episodic alcohol dependence. One hundred eighteen patients were randomly assigned to either placebo or acamprosate, and both groups were stratified for concomitant voluntary use of disulfiram. Treatment lasted for 360 days, with an additional 360-day follow-up period. The primary efficacy parameters evaluated were: relapse rate and cumulative abstinence duration (CAD). Results were analyzed according to Intention-To-Treat principles using chi2, t, and multiple regression analyses where appropriate. After 30 days on study medication, 40 of 55 (73%) acamprosate-treated patients were abstinent, compared with 26 of 55 (43%) placebo-treated patients (p = 0.019). The treatment advantage remained throughout the study medication period and was statistically significant until day 270 (p = 0.028). Twenty-seven percent of patients on acamprosate and 53% of patients on placebo had a first drink within the first 30 days of the study. The mean CAD was 137 days (40% abstinent days) for the patients treated with acamprosate and 75 days (21% abstinent days) for the placebo group (p = 0.013). No adverse interaction between acamprosate and disulfiram occurred, and the subgroup who received both medications had a better outcome on CAD than the those on only one or no medication. Acamprosate was well tolerated. Diarrhea was the only significant treatment-induced effect. It was concluded that acamprosate was a useful and safe pharmacotherapy in the long-term treatment of alcoholism. Concomitant administration of disulfiram improved the effectiveness of acamprosate.


A survey of cancer and occupation in young and middle aged men. I. Cancers of the respiratory tract.
In a search for clues to previously industrial carcinogens the occupational and smoking histories of young and middle aged men with different types of cancer were compared. The study population comprised men aged 18-54 and resident in the counties of Cleveland, Humberside, and Cheshire (including the Wirral). From hospital and cancer registration records 2942 members of the study population in whom cancers were diagnosed during the period 1975-80 were identified retrospectively. The occupational and smoking histories of these patients were sought by a postal questionnaire addressed either to the patients themselves or, if they had died, to their next of kin. The overall response rate to the questionnaire was 52.1%. Additionally, limited occupational information was obtained for 89% of cases from their hospital notes. Analysis of these data suggests that no serious bias arose as a consequence of the incomplete response to the questionnaire. This paper concentrates on the results for cancers of the respiratory tract and mesothelioma. Mesothelioma was found to cluster in laggers, electricians, and shipyard workers, and nasal carcinoma in woodworkers. Carcinomas of the larynx and of the bronchus were examined by formal statistical techniques, each being compared with a control group made up of all other cancers combined. Several interesting occupational and industrial associations were shown, in particular, an excess of bronchial carcinoma in the leather industry (RR = 2.6, CI 1.2-6.0), in building labourers (RR = 1.7, CI 1.0-2.9) and other construction workers (RR = 1.8, CI 1.0-3.0), in bakers and pastry cooks (RR = 3.6, CI 1.3-10.4). and in cooks (RR = 2.5, CI 1.2-5.1). In addition, a small cluster of lung tumours was observed in men who had worked as dental mechanics.


Novel 3alpha-diphenylmethoxytropane analogs: selective dopamine uptake inhibitors with behavioral effects distinct from those of cocaine.
The pharmacological effects were assessed for a series of 3alpha-diphenylmethoxy-1alphaH,5alphaH-tropane analogs which have structural similarities to cocaine. Like cocaine, these compounds displaced [3H]WIN 35,428 binding from rat caudate and had affinities ranging from approximately 10-fold greater than cocaine (Ki=11.8 nM) to relatively low affinity (Ki=2000 nM). The compounds also inhibited dopamine uptake with potencies corresponding to their affinities for WIN 35,428 binding sites. Like the parent compound, benztropine, the 3alpha-(diphenylmethoxy)tropane analogs displaced [3H]pirenzepine from muscarinic M1 receptors with affinities ranging from 2 to 120 nM. Cocaine produced dose-related increases in locomotor activity (horizontal ambulation) in Swiss Webster mice, whereas the 3alpha-(diphenylmethoxy)tropane analogs generally had lower efficacy than cocaine. Compounds with fluoro-substituents in the phenyl rings generally were among those with efficacy approaching that of cocaine; those with chloro- and bromo-substituents were markedly less efficacious, despite having binding affinities comparable to those of the corresponding fluoro-substituted compounds. The 3alpha-(diphenylmethoxy)tropane analogs were also examined in rats trained to discriminate saline from cocaine (10 mg/kg, i.p.). Cocaine produced a dose-related increase in responding on the cocaine-appropriate lever, reaching 100% at 10 mg/kg. Only the 4',4"-difluoro-substituted analog produced effects similar to those of cocaine; the other compounds showed markedly reduced efficacy compared to cocaine. Drug interaction studies showed that the antimuscarinics, atropine and scopolamine, potentiated rather than attenuated the locomotor stimulant and cocaine-like discriminative-stimulus effects of cocaine, indicating that the antimuscarinic effects of the 3alpha-diphenylmethoxytropane analogs did not contribute to their diminished cocaine-like activity. Studies of the time course of selected compounds indicated that their reduced cocaine-like efficacy was likely not due to behavioral observations being conducted at an inopportune time period. Because none of the 3alpha-diphenylmethoxytropane analogs studied showed evidence that they were binding to more than one site, and because the structure activity relationships among these drugs are distinctly different from those obtained with cocaine, these data suggest that the 3alpha-diphenylmethoxytropane analogs are accessing a different binding domain than that accessed by cocaine. Binding to this domain may produce a behavioral profile that is distinct from that of the cocaine-like dopamine uptake inhibitors.


Increasing asthma mortality in Denmark 1969-88 not a result of a changed coding practice.
We have studied asthma mortality in Denmark from 1969 to 1988. Age standardized mortality rates calculated in three age groups, 10-34, 35-59, and greater than or equal to 60 years, disclosed similar trends. Increasing mortality from asthma in the mid-1970s to 1988 was seen in all three age groups with higher mortality in 1979-88 as compared with 1969-78 of 95%, 55%, and 69%, respectively. Since the eighth revision of the International Classification of Diseases (ICD8) was used in Denmark over the entire 20-year period, changes in coding practice due to change of classification system cannot explain the findings.


