The occurrence of a macular hole due to posterior uveitis is infrequently reported. We report the evolution of three cases of macular holes secondary to posterior segment inflammation. A complete inflammatory and infectious assessment found one case of toxocariasis, one of sarcoidosis, and one of syphilis. After medical etiological treatment, macular hole closure was rapidly obtained in all the cases and confirmed by spectral domain optic coherence tomography, with visual acuity improvement. Fibrous scarring developed in two cases, and foveal photoreceptor complex normalization was observed in the sarcoidosis case. These observations demonstrate that macular holes secondary to posterior uveitis frequently resolve without surgical intervention and so could be underdiagnosed if the patient is not evaluated at the time of onset before spontaneous hole closure. Ocular inflammatory diseases can cause sight loss by macular impairment. Cystoid macular edema is the principal sight-threatening complication  in uveitHere we report three cases of macular hole secondary to posterior uveitis that spontaneously resolved after etiological treatment, and present a review of relevant literature. Written informed consent was obtained from all patients for publication of this report.Toxocara canis, and albendazole was given to the patient for 2 weeks. At the end of the treatment, the OCT displayed the appearance of a stage III macular hole , as the posterior hyaloid was detached from the fovea  overlying a yellowish macular lesion estimated at two papillary diameters. It was not pigmented Figure A. FluoreA 28-year-old woman presented for sight loss in her left eye. Her visual acuity was 20/20 in her right eye and 20/100 in her left eye. Anterior chamber examination showed granulomatous keratic precipitates in the left eye but no Tyndall effect. Fundus examination showed bilateral optic disc edema and a macular hole on the left. Fluorescein angiography confirmed the bilateral optic nerve head diffusion and showed bilateral phlebitis Figure A,B. BothTreponema pallidum hemagglutination assay-Venereal Disease Research Laboratory (TPHA-VDRL). His visual acuity was 20/20 in his right eye and counting fingers in his left eye. Slit-lamp examination showed a mild Tyndall effect in the anterior chamber and a macular hole  an The relatively old references on the low prevalence of macular hole in uveitic patients could be explained by the fact that OCT is a recent tool. Our cases also show the importance of the SD-OCT in uveitis to confirm cystoid macular edema, the principal sight-threatening effect in uveitis . OCT canSD-OCT is useful for the preoperative evaluation of the inflammatory secondary epiretinal membrane to evaluate the benefits of the procedure: in our first case, in which an epiretinal membrane developed, there was a partial posterior vitreous detachment, and so there is a persistent risk of macular hole recurrence in a such damaged and weakened retina, with very small hope of visual improvement.The occurrence of a macular hole linked to posterior uveitis is an uncommon but possibly underestimated cause of sight loss. Etiological treatment seems to lead to macular hole closure in most such cases. SD-OCT is very useful for assessing the evolution of these cases and should be performed whenever there is a posterior involvement or unexplained sight loss in uveitis patients.The authors declare that they have no competing interests.NB wrote the manuscript, synthetized the cases, and made the literature review. PLC was the co-author; he corrected and directed the redaction of the manuscript and followed the cases. FC, EL, HJM, AF, and LP participated to the management of the cases and the diagnosis. FC, FB, and CB participated in the design of the study and its coordination. All authors read and approved the final manuscript.


Several suicide and suicidal behaviour risk factors are highly prevalent in asylum seekers, but there is little insight into the suicide death rate and the suicidal behaviour incidence in this population. The main objective of this study is to assess the burden of suicide and hospital-treated non-fatal suicidal behaviour in asylum seekers in the Netherlands and to identify factors that could guide prevention.We obtained data on cases of suicide and suicidal behaviour from all asylum seeker reception centres in the Netherlands . The suicide death rates in this population and in subgroups by sex, age and region of origin were compared with the rate in the Dutch population; the rates of hospital-treated suicidal behaviour were compared with that in the population of The Hague using indirect age group standardization.The study included 35 suicide deaths and 290 cases of hospital-treated suicidal behaviour. The suicide death rate and the incidence of hospital-treated suicidal behaviour differed between subgroups by sex and region of origin. For male asylum seekers, the suicide death rate was higher than that of the Dutch population . No difference was found between suicide mortality in female asylum seekers and in the female general population of the Netherlands . The incidence of hospital-treated suicidal behaviour was high in comparison with the population of The Hague for males and females from Europe and the Middle East/South West Asia, and low for males and females from Africa. Health professionals knew about mental health problems prior to the suicidal behaviour for 80% of the hospital-treated suicidal behaviour cases in asylum seekers.In this study the suicide death rate was higher in male asylum seekers than in males in the reference population. The incidence of hospital-treated suicidal behaviour was higher in several subgroups of asylum seekers than that in the reference population. We conclude that measures to prevent suicide and suicidal behaviour among asylum seekers in the Netherlands are indicated. In 2008 an estimated 383 000 asylum applications were recorded in 51 Western countries, including most European countries, the USA and Canada [Recent reviews quite clearly identify mental disorders, such as depression, schizophrenia, substance use disorder, personality disorder and comorbid anxiety disorder, as the most prominent risk factors for suicide -5. OtherIt is known that several suicide and suicidal behaviour risk factors are highly prevalent in asylum seekers -13. HoweInsight into the burden of suicide death and suicidal behaviour is necessary in order to determine whether extra preventive efforts are required for asylum seekers; such insight could also provide directions for prevention ,17. The The specific steps taken were as follows:• to assess the suicide mortality rate and the incidence of hospital-treated suicidal behaviour in asylum seekers, and compare it to the Dutch population and the population of The Hague;• to assess the extent to which health staff were aware of the existence of mental health problems in asylum seekers prior to the date of hospital-treated suicidal behaviour and the extent to which these cases were under mental health treatment prior to the date of the hospital-treated suicidal behaviour;• to determine which methods were used by cases of suicide death and of hospital-treated suicidal behaviour and what stressors were reported in cases of hospital-treated suicidal behaviour.Asylum seekers in the Netherlands are housed in residential reception centres, managed by the Central Agency for the Reception of Asylum Seekers (COA). Asylum seekers are free to leave the centres and are allowed to work for a limited number of weeks per year. They are entitled to full access to health care. Up until 2008, COA contracted a health insurance company to arrange curative health care for asylum seekers through access to mainstream health services, including inpatient and outpatient mental health services. COA also contracted local public health services (GGDs) to provide preventive health services and specific nurse practitioner services, collectively called Community Health Services for Asylum Seekers (MOA). MOA nurse practitioners working at the reception centres provided a bridge function between the asylum seeker and regular health care. Asylum seekers with mental health problems could be offered up to five consultations with a public health doctor specialized in refugee health care to clarify any mental health or other health problems and needs. Asylum seekers could be referred, with or without these consultations, to the mental health service and/or offered preventive interventions. Since January 2009 the health system for asylum seekers in the Netherlands has changed.We collected data on suicide deaths and hospital-treated suicidal behaviour cases that took place among asylum seekers living in reception centres in the Netherlands from 2002-2007. Under a national protocol, public health doctors and nurses at the MOA were required to complete a standard form for every case of death  and suicidal behaviour . NeitherRepeated suicidal behaviour cases were included in the database as separate events if these were reported on different forms. Data about suicide deaths were extracted from the general asylum seeker mortality database . StatistWe grouped countries of origin into regions according to the United Nations High Commissioner for Refugees (UNHCR) classification . Some reThe suicidal behaviour notification form included open questions on medical history, stressors and methods used. Classification of these variables was performed by SG and AK, who also classified the methods used in suicide deaths. The form also contained dichotomous questions on whether the health professional knew of any mental health problems in the asylum seeker prior to the suicidal behaviour (without any further specification) and whether the asylum was using mental health treatment prior to the suicidal behaviour. No further specification of mental health problems and treatment were included as the questions were included with an exploratory objective.The COA (box 1) provided data on the number of asylum seekers by sex, age group and country of origin on