Copper chelation and interleukin-6 proinflammatory cytokine effects on expression of different proteins involved in iron metabolism in HepG2 cell line.
In vertebrates, there is an intimate relationship between copper and iron homeostasis. Copper deficiency, which leads to a defect in ceruloplasmin enzymatic activity, has a strong effect on iron homeostasis resulting in cellular iron retention. Much is known about the mechanisms underlying cellular iron retention under "normal" conditions, however, less is known about the effect of copper deficiency during inflammation. We show that copper deficiency and the inflammatory cytokine interleukin-6 have different effects on the expression of proteins involved in iron and copper metabolism such as the soluble and glycosylphosphtidylinositol anchored forms of ceruloplasmin, hepcidin, ferroportin1, transferrin receptor1, divalent metal transporter1 and H-ferritin subunit. We demonstrate, using the human HepG2 cell line, that in addition to ceruloplasmin isoforms, copper deficiency affects other proteins, some posttranslationally and some at the transcriptional level. The addition of interleukin-6, moreover, has different effects on expression of ferroportin1 and ceruloplasmin, in which ferroportin1 is decreased while ceruloplasmin is increased. These effects are stronger when a copper chelating agent and IL-6 are used simultaneously. These results suggest that copper chelation has effects not only on ceruloplasmin but also on other proteins involved in iron metabolism, sometimes at the mRNA level and, in inflammatory conditions, the functions of ferroportin and ceruloplasmin may be independent.


Introduced Rats and an Endemic Roundworm: Does Rattus rattus Contribute to Baylisascaris procyonis Transmission in California?
The introduced black rat, Rattus rattus, occurs throughout the native range of the raccoon roundworm, Baylisascaris procyonis, and might incorporate into its life cycle if rats consume parasite eggs, acquire viable infections, and are eaten by raccoons. Although rats forage at raccoon latrines, their role in B. procyonis transmission remains unknown. Here I tested the potential for rats to amplify B. procyonis transmission in California by surveying wild rodents for B. procyonis and conducting scavenger trials with the use of motion-activated cameras. Rattus rattus were infected with B. procyonis at intensities more than 100 times greater than that of co-occurring native Reithrodontomys megalotis and Peromyscus maniculatus. Rodent carcasses were scavenged by opossums, skunks, and raccoons, suggesting that these rodents, particularly R. rattus, contribute to B. procyonis transmission in this coastal California ecosystem.


Drug-related pityriasis rubra pilaris with acantholysis.
Acantholysis is rarely reported histological feature of Pityriasis rubra pilaris (PRP), recently recognized as having diagnostic specificity for differentiating PRP from psoriasis. Adult male patient one week after the introduction of simvastatin had experienced pruritic erythemo-squamous eruption on head and upper trunk that in a month progressed to erythrodermia, with islands of sparing. Histological picture combined pemphigus-like acantholysis with alternating hyper- and parakeratosis, follicular plugs and dermal inflammation, and confirmed the clinical diagnosis of classic adult type 1 PRP. Acitretin therapy resulted in a resolution of skin disease. Patch test with simvastatin was negative, scratch test was positive, and it was estimated that potential risk of oral challenge with simvastatin outweighed actual need for it. Drug triggering PRP episode is the most likely explanation for temporal relation between the start of simvastatin treatment and skin eruption. In management of rare inflammatory skin disease, such as PRP, we have to carefully observe and evaluate not only diagnostic features but possible external influences on its course also.


Ecophysiological and behavioural response of juveniles of the Chilean cold-water coral Caryophyllia (Caryophyllia) huinayensis to increasing sediment loads.
Chilean Patagonia is a hotspot of biodiversity, harbouring cold-water corals (CWCs) that populate steep walls and overhangs of fjords and channels. Through anthropogenic activities such as deforestation, roadworks, aquafarming and increased landslide frequency, sediment input increases in the fjord region. While the absence of CWCs on moderately steep slopes has been suggested to reflect high vulnerability to sedimentation, experimental evidence has been lacking. Here, we investigated the sensitivity of CWCs to sediment stress, using juvenile Caryophyllia (Caryophyllia) huinayensis as a model. A 12-week aquarium experiment was conducted with three sediment loads: the average natural sediment concentration in Comau Fjord, 100- and 1000-fold higher sediment levels, expected from gravel road use and coastal erosion. Changes in coral mass and calyx dimensions, polyp expansion, tissue retraction and respiration were measured. For CWCs exposed to two and three order of magnitude higher sediment concentrations, 32% and 80% of the animals experienced a decrease in tissue cover, respectively, along with a decrease in respiration rate of 34% and 66%. Under the highest concentration corals showed reduced polyp expansion and a significantly reduced growth of ~ 95% compared to corals at natural concentration. The results show that C. huinayensis is affected by high sediment loads. As human activities that increase sedimentation steadily intensify, coastal planners need to consider detrimental effects on CWCs.


Three-dimensional structure of cytoskeletal system in human hepatocytes viewed by polyethylene-glycol-embedding method.
In an attempt to demonstrate the three-dimensional cytoskeletal system of human hepatocytes, we used two kinds of tissue processing. In one, specimens were immediately fixed with 1% glutaraldehyde, saponin 0.5 mg/ml, and tannic acid 2 mg/ml (procedure A) and in the other, cytoplasmic matrix and organelles were washed out with a solution containing saponin 0.5 mg/ml and 0.15% Triton X-100, followed by fixation with glutaraldehyde (procedure B). The specimens were embedded in polyethylene glycol, sectioned at 500 nm, critical point-dried and observed in a TEM. With procedure A, a fine lattice was shown to spread throughout the cytoplasm so as to connect plasma membranes with cytoplasmic organelles, condensed around the bile canaliculi. With procedure B, microfilaments, microtubules and intermediate filaments could be clearly visualized three-dimensionally instead of the lattice structure. At a higher magnification, microvilli of canaliculus were found to contain a core microfilament which were enmeshed in a pericanalicular filament plexus. This plexus looking like the terminal web of intestinal epithelia, encircled the canaliculus and was attached to the zonula adherens. Outside the plexus, intermediate filament network was shown attached to the desmosome. These morphological findings indicated that the cytoskeleton of human hepatocytes is composed of microfilaments, microtubules, intermediate filaments and the fine lattice structure, suggesting that the bile canaliculi could contract in vivo.