every first day of the month in the study period. These were used to calculate estimates of the person years spent in reception facilities. These data are considered good estimates for the denominator.Comparison of the suicide death rate in asylum seekers with that of the general population of the Netherlands was performed using 2002-2007 data from the CBS national mortality register .The rates used - the suicide mortality rate and the incidence rate of hospital-treated suicidal behaviour - were calculated for the population aged 15 years and older per 100 000 person-years. The numerators were the reported number of suicide deaths and cases of hospital-treated suicidal behaviour. Person-years at risk were calculated on the basis of the occupancy numbers for asylum seeker centres on the first day of each month during the study period.Rate ratios were calculated using indirect standardization . The obsTo make comparisons across subgroups of asylum seekers, with regards to the percentage of people with hospital-treated suicidal behaviour known to have had mental health problems and the percentage receiving treatment for these problems, we calculated prevalence rate ratios and 95%CI with SISA's t-test procedure .In total 35 cases of death from suicide were recorded table , resultiThere were 290 cases of suicidal behaviour treated in hospital . The other stressors were: relationship issues (21.2%), loss of a family member (13.1%), transfer between centres (9.2%), substance abuse (9.2%) and living conditions (3.9%).The distribution of methods used differed considerably between cases of death from suicide and hospital-treated suicidal behaviour table . In suicThis study is, to our knowledge, unique in the length of the study period, the number of cases observed and the combination of suicide death and suicidal behaviour data. The suicide death rate was high in male asylum seekers compared with the reference population, whereas no conclusion could be drawn for females due to the small number of cases. The hospital-treated suicidal behaviour incidence was not homogenously distributed in the asylum seeker population. In several subgroups the rates were higher than in the reference population, but lower rates were also found. Among African asylum seekers, male suicide mortality was high, but male and female hospital-treated suicidal behaviour rates were low. Among Europeans, the suicide mortality rate was low for males and hospital-treated suicidal behaviour rates were high for both sexes. For Middle East/South West Asians, only hospital-treated suicidal behaviour rates were increased. Health professionals were aware of mental health problems existing prior to the hospital-treated suicidal behaviour in nearly 80% of the cases.All suicide death notifications contained clear case descriptions, so we do not expect any overestimation with regard to suicide death. It is possible, as in other studies of this kind, that some suicide deaths have not been included because they may have been coded under other external causes of death . Cases oThe results of this study should be interpreted with caution because of the small number of cases, particularly for suicide death. No conclusion could be drawn with respect to suicide mortality among females because of the small number of cases. Comparison with data from other studies has to be done cautiously because of differences in data sources, particularly for the hospital-treated suicidal behaviour rate. The use of suicidal behaviour reference data for the city of The Hague may have influenced our results. The incidence rate in The Hague is 10-20% higher than estimates for the Netherlands . This imThe current study suggests that suicide death is higher in male asylum seekers than in the general male population of the Netherlands. The incidence was higher than in the reference population for several regions of origin, despite possible underreporting. As in many populations, in asylum seekers suicide was more prevalent in men and hospital-treated suicidal behaviour more prevalent in women . The malThe regional differences found in hospital-treated suicidal behaviour rates are fairly consistent with data from Sweden, where the rates showed considerable differences between countries and regions of origin, with the lowest risk among Africans . In geneThe majority of asylum seekers with hospital-treated suicidal behaviour were known to suffer from mental health problems. A recent review states that evidence on a relationship between PTSD and suicide or suicidal behaviour among refugees is limited . In a reThe much lower treatment rate of mental health problems in people with hospital-treated suicidal behaviour from Africa, compared with people from ME/SW Asian and CES European origin, is a concern. Low mental health treatment rates in African asylum seekers and refugees have been reported in other studies in the Netherlands and the UK ,31.Hanging was the most common method in deaths from suicide in asylum seekers; it is also the most common method in deaths from suicide in the general population, according to a European study into suicide methods . HoweverRelationship issues, loss of family members, and other stressful life events are associated with suicidal behaviour in the general population ,5, and aThe asylum procedure, however, is a stressor specific for this population. Asylum procedure recognition rates may well influence suicide death and suicidal behaviour rates. As recognition rates and other factors, such as composition of the asylum population, reception conditions and accessibility of health care for asylum seekers vary between countries and over time ,35, we eTraining physicians to recognize and treat depression and suicidal behaviour has already shown impressive effects in reducing suicide death rates in general populations and might contribute to reduction in asylum seekers as well . In paraThis study suggests that male asylum seekers are at increased risk of death from suicide in comparison with the population of the Netherlands. No conclusion could be drawn for females due to the small number of cases. For males and females the incidence of hospital-treated suicidal behaviour was higher for asylum seekers from ME/SW Asia and CES Europe than in the reference population and lower for asylum seekers from the African sub regions. The majority of people with hospital-treated suicidal behaviour from ME/SW Asia and CES Europe had received some form of mental health treatment prior to the hospital-treated suicidal behaviour. For asylum seekers from Africa the rate of mental health treatment seemed to be lower. On the basis of this study we conclude that targeted prevention of suicide death and suicidal behaviour in asylum seekers is indicated.Ethics Committee approval was not necessary as only anonymous data were used that were collected in the light of regular health service provision. The use of anonymous data for epidemiological studies is, in line with the medical ethical standards in the Netherlands, included in the privacy statement of the Community Health Services for Asylum Seekers.The authors declare that they have no competing interests.SG and AK designed the study; all authors critically contributed to the interpretation of the data and to the content of the article; all authors approved the final version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/484/prepub


We use the qualitative insight of a planar neuronal phase portrait to detect an excitability switch in arbitrary conductance-based models from a simple mathematical condition. The condition expresses a balance between ion channels that provide a negative feedback at resting potential (restorative channels) and those that provide a positive feedback at resting potential (regenerative channels). Geometrically, the condition imposes a transcritical bifurcation that rules the switch of excitability through the variation of a single physiological parameter. Our analysis of six different published conductance based models always finds the transcritical bifurcation and the associated switch in excitability, which suggests that the mathematical predictions have a physiological relevance and that a same regulatory mechanism is potentially involved in the excitability and signaling of many neurons. Understanding the changing electrophysiological signatures of neurons in different physiological and pharmacological conditions is a central focus of experimental electrophysiology because a key component of cell signaling in the nervous system. Computational modeling may assist experimentalists in this quest by identifying core mechanisms and suggesting pharmacological targets from a mathematical analysis of the model. But a successful interplay between experiments and mathematical predictions requires new analysis tools adapted to the complexity of high-dimensional computational models nowadays available. We use bifurcation theory to propose a mathematical condition that can detect an important switch of neuronal excitability in arbitrary conductance-based neuronal models and we illustrate its physiological relevance in six published state-of-the art models of different neurons. Detailed computational conductance-based models have long demonstrated their ability to faithfully reproduce the variety of electrophysiological signatures that can be recorded from a single neuron in varying physiological or pharmacological conditions. But the predictive value of a computational model is limited unless its analysis sheds light on the core mechanisms at play behind a computer simulation. Because conductance-based models are nonlinear dynamical models, their analysis often requires a drastic reduction of dimension. The reduced model is amenable to the geometric methods of dynamical systems theory, but the mathematical insight is often gained at the expense of physiological interpretability; hence the need for methodological tools that can relate mathematical predictions of low-dimensional models to physiological predictions in detailed conductance based models.reduced-order neurodynamics models a switch of excitability that is consistent with many physiological observations. More precisely, a transcritical bifurcation governed by a single parameter was shown to organize a switch from restorative excitability, extensively studied in most models inspired from the Hodgkin-Huxley model, to regenerative excitability whose distinct electrophysiological signature include spike latency, plateau oscillations, and afterdepolarizeation potentials.In recent work high-dimensional conductance-based models and that the resulting mathematical predictions have physiological relevance. Although purely mathematical in nature, the detection of the transcritical bifurcation relies on an ansatz that leads to a simple physiological interpretation: the switch of excitability is determined by a balance between restorative (those providing a negative feedback) and regenerative (those providing a positive feedback) ion channels at the resting potential. Because this simple balance equation can take many different physiological forms, it is potentially shared by very different neurons.The main contribution of the present paper is to show that this transcritical bifurcation, and the associated excitability switch, exist in a number of We use the balance equation to provide an algorithm to trace the transcritical bifurcation in arbitrary conductance-based models. We apply the algorithm to detailed conductance-based models of six neurons known to exhibit drastic changes in their electrophysiological signatures depending on environmental conditions: the squid giant axon After defining a novel classification of ion channels based on their restorative or regenerative nature, we briefly review the planar model presented in Conductance-based models of neurons describe the dynamic interaction between the membrane potential Fast gating variables: These variables have a time-constant in the millisecond range. They generate the rapid regenerative upstroke of an action potential. Prominent representatives of this family are the activation gating variables of fast voltage-gated sodium channels  variables: These variables gate too slowly to be strongly activated by single action potentials. They modulate neuronal excitability only over periods of many action potentials. Prominent representative of this family are the inactivation gating variables of transient calcium channels . Ion