Photocontrol of subcellular partitioning of phytochrome-B:GFP fusion protein in tobacco seedlings.
Photomorphogenesis of higher plants is regulated by photoreceptors including the red/far-red light-absorbing phytochromes, blue-UV/A sensing cryptochromes and as yet uncharacterized UV/B receptors. Specific phototransduction pathways that are controlled by either individual or interacting photoreceptors mediate regulation. Phytochrome B (phyB) is the major red light-sensing photoreceptor. Phototransduction mediated by this light sensor has been shown to include light-dependent nuclear import and interaction of phyB with transcription factor-like proteins in the nucleus. Here we report that nuclear import of phyB and physiological responses regulated by this photoreceptor exhibit very similar wavelength- and fluence rate-dependence. Nuclear import of phyB is insensitive to single red, blue and far-red light pulses. It is induced by continuous red light and to a lesser extent by continuous blue light, whereas far-red light is completely ineffective. The data presented indicate that light-dependent partitioning of phyB exhibits features characteristic of blue light responsiveness amplification, a phenomenon that is thought to be mediated by interaction of phyB with CRY1.


Fostering accurate HIV/AIDS knowledge among unmarried youths in Cameroon: do family environment and peers matter?
The last three decades have seen a series of HIV interventions in sub-Saharan Africa. However, youths still have a mixture of correct and incorrect HIV/AIDS knowledge of transmission routes and prevention strategies. Previous studies have identified parents and peers as the most important socializing agents for youths. This paper assesses the relationships between family structure, family/peer communication about sexuality and accurate knowledge of transmission routes and prevention strategies. Data were drawn from the Cameroon Family Life and Health Survey (CFHS) conducted in 2002. The CFHS collected information on a representative sample of 4950 people aged 10 years and over nested within 1765 selected households from the 75 localities forming the administrative prefecture of Bandjoun, using detailed questionnaires about family, HIV/AIDS/STDs knowledge, sexual behaviors, contraception, health, media exposure, household assets and neighborhood characteristics. The survey cooperation rates were high (97%). For the purpose of this study, a sub-sample of 2028 unmarried youths aged 12-29 years was utilized. Overall, 42% of respondents reported accurate knowledge of documented HIV transmission routes whereas 21% of them had inaccurate knowledge such as AIDS can be transmitted through mosquito bites or casual contact with an infected person. Only 9% of respondents were knowledgeable about all HIV prevention strategies. Multivariate analyses showed that family structure, communication with parents/guardians and peers about sexual topics were significantly associated with accurate HIV knowledge. Additionally, age, education, sexual experience and migration had significant effects on accurate knowledge. Finally, living in poor households and disadvantaged neighborhoods significantly increased inaccurate knowledge of HIV transmission modes and prevention strategies. This paper evidenced the limited effects of HIV interventions/programmes in sub-Saharan Africa. Indeed, few respondents reported accurate knowledge about HIV transmission routes and prevention strategies. Findings showed that the role of family environment as source of accurate HIV knowledge transmission routes and prevention strategies is of paramount significance; however, families have been poorly integrated in the design and implementation of the first generation of HIV interventions. There is an urgent need that policymakers work together with families to improve the efficiency of these interventions. Peer influences is likely controversial because of the double positive effect of peer-to-peer communication on both accurate and inaccurate knowledge of HIV transmission routes.


The shortcoming of using glibenclamide in exploratory clinical headache provocation studies.
Preclinical and clinical studies implicate the vascular ATP-sensitive potassium (KATP) channel in the signaling cascades underlying headache and migraine. However, attempts to demonstrate that the KATP channel inhibitor glibenclamide would attenuate triggered headache in healthy volunteers have proven unsuccessful. It is questionable, however, whether target engagement was achieved in these clinical studies. Literature data for human glibenclamide pharmacokinetics, plasma protein binding and functional IC50 values were used to predict the KATP receptor occupancy (RO) levels obtained after glibenclamide dosing in the published exploratory clinical headache provocation studies. RO vs. time profiles of glibenclamide were simulated for the pancreatic KATP channel subtype Kir6.2/SUR1 and the vascular subtype Kir6.1/SUR2B. At the clinical dose of 10 mg of glibenclamide used in the headache provocation studies, predicted maximal occupancy levels of up to 90% and up to 26% were found for Kir6.2/SUR1 and Kir6.1/SUR2B, respectively. The findings of the present study indicate that effective Kir6.1/SUR2B target engagement was not achieved in the clinical headache provocation studies using glibenclamide. Therefore, development of novel selective Kir6.1/SUR2B inhibitors, with good bioavailability and low plasma protein binding, is required to reveal the potential of KATP channel inhibition in the treatment of migraine.


[Efficacy of long-term enalapril use in combined therapy of chronic pulmonary heart].
86 patients with chronic obstructive pulmonary diseases (COPD) and tuberculosis in combination with COPD complicated by chronic pulmonary heart (CPH) received a 18-month continuous treatment with enalapril (enap, D. Reddis Laboratories). It was found that the addition of enap, an inhibitor of ACE, to combined therapy of CPH patients is pathogenetic as it results in lowering of blood pressure in pulmonary artery, remodeling of hypertrophic right ventricle of the heart and decline of left ventricular dysfunction, in improvement of functional state of the lungs, in arrest of progression of cardiac failure. Long-term administration of the drug induced no serious side effects and is well tolerated.


[A comparative evaluation of methods for treating the sequelae of fractures and dislocations of the bones of the hand].
A comparative clinical investigation of effectiveness of different methods of treatment of sequelae of injuries of the hand bones and joints in 159 patients was carried on. Traditional methods of treatment and devices for external fixation were used. An analysis of long-term results of treatment of 145 patients has shown that methods of external fixation by compressive-distraction and hinge-distraction devices are most effective.


Urea biosynthesis I. The urea cycle and relationships to the citric acid cycle.
The urea cycle consist of five enzymatically controlled steps that are catalyzed by carbamyl phosphate synthetase, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinase, and arginase, respectively. The complete cycle is present in physiological meaningful levels in the liver of terrestrial vertebrates, and in man represents the sole mechanism for ammonia disposal. The formation of carbamyl phosphate and the synthesis of argininosuccinate are potential limiting steps in urea biosynthesis but substrate and not enzymes levels are rate-limiting under physiological conditions. In the adult, urea cycle enzymes change as a unit, and are largely influenced by dietary protein content. The urea cycle is closely linked to the citric acid cycle deriving one of its nitrogens through transamination of oxalacetate to form asparate and returns fumarate to that cycle. The biosynthesis of urea demands the expenditure of energy but less than 20% of the energy derived from metabolism of gluconeogenic amino acids is required for ureogenesis. Embryological development of the urea cycle in the tadpole and in mammalian fetal liver therefore permits use of amino acids as new sources of energy to meet oxidative demands for continuing growth.


The Universal Plausibility Metric (UPM) & Principle (UPP).
Mere possibility is not an adequate basis for asserting scientific plausibility. A precisely defined universal bound is needed beyond which the assertion of plausibility, particularly in life-origin models, can be considered operationally falsified. But can something so seemingly relative and subjective as plausibility ever be quantified? Amazingly, the answer is, "Yes." A method of objectively measuring the plausibility of any chance hypothesis (The Universal Plausibility Metric [UPM]) is presented. A numerical inequality is also provided whereby any chance hypothesis can be definitively falsified when its UPM metric of xi is < 1 (The Universal Plausibility Principle [UPP]). Both UPM and UPP pre-exist and are independent of any experimental design and data set. No low-probability hypothetical plausibility assertion should survive peer-review without subjection to the UPP inequality standard of formal falsification (xi < 1).


The effects of Uber diffusion on the mental health of drivers.
While the spread of digital technologies and the growth of associated atypical forms of work are attracting increasing attention, little is known about the impact of these new forms of work on psychological well-being. This paper examines the effect of Uber diffusion on the mental health of drivers, taking advantage of the rollout of Uber across UK regions. We match individual-level information on health and sociodemographic characteristics from the UK Household Longitudinal Study (Understanding Society) between 2009 and 2019 with data on the diffusion of Uber across the country. We first show that Uber diffusion is positively associated with mental health, as measured by the General Health Questionnaire, in the population group of self-employed drivers. We argue that this positive correlation captures a selection effect (of comparatively healthier individuals into the category of self-employed drivers after Uber entry) and the omission of unobserved factors, rather than a causal effect. Indeed, we do not observe any improvement in mental health for workers who were already self-employed drivers before Uber entry. In parallel with this, among individuals who remained salaried drivers over time, our results suggest there may be a decline in mental health after Uber's introduction, probably because they feel the competition from Uber drivers.


Perioperative Outcomes for Abdominal Aortic Aneurysm Repair Based on Aneurysm Diameter.
Guidelines from the Society for Vascular Surgery recommend elective repair in asymptomatic patients with an abdominal aortic aneurysm (AAA) only if their diameter is greater than or equal to 5.5 cm, yet smaller ones are routinely repaired. This study aims to evaluate perioperative outcomes based on aneurysm size at the time of repair. Male patients who underwent elective endovascular aneurysm repair (EVAR) or open abdominal aneurysm repair (OAAR) repair of an infrarenal AAA were abstracted from 2011 to 2015 Targeted National Surgical Quality Improvement Program (NSQIP) database. Patients with symptoms or with aneurysmal extension into the visceral or iliac vessels were excluded. Outcomes of open versus endovascular repair were reported, with multivariate analyses to identify factors associated with the decision to repair AAA ≤5.4 cm. A total of 2115 (90.9%) patients underwent EVAR, while 213 (9.1%) underwent OAAR. The mean diameter in patients who underwent OAAR was 6.1 cm (interquartile range [IQR]: 5.2-6.1 cm) versus 5.7 cm (IQR: 5.2-6.0 cm) for EVAR. However, in 42.5% of EVAR and 32.8% of OAAR patients, the diameter of the AAA was 5.4 cm or less. The group undergoing repair of AAA ≤5.4 cm was younger compared to the larger AAA group (71.9 vs 73.9 years; P < .0001). Patients older than 80 years were less likely to have a repair of AAA measuring ≤5.4 cm (odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.30-0.65). Additionally, patients who underwent EVAR were more likely to have AAA measuring ≤5.4 cm repaired compared to those who underwent OAAR (OR = 1.62, 95% CI = 1.19-2.21). There were no differences in perioperative morbidity or mortality between the groups. There were no differences in perioperative outcomes after AAA repair, independent of aneurysm diameter. We found a higher likelihood of repairing AAA ≤5.4 cm in younger patients who were more likely to have been repaired with EVAR. Patients older than 80 years were less likely to undergo small AAA repair.