channels that do not possess a slow gating variable are neither restorative nor regenerative and are called neutral. Neutral ion channels solely regulate the “quantity” of excitability without affecting its “quality”.In view of their importance for neuronal excitability, we focus only on slow gating variables to classify ion channels: when the slow channel provides a negative feedback on membrane potential variations, we term the associated channel a It is important to observe that the restorative (resp. regenerative) nature of channels is not solely linked to the outward (resp. inward) nature of the current. For instance, transient sodium channels  are slow restorative, because their slow variable inactivates an inward current, inducing a negative-feedback on membrane potential variations. Similarly, potassium channels can be slow regenerative when their slow inactivation massively decreases the outward current, like in the case of A-type potassium channels.Although elementary, the classification above seems novel. It is motivated by the central message of this paper, that the balance between regenerative and restorative ion channels in slow timescale determines its neuronal excitability type. In the remainder of the paper, we simply write restorative (resp. regenerative) for slow restorative (resp. slow regenerative) channels.Planar models - that only consist of two state variables - have been instrumental to study excitability since the early days of neurodynamics Motivated by the phase portrait of such an empirical reduction of the Hodgkin-Huxley model augmented with a calcium channel The spike generation mechanism in the phase portrait of The phase portrait in A simple mathematical distinction between the two phase portraits shown in The model is said to be restorative at steady state if:The model is said to be regenerative at steady state if:The planar model (1) can smoothly switch from restorative to regenerative excitability, with a transition occurring for A convenient way to algorithmically track this excitability switch is to use bifurcation analysis and to impose that the critical condition (2) coincides with a bifurcation of the model, which imposes the additional algebraic conditionSimultaneously imposing (2) and (3) impliesThe theory of bifurcation unfolding is further exploited in Our main contribution in the present paper is to show that the diagram in We start by grouping gating variables of a given conductance-based model according to their time scales. The family We will detect a switch from restorative to regenerative excitability by mimicking the two-dimensional algorithm of the previous section. We first impose the bifurcation condition As for the planar model (1), we track the switch between restorative and regenerative excitability by imposing the high-dimensional equivalent of the balance condition (2). We therefore look for solutions of (6) satisfying the ansatzThe two conditions (6) and (7) now implyThe singularity condition (8) is the high-dimensional counterpart of the regenerative slow gating variables restorative slow gating variables We split The model is said to be restorative at steady state if:The model is said to be regenerative at steady state if:The Hodgkin-Huxley (HH) model At first sight, the balance condition (13) cannot be satisfied because both sodium and potassium channels are restorative channels according to their corresponding kinetics in the model, and in agreement with our proposed classification. This is consistent with the fact that the excitability of the HH model is always restorative in physiological conditions.However, it was long recognized i.e.The two conditions (12) and (14) can numerically be solved to determine the critical values The bifurcation diagram in model 1, . As  is dy state ,middle. tractors ,right. TIn vitro recordings of the squid giant axon with isotonic extracellular The same qualitative excitability switch was described by Rinzel in The mathematical analysis of the previous section follows an algorithm that allows to detect a transcritical bifurcation in generic conductance based models of arbitrary dimension and to track associated excitability switches. The steps of the algorithm are summarized in For the sake of illustration, we apply this algorithm to a number of published conductance-based models and show that all these models can switch between restorative and regenerative excitability through a transcritical bifurcation, as sketched in Model equations and parameters are taken from Classification of gating variables as fast , slow , and adaptation  variables. The model includes fast sodium channels  and (iv) of the algorithm above gives the following results :The resulting bifurcation diagram is drawn in These excitability switches induce the predicted changes in the electrophysiological signatures, as illustrated in Model equations and parameters are taken from Classification of gating variables as fast , slow , and adaptation  variables. The model includes fast sodium channels Balance equation and choice of the bifurcation parameter. The only source of regenerative excitability is provided by T-type calcium channels. The associated balance equation readsi.e.T-type calcium channels are dynamically regulated by a (slow) voltage-gated inactivation Solving Steps (iii) and (iv) of the algorithm above gives the following results:ches see .Model equations and parameters are taken from Classification of gating variables as fast , slow , and adaptation  variables The model includes fast sodium channels Balance equation and choice of the bifurcation parameter The only source of regenerative excitability is provided T-type calcium channels. The associated balance equation has the same structure as for the thalamic relay neuron model considered above. Along the same line, we choose the T-type calcium channel inactivation i.e.Solving Steps (iii) and (iv) of the algorithm above gives the following results:As in the case of the thalamic relay neuron model, the T-type calcium channel inactivation generates a dynamical switch between restorative and regenerative excitability, significantly affecting neuron response to external inputs .Model equations and parameters are taken from Classification