Active defence by an Australian native host, Lomandra longifolia, provides resistance against Phytophthora cinnamomi.
Resistance is rare against the oomycete plant pathogen Phytophthora cinnamomi Rands. Only a limited number of species have been recorded as field-resistant species in Australia. However, understanding the nature of resistance of those species when grown under controlled conditions is challenging because of their slow growth and the inherent difficulties of working with a root pathogen. We assessed the Australian native species, Lomandra longifolia Labill., as a resistant species by analysing in detail the response of roots to infection by P. cinnamomi in a series of comparative tests with Lupinus angustifolius L., a highly susceptible species. Following inoculation of L. longifolia roots, lesion length and colonisation percentage were significantly less than in roots of the susceptible species. Moreover, there was no statistical difference in root growth rate, whole-plant FW and leaf relative chlorophyll content between controls and inoculated L. longifolia. We then examined three key cellular responses that are related to resistance: the production of the reactive oxygen species, H2O2, callose formation and lignin deposition in L. longifolia roots following inoculation with P. cinnamomi. The upregulation of these resistance-related components in the early hours after inoculation suggested their involvement in resistance and that this is controlled by the coordinated response of multiple components. Resistance assessment and a detailed investigation of cellular resistance components along with gene expression analysis provides a platform for further understanding of the mechanisms of resistance against this generalist pathogen and presents opportunities for manipulating susceptible species for disease resistance.


The role of the interface in germanium quantum dots: when not only size matters for quantum confinement effects.
Quantum confinement (QC) typically assumes a sharp interface between a nanostructure and its environment, leading to an abrupt change in the potential for confined electrons and holes. When the interface is not ideally sharp and clean, significant deviations from the QC rule appear and other parameters beyond the nanostructure size play a considerable role. In this work we elucidate the role of the interface on QC in Ge quantum dots (QDs) synthesized by rf-magnetron sputtering or plasma enhanced chemical vapor deposition (PECVD). Through a detailed electron energy loss spectroscopy (EELS) analysis we investigated the structural and chemical properties of QD interfaces. PECVD QDs exhibit a sharper interface compared to sputter ones, which also evidences a larger contribution of mixed Ge-oxide states. Such a difference strongly modifies the QC strength, as experimentally verified by light absorption spectroscopy. A large size-tuning of the optical bandgap and an increase in the oscillator strength occur when the interface is sharp. A spatially dependent effective mass (SPDEM) model is employed to account for the interface difference between Ge QDs, pointing out a larger reduction in the exciton effective mass in the sharper interface case. These results add new insights into the role of interfaces on confined systems, and open the route for reliable exploitation of QC effects.


Guidelines for the measurement of vascular function and structure in isolated arteries and veins.
The measurement of vascular function in isolated vessels has revealed important insights into the structural, functional, and biomechanical features of the normal and diseased cardiovascular system and has provided a molecular understanding of the cells that constitutes arteries and veins and their interaction. Further, this approach has allowed the discovery of vital pharmacological treatments for cardiovascular diseases. However, the expansion of the vascular physiology field has also brought new concerns over scientific rigor and reproducibility. Therefore, it is appropriate to set guidelines for the best practices of evaluating vascular function in isolated vessels. These guidelines are a comprehensive document detailing the best practices and pitfalls for the assessment of function in large and small arteries and veins. Herein, we bring together experts in the field of vascular physiology with the purpose of developing guidelines for evaluating ex vivo vascular function. By using this document, vascular physiologists will have consistency among methodological approaches, producing more reliable and reproducible results.


Update on essential tremor.
Essential tremor (ET) is one of the most common neurological disorders among adults, and is the most common tremor disorder. ET has classically been viewed as a benign monosymptomatic condition. Yet over the past 10 years, a growing body of evidence indicates that this is a progressive condition that is clinically heterogeneous, and may be associated with a variety of different features such as gait abnormalities, parkinsonism, cognitive impairment, dementia, personality disturbances, depressive symptoms, and sensory abnormalities (e.g., mild olfactory dysfunction and hearing impairment). In addition, postmortem studies are showing a pathologically heterogeneous neurodegenerative disease. The emerging view is that ET might be a family of diseases, unified by the presence of kinetic tremor, but further characterized by etiological, clinical and pathological heterogeneity. The diagnosis of ET is clinical and made by history and physical examination. Effective pharmacological treatments for the disorder currently remain limited. Drugs are generally initiated when the tremor begins to interfere with the patient's ability to perform daily activities or when the tremor becomes embarrassing. For severe, medically refractory ET, thalamic ventralis intermedius nucleus deep brain stimulation may lessen tremor and improve function.


Neighbourhood-level housing quality indices for health assessment in Dakar, Senegal.
In sub-Saharan African cities, the dearth of accurate and detailed data is a major problem in the study of health and socioeconomic changes driven by rapid urbanization. Data on both health determinants and health outcomes are often lacking or are of poor quality. Proxies associated with socioeconomic differences are needed to compensate the lack of data. One of the most straightforward proxies is housing quality, which is a multidimensional concept including characteristics of both the built and natural environments. In this work, we combined the 2013 census data with remotely sensed land cover and land use data at a very high resolution in order to develop an integrated housing quality-based typology of the neighbourhoods in Dakar, Senegal. Principal component analysis and hierarchical classification were used to derive neighbourhood housing quality indices and four neighbourhood profiles. Paired tests revealed significant variations in the censusderived mortality rates between profile 1, associated with the lowest housing quality, and the three other profiles. These findings demonstrate the importance of housing quality as an important health risk factor. From a public health perspective, it should be a useful contribution for geographically targeted planning health policies, at the neighbourhood spatial level, which is the most appropriate administrative level for interventions.


Controlled infusion of intravenous cardiac drugs using global optimization.
The objective of the study is to develop an automatic drug infusion control system during cardiovascular surgery. Based on the clinical drug dosage analysis, the modeling of cardiovascular system with baroreceptor model is mathematically modeled using compartmental approach, considering the relationship between the volume and flow rate of blood during each heartbeat. This model is then combined with drug modeling of noradrenaline and nitroglycerine by deriving the volume and drug mass concentration equations, based on pharmacokinetics and pharmacodynamics of the drugs. The closed-loop patient models are derived from the open-loop data obtained from the physiology-drug model with covariate as age. The proportional-integral controller is designed based on optimal values obtained from bacterial foraging-oriented particle swarm optimization algorithm. The controllers are implemented individually for each control variable such as aortic pressure and cardiac output (CO), irrespective of varying weights based on the relative gain array analysis which depicts the maximum influence of cardiac drugs on control variables. The physiology-drug model output responses are simulated using MATLAB. The controlled responses of aortic pressure and CO with infusion rate of cardiac drugs are obtained. The robustness of the controller is checked by introducing variations in cardiovascular model parameters. The efficiency of the controller during normal and abnormal conditions is compared using time domain analysis. The controller design was efficient and can be further improved by designing switching-based controllers.


[Medical-social aspects of medical staff migration].
The migration of the medical staff represents an increasingly worring reason for romanian health policy-makers. According to the Ministry of Health, in 2009 year, the human resources indicators pointed out 26.5 physicians/ 10,000 inhabitants (whereas the European Union average was 32.8) and 60.4 nurses and midwives (whereas the European Union average was 108.5). Between 2007-2010, over 9000 physicians requested professional certificates in order to practice abroad and the majority have left the country. This phenomenon is related to the Romania's entrance in European Union and it is supposed to continue in the coming years. The direct consequences of the migration of the medical staff consist of significant differences between the country's regions in the health workforce distribution, the most affected by the critical shortage of health service providers being the North-Eastern region, especially in rural area. In order to limit the migration phenomenon, the Ministry of Health elaborated some strategies and workforce policies on medium and long-term, but the results will be difficult to assess.


A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway.
The formation of boundaries between groups of cells is a universal feature of metazoan development. Drosophila fringe modulates the activation of the Notch signal transduction pathway at the dorsal-ventral boundary of the wing imaginal disc. Three mammalian fringe-related family members have been cloned and characterized: Manic, Radical and Lunatic Fringe. Expression studies in mouse embryos support a conserved role for mammalian Fringe family members in participation in the Notch signaling pathway leading to boundary determination during segmentation. In mammalian cells, Drosophila fringe and the mouse Fringe proteins are subject to posttranslational regulation at the levels of differential secretion and proteolytic processing. When misexpressed in the developing Drosophila wing imaginal disc the mouse Fringe genes exhibit conserved and differential effects on boundary determination.


Electrowetting of nitro-functionalized oligoarylene thiols self-assembled on polycrystalline gold.
Four linear terarylene molecules (i) 4-nitro-terphenyl-4″-methanethiol (NTM), (ii) 4-nitro-terphenyl-3″,5″-dimethanethiol (NTD), (iii) ([1,1';4',1″] terphenyl-3,5-diyl)methanethiol (TM), and (iv) ([1,1';4',1″] terphenyl-3,5-diyl)dimethanethiol (TD) have been synthesized and their self-assembled monolayers (SAMs) have been obtained on polycrystalline gold. NTM and NTD SAMs have been characterized by X-ray photoelectron spectroscopy, Kelvin probe measurements, electrochemistry, and contact angle measurements. The terminal nitro group (-NO2) is irreversibly reduced to hydroxylamine (-NHOH), which can be reversibly turned into nitroso group (-NO). The direct comparison between NTM/NTD and TM/TD SAMs unambiguously shows the crucial influence of the nitro group on electrowetting properties of polycrystalline Au. The higher grade of surface tension related to NHOH has been successfully exploited for basic operations of digital μ-fluidics, such as droplets motion and merging.


[Validity and reproducibility of osteodensitometric DEXA-measurements following total hip endoprosthesis].
For the determination of reproducibility of bone densitometric measurements we performed a measurement according to the DEXA- method. 35 patients after implantation of total hip replacement were examined with a Lunar DPX-L. We received a maximum reproduction error of 1.2% according to the GRUEN-analysis. The operated hip of 17 patients showed an increase in bone density between 5 and 18% by the implantation of an arthroplasty compared to the preoperative values. The non-operated prosthesis-corrected hip showed a reproduction error of 3.8% in ROI 1 in 17 patients, otherwise a maximum of 1.3%. Considering an interfemoral difference in bone density of up to 20%, differences in periprosthetic bone density of up to 40% compared to the contralateral side can be within the normal range in a retrospective measurement. Therefore retrospective determination of bone density after cementless hip arthroplasty only is of limited value. Only prospective analysis can provide reliable information about the actual loss of bone density.


AMP-activated protein kinase as a target for preconditioning in transplantation medicine.
Graft quality before transplantation is a major factor influencing chronic rejection. Organ preservation and ischemia/reperfusion play an important role in the induction of organ injury. Although both suppression of metabolism by hypothermic preservation and preconditioning before ischemia limit injury, understanding the biochemical signaling pathways will allow us to optimize graft preservation further. Adenosine monophosphate-activated protein kinase (AMPK) is an important enzyme sensing cellular energy balance and regulating downstream signaling pathways, signaling toward an energy-conserving state. In this review, we summarize available literature regarding the protective signaling pathways activated by (hypothermic) ischemia and preconditioning and how they can be activated pharmacologically. Optimizing the graft quality before transplantation improves long-term graft survival. The major factor influencing organ quality is organ preservation, cold storage, currently, being a common practice. Loss of cellular homeostasis, inflammation, and endothelial dysfunction are the major factors inducing injury after cold storage. Adenosine triphosphate depletion and anaerobic metabolism during the cold ischemic period lead to mitochondrial dysfunction, disturbed osmoregulation, and cell death inducing inflammation. Ischemic preconditioning consists of brief periods of ischemia preceding preservation and protects organs against injury because of subsequent ischemia/reperfusion, in which endothelial nitric oxide synthase, nuclear factor-kB, and adenosine play a major role. After conversion of adenosine to AMP, AMPK can be activated, a central kinase involved in sensing cellular [AMP]:[adenosine triphosphate] levels and signaling toward an energy-conserving state. Pharmacologic activation of AMPK demonstrated its ability to activate endothelial nitric oxide synthase and inhibit nuclear factor-kB, thereby limiting endothelial dysfunction and inflammation. Further, studies in knock-out mice lacking ENTDP1 and NT5E (enzymes catalyzing formation and degradation of AMP, respectively) demonstrated a clear protective role for AMP in ischemia/reperfusion. AMPK activation before or during organ preservation might be a promising pharmacologic approach to limit organ injury and maintain graft quality before transplantation.