of gating variables as fast , slow , and adaptation  variables. The model includes fast sodium channels The intracellular calcium conductance is fixed at Balance equation and choice of the bifurcation parameter. As in the case of DA neurons, the source of regenerative excitability is provided by L-type calcium channels, and we take their maximal conductance Solving Steps (iii) and (iv) of the algorithm above gives the following results:Model equations and parameters are taken from Classification of gating variables as fast , slow , and adaptation  variables. The model includes the following ion channels: fast . The extended hysteresis is what determines the specific electrophysiological signature of regenerative excitability: a pronounced spike latency, a possible plateau oscillation, and an after depolarization potential. As a consequence, those features cannot be robustly reproduced in physiologically plausible conductance based models of restorative excitability. Because those features are important markers of modern electrophysiology In conclusion, the bistability associated to regenerative excitability is specific in that it produces a robust electrophysiological signature in physiologically plausible parameter ranges and consistent with many experimental observations. It is in that sense that the balance equation delineates a switch of excitability of physiological relevance.Early in the history of neurodynamics Class I: The spiking frequency vs. input current amplitude (f/I) curve is continuous, i.e., the spiking frequency continuously increases from zero to high-frequency firing as the input current amplitude rises. Class I excitability is also referred to as “soft” excitation.Class II: The f/I is discontinuous, i.e., the spiking frequency abruptly switches from zero to high-frequency firing as the amplitude of the applied current is raised above a certain threshold. Class II excitability is also referred to as “hard” excitation.Class III: The spiking frequency is zero for all amplitudes of the applied current. Transient action potentials can be generated in response to high-frequency stimuli.Because regenerative excitability exhibits hard excitation, it is a physiologically distinct subtype of Class II excitability.Bifurcation theory helps relating this physiological classification to mathematical signatures of the associated neuron models. Distinct bifurcations delineate the different excitability classes as well as the different excitability mechanisms within a given class. They are summarized in Ermentrout Our recent paper Motivated by a geometric analysis of a qualitative phase portrait, we have proposed an algorithm that easily detects a transcritical bifurcation in arbitrary conductance based models. Owing to the special structure of such models, the algorithm leads to solving an algebraic equation of remarkable simplicity and physiological relevance: a balance between slow restorative and slow regenerative ion channels. The condition is also robust because the balance is independent of the detailed kinetics, even though it critically relies on a classification of variables in three well separated time-scales, in good agreement with what is known on ion channels kinetics The detection of the transcritical bifurcation relies on the sole existence of a physiological balance between restorative and regenerative ion channels. Given that all neuronal models possess restorative sodium and potassium channels, this implies that a transcritical bifurcation exists in every conductance-based model that possesses at least one regenerative ion channel. Moreover, the channel balance, and therefore the TC bifurcation, are readily detectable in a model of arbitrary dimension (both in the state and parameters): the balance (9) simply defines a hypersurface in the parameter space that can algebraically be tracked under arbitrary parameter variations. An illustration was provided on the GC model above.In spite of its ubiquity and of its physiological significance, we are not aware of an earlier reference to a transcritical bifurcation in conductance based models. A reason for this omission might be accidental: there are no regenerative channels in the seminal model of Hodgkin and Huxley  and Class II (“hard”) excitability. Regenerative (and restorative) excitability faithfully capture the presence (or the absence) of specific electrophysiological signatures of modern electrophysiology such as spike latency, afterdepolarization potentials, or robust coexistence of resting state and repetitive spikes.Although purely mathematical in nature, the transcritical bifurcation has a remarkable predictive value in several published conductance based models. In each of the six analysed models, the proposed algorithm identifies a physiological parameter that acts as a tuner of neuronal excitability in a physiologically plausible range and in full agreement with existing experimental data. At the same time, the distinct nature of the regulating parameter, which can be either the maximal conductance or the inactivation gating variable of a regenerative ion channel depending on the neuron model, is associated to distinctly different regulation mechanisms.The classification of gating variables in three distinct time scales is an essential modeling step both for the proposed algorithm and for the reduction of full conductance-based models to low-dimensional models that can be used in population studies In each of the analysed conductance-based models, the balance equation responsible for the switch of excitability is satisfied for a set of parameters that is close to the published parameter values. This observation supports the hypothesis that neuronal excitability is tightly regulated by molecular mechanisms and that the influence of the channel balance condition on neuronal excitability might play a role in neuronal signaling.http://www.mathworks.com) the original models as described in the associated papers. The phase portraits in http://inkscape.org). The phase portraits in Numerical temporal traces of the different neurons , 6, 8, 9Supplementary Material S1Algorithmic detection of a transcritical bifurcaton in conductance-based models.(PDF)Click here for additional data file.