Factors affecting prognosis in locoregional recurrence of oral squamous cell carcinoma.
Recurrence of oral squamous cell carcinoma (rOSCC) after primary treatment is associated with poor survival outcomes. Salvage treatment with further surgery, radiotherapy and chemotherapy has high morbidity, making patient selection crucial. However, in the recurrence setting, reliable stratification data are scarce. Decision-making in this context is consequently complex. We investigated factors influencing overall survival after rOSCC. Retrospective cohort study of patients with rOSCC (n = 83) at the Queen Elizabeth Hospital Birmingham, UK between 2006 and 2016. Associations with overall survival were analysed using univariate and multivariate analyses to identify important clinical prognostic indicators. Overall survival at 1 year was 32.5% and at 5 years was 18.1% after a median follow-up of 7.4 months. Multivariate analysis identified four independent predictors of overall survival following rOSCC: size of primary tumour (HR 2.077; 95% CI 1.034-4.172), extent of recurrent disease (HR 3.286; 95% CI 1.545-6.991), history of moderate alcohol consumption (HR 0.351; 95% CI 0.162-0.763), and close or positive margins at primary resection (HR 1.955; 95% CI 1.063-3.595). We identified four key factors that help prognostication and risk stratification of rOSCC. Given the high morbidity associated with salvage treatment, we recommend that the multidisciplinary team (MDT) and the patient weigh these factors carefully when considering further treatment. Further investigation of the biology underlying these oncophenotypes may contribute to better patient stratification.


Acoustic impedance measurements-correction for probe geometry mismatch.
The effect of evanescent mode generation, due to geometrical mismatch, in acoustic impedance measurements is investigated. The particular geometry considered is that of a impedance probe with an annular flow port and a central microphone, but the techniques are applicable to other geometries. It is found that the imaginary part of the measured impedance error is proportional to frequency, and that the sign of the error is positive for measurements made on tubes with diameter much larger than that of the inlet port, but negative for tubes with diameter close to that of the inlet. The result is a distortion of the measured frequencies of the impedance minima of the duct while the maxima are largely unaffected. There is, in addition, a real resistive component to the error that varies approximately as the square root of the frequency. Experiment confirms the results of the analysis and calculations, and a calibration procedure is proposed that allows impedance probes that have been calibrated on a semi-infinite tube of one diameter to be employed for measurements on components with an inlet duct of some very different diameter.


Sensitivity of gait parameters to the effects of anti-inflammatory and opioid treatments in knee osteoarthritis patients.
The study aim was to address the need for objective markers of pain-modifying interventions by testing the hypothesis that selective gait measures of knee joint loading can distinguish differences between non-steroidal anti-inflammatory (NSAID), analgesic treatment (opioid-receptor agonist), and placebo in patients medial knee osteoarthritis (OA). A randomized, single-blind washout, double-blind treatment, double-dummy cross-over trial using three treatment arms placebo, opioid (Oxycodone), and NSAID (Celecoxib) in medial compartment knee OA patients. Six patients with Kellgren-Lawrence radiographic severity grades of 2 or 3 completed six testing sessions (gait and pain assessment) at 2-week intervals. A significant increase was found in the knee total reaction moment and vertical ground reaction force (GRF) for Celecoxib compared to placebo (p=0.005, p=0.003), but not for Oxycodone compared to placebo (p=0.20, p=0.27) treatments. Walking speed was significantly higher for the Celecoxib and Oxycodone compared to placebo treatment (p=0.041 and p=0.031, respectively). Self-reported function (WOMAC scores) was not different among treatments (p>0.05). The changes in total reaction moments and GRFs for only the NSAID suggest that greater increases in joint loading occurs when joint inflammation is treated in addition to pain. The total knee reaction moment, representing the magnitude of the extrinsic moment, appears to be a sensitive marker, more so than self-reported metrics, for evaluating knee OA treatment effects.


Molecular analysis of the APC gene in 71 Israeli families: 17 novel mutations.
Familial adenomatous polyposis (FAP) is caused by germline mutations in the APC gene. This study included 71 Israeli families referred for molecular analysis of the APC gene. Analysis was performed by the protein truncation test (PTT) of exon 15, and if negative, by direct sequencing of exon 1 to 14. Mutations were found in 36 (50.7%) probands. Mutation detection rates depended on the pattern of referral, such that among the 40 probands referred from the Service for Hereditary Cancer the mutation detection rate was 70%, whereas among the 31 probands referred by other gastroenterologists detection rate was significantly lower (25.8%). Of the 36 mutations detected, 21 were within exon 15, 13 within exons 1 to 14 and 2 were newly-described splicing mutations in introns 9 and 14. A relatively high proportion of the mutations was detected in exon 9 (6/36), five of them newly described. Altogether, we describe here 17 new mutations. Within the two major ethnic groups in Israel, patients of Ashkenazi and non-Ashkenazi origin, there was no significant differences in the mutation detection rate or the distribution of mutations within the APC gene. No founder mutation was detected in any of these populations. Our data confirm that higher detection rates may be expected in patients referred by clinical services specializing in hereditary colon cancer. These results further underscore the importance of complete analysis of all exons and exon/intron boundaries, in order to achieve maximal detection rate in patients suspected of FAP.


[The role of blood-sucking ticks and insects in natural foci of infections].
During 60 years passed after the creation of the conception on natural focus of human infections by the academician E. N. Pavlovskiĭ our knowledge on a role of blood-sucking insects and ticks in this phenomenon have been significantly enlarged. It has been recovered, that these arthropods serve not only as vectors of infection agents, but also as natural reservoirs and amplificators of these agents. In the process of the infection agent circulation in the natural focus there are several additional pathways of circulations without a participation of vertebrates. These pathways are as follows: the dispersion of infection agent in cases of simultaneous feeding of infected and "clean" ticks, and also the sexual, transovarial and transphase transmissions of pathogens. These mechanism of circulation are most often occur in the ixodid ticks, which can play the main role in supporting the infection agent in the focus.


The second Kunitz domain of human tissue factor pathway inhibitor: cloning, structure determination and interaction with factor Xa.
Tissue Factor Pathway Inhibitor (TFPI) is a 36 kDa glycoprotein that helps maintain haemostasis by inhibiting Factor Xa and the Factor VIIa/Tissue Factor (TF) complex. TFPI contains three tandemly linked Kunitz inhibitor domains, of which the second inhibits factor Xa. We have undertaken a multidisciplinary approach to study the structure and function of the second Kunitz domain of TFPI, with a view towards the rational design of factor Xa inhibitors. Amino acid residues 93 to 154 of the mature TFPI protein, corresponding to the second Kunitz domain (TFPI-kII), were expressed in Escherichia coli. The protein was purified to near homogeneity by ion exchange, hydrophobic interaction, and size exclusion chromatography, respectively. TFPI-kII is a potent factor Xa inhibitor with a Ki of 1.5 x 10(-10) M, a value that does not differ significantly from that of intact TFPI. The three-dimensional structure of TFPI-kII in aqueous solution was determined by 1H nuclear magnetic resonance spectroscopy (NMR). A set of 30 conformers was calculated with the program DIANA using 906 distance constraints derived from nuclear Overhauser effects and 23 dihedral angle constraints. This set, representing the solution structure of TFPI-kII, has an average root-mean-square deviation of 0.78 A for the backbone atoms and 1.38 A for all heavy atoms of residues 1 to 58. The structure of TFPI-kII has also been determined in complex with porcine trypsin using X-ray crystallographic techniques. The complex has been solved to a resolution of 2.6 A, with a final R-factor of 16.2%. Comparison of the NMR derived structure with that of TFPI-kII in complex with trypsin reveals little divergence of the two structures, with the exception of residue Tyr17. Superposition of the trypsin:TFPI-kII complex on factor Xa provides insights into macromolecular determinants for the inhibition of factor Xa. Complexation would require a degree of reorganisation of factor Xa residues, in particular of TyrF99, but also perhaps of the F148-loop. The interaction was further investigated using restrained molecular dynamics. Electrostatic interactions would appear to play a major role. The reorganisation of factor Xa is in contrast to the proposed factor Xa:TAP interaction, where TAP would bind to the "ground state" structure of factor Xa.


Transcription and translation of deleted mitochondrial genomes in Kearns-Sayre syndrome: implications for pathogenesis.
Large-scale deletions of human mitochondrial DNA (mtDNA) have been described in a clinical subgroup of mitochondrial encephalomyopathies associated with progressive external ophthalmoplegia and ragged-red fibers in skeletal muscle, including cases of Kearns-Sayre syndrome (KSS). Since the decrease in the activities of mtDNA-encoded respiratory-chain enzymes did not seem to be correlated to the sites of the deletions, the role played by the mtDNA deletions in the pathogenesis of these disorders has been unclear. To address this issue, we studied transcription and translation of deleted mtDNA in two patients with KSS harboring two different deletions. We found that the deleted genomes were transcriptionally active in both cases. Analysis of translation in one of the patients showed that the "fusion" mRNA derived from the region spanning the deletion did not seem to be translated. Thus, the biochemical defects in KSS can be explained by a lack of translation of mtDNA-encoded respiratory-chain polypeptides in some mitochondria, which, in turn, is probably due to the lack of indispensable mtDNA-encoded tRNAs in these organelles. These results imply that deleted mtDNAs may be segregated from normal genomes in this group of diseases. It seems likely that the absence of translation in proliferating mitochondria containing partially deleted genomes plays a major role in the pathogenesis of these disorders.


Embracing complexity and uncertainty to create impact: exploring the processes and transformative potential of co-produced research through development of a social impact model.
The potential use, influence and impact of health research is seldom fully realised. This stubborn problem has caused burgeoning global interest in research aiming to address the implementation 'gap' and factors inhibiting the uptake of scientific evidence. Scholars and practitioners have questioned the nature of evidence used and required for healthcare, highlighting the complex ways in which knowledge is formed, shared and modified in practice and policy. This has led to rapid expansion, expertise and innovation in the field of knowledge mobilisation and funding for experimentation into the effectiveness of different knowledge mobilisation models. One approach gaining prominence involves stakeholders (e.g. researchers, practitioners, service users, policy-makers, managers and carers) in the co-production, and application, of knowledge for practice, policy and research (frequently termed integrated knowledge translation in Canada). Its popularity stems largely from its potential to address dilemmas inherent in the implementation of knowledge generated using more reductionist methods. However, despite increasing recognition, demands for co-produced research to illustrate its worth are becoming pressing while the means to do so remain challenging. This is due not only to the diversity of approaches to co-production and their application, but also to the ways through which different stakeholders conceptualise, measure, reward and use research. While research co-production can lead to demonstrable benefits such as policy or practice change, it may also have more diffuse and subtle impact on relationships, knowledge sharing, and in engendering culture shifts and research capacity-building. These relatively intangible outcomes are harder to measure and require new emphases and tools. This opinion paper uses six Canadian and United Kingdom case studies to explore the principles and practice of co-production and illustrate how it can influence interactions between research, policy and practice, and benefit diverse stakeholders. In doing so, we identify a continuum of co-production processes. We propose and illustrate the use of a new 'social model of impact' and framework to capture multi-layered and potentially transformative impacts of co-produced research. We make recommendations for future directions in research co-production and impact measurement.