Cross-country differences in dietary behaviours and obesity rates have been previously reported. Consumption of energy-dense snack foods and soft drinks are implicated as contributing to weight gain, however little is known about how the availability of these items within supermarkets varies internationally. This study assessed variations in the display of snack foods and soft drinks within a sample of supermarkets across eight countries.Within-store audits were used to evaluate and compare the availability of potato chips (crisps), chocolate, confectionery and soft drinks. Displays measured included shelf length and the proportion of checkouts and end-of-aisle displays containing these products. Audits were conducted in a convenience sample of 170 supermarkets across eight developed nations , and United States of America (US)).The mean total aisle length of snack foods (adjusted for store size) was greatest in supermarkets from the UK (56.4 m) and lowest in New Zealand (21.7 m). When assessed by individual item, the greatest aisle length devoted to chips, chocolate and confectionery was found in UK supermarkets while the greatest aisle length dedicated to soft drinks was in Australian supermarkets. Only stores from the Netherlands (41%) had less than 70% of checkouts featuring displays of snack foods or soft drinks.Whilst between-country variations were observed, overall results indicate high levels of snack food and soft drinks displays within supermarkets across the eight countries. Exposure to snack foods is largely unavoidable within supermarkets, increasing the likelihood of purchases and particularly those made impulsively. There has been a continued growth in global obesity rates over recent decades although the trajectory of these increases has varied across developed nations ,2. The hSnacking behaviours have increased in parallel with obesity prevalence -8. EvideEnvironmental factors including opportunities to purchase and consume food are increasingly seen as an important determinant of dietary behaviours . Within et al. who conducted one study across 19 US cities [Supermarket retailers have long known that the placement and marketing of products is a key determinant of purchasing decisions with marketing tactics being particularly important for sales of impulse items in comparison with staples ,36-40. MS cities  and anotS cities ). These S cities ,50. All In the present paper we use data gathered in a standardized manner from supermarkets in eight different countries to examine the availability of snack food  and soft drinks in the shelves, at checkouts and in end-of-aisle displays. Shelf space of fruit and vegetables were also assessed for comparative purposes. Our focus on energy-dense snack foods and soft drinks was based on the above mentioned established links between consumption of such products and health and the fact that consumption of such products is common across the eight developed countries. International comparison studies of the within-store food environment such as this are an important way of placing local findings into a global context and can provide significant insights for policy and advocacy toward healthier food environments.A total of 170 supermarkets were audited across selected cities in eight developed countries  dedicated to each of the four snack food and beverage groups  was measured using a measuring wheel or measuring tape. This involved measuring from the point in the aisle where the snack food category began to where the display of that category ended. In the stores from the Bethesda/Washington DC area, a measuring device was not available and instead the length was determined by calibrated length of paces. If an item (e.g. confectionery) was displayed in multiple aisles, the total length across the multiple aisles was summed. For fruits and vegetables, the length of shelf space (refrigerated and un-refrigerated) as well as the circumference of island displays dedicated to fresh fruits and vegetables were measured and summed.Auditors assessed whether snack foods were available at each checkout and at end-of-aisle displays at both the front and the back of an aisle. Using a checklist, the presence of each of the following items was recorded: 1) potato chips; 2) chocolate; 3) confectionery; 4) soft drink – regular; 5) soft drink –diet. Multiple item types could be recorded for each checkout or end-of-aisle display.Total store size was calculated as total length of all aisles in the supermarket measured using a measuring wheel, measuring tape, or calibrated paces.The estimated marginal mean of the total aisle length of snack food items and the aisle length of individual snack food items was calculated adjusting for total store size across all countries. The ratio of aisle length dedicated to snack foods compared to fruits and vegetables was calculated by dividing the total aisle length of snack foods by the total length of displays of fruits and vegetables. Shelf length of each product type and the ratio of snack food to fruits and vegetables for each country were ranked from the most (1) to the least (8). The proportion of total snack food aisle length dedicated to each of the snack food and soft drink items was calculated for each store to produce a within-country mean. This measure allowed us to assess the relative amount of each item within countries. For checkouts and end-of-aisle displays, results are reported as a percentage  of the total number of checkouts or end-of-aisle displays that displayed any snack food item.Included data originated from Oceania, North America and Europe. In Oceania, in addition to a sample of 35 supermarkets from Melbourne, Australia on which we have previously reported ,43, dataAisle length dedicated to each snack food type is presented in Table The proportion of the total snack food aisle length dedicated to each type of snack food is presented in Figure The only sample of supermarkets in which less than half of all checkout displays featured any of the snack foods or soft drinks assessed were those in the Netherlands (41%) Figure . In everAustralian supermarkets also exhibited the highest percentage (39%) of end-of-aisle displays featuring snack foods or soft drinks, with the proportion from the samples in other countries ranging from 16%  to 30% (Canada) Figure . AdditioThis study investigated the exposure to energy-dense snack foods  and soft drinks in a sample of supermarkets across selected cities in eight developed countries. The shelf length of snack foods and the presence of these foods at checkouts and in end-of-aisle displays were assessed with noticeable variations detected between countries. UK supermarkets had the greatest aisle length devoted to chips, chocolate and confectionery, while soft drink aisle length was greatest in Australia. The proportion of both checkouts and end-of-aisle displays containing snack food was also highest in the Australian supermarkets sampled. In every country other than the Netherlands, snack foods were present at over 70% of checkouts.From the results of this cross-sectional study, we are not able to discern whether variation is a result of differences in demand between countries, or whether supply is driving demand. It is likely that both are contributing. Demand may be driven strongly by cultural norms and traditional diet preferences. Influences on the supply side of the equation may include specific commercial arrangements between retailers and the food industry/suppliers, climatic differences between countries that influence the availability and price of supermarket items, agricultural policies such as the subsidisation of high-fructose corn-syrup production (for use as a sweetener in soft drinks) by the US government , import Some of the findings reported here can be compared with the results of previous studies from individual countries. A 2006 study from Melbourne, Australia reported that 99% of checkouts displayed snack foods or soft drinks  which isWhilst the broader dietary and health implications of supermarkets have been discussed elsewhere ,30, the While ecological data of the type reported from this study cannot infer causality, links between availability and national consumption patterns are of interest. In Dutch supermarkets, greater shelf space was allocated to soft drinks in comparison with the other snack foods assessed. This result correlates with the findings from the ENERGY study  in which extremely high soft drink consumption amongst Dutch children was reported . FurtherWhilst limiting snack food exposure in other settings such as schools and workplaces has been a focus of some public health campaigns ,62, the The major strength of this study is the within-store assessment of energy-dense snack foods and soft drinks conducted in a sample of supermarkets across cities in multiple countries using a standardized measurement tool. Multiple aspects of the within-store food environment were captured, including static displays of shelf space and dynamic displays at ends-of-aisles and checkouts. Previously, within-store assessments of supermarket snack foods have been rare, limited in their ability to compare findings between countries and did not include the multiple aspects of the supermarket snack food environment assessed here.We acknowledge that our definition of snack food was limited to four food categories. Other types of energy-dense snack foods not captured here are also available in supermarkets and in certain contexts these products may also be important snack foods (e.g. cookies and ice-cream in North America). While no universal definition of snack foods exists ,52, the Globally, supermarkets play an increasingly important role in shaping dietary behaviours. This study has highlighted the ubiquitous presence of energy-dense snack food items in the supermarkets of eight developed countries. Although differences were observed between countries, snack food was extremely common in the aisles of supermarkets in all countries. The prominence of snack foods in displays at checkouts and the ends-of-aisles may be an important determinant of snack purchases as such displays are largely unavoidable. The relatively low prominence of snack food in supermarkets in both the Netherlands (checkouts in particular) and New Zealand suggest that lessons about the reduction of such displays may be learnt from these countries.The authors declare that they have no competing interests.LET and AJC designed the audit tool with the assistance of SAM. LET and AJC oversaw the data collection within Melbourne and analysed the data for the entire sample. All other listed authors either coordinated or conducted the data collection within their country. LET and AJC wrote the first draft of the paper with the assistance of SAM and DAC. All authors assisted in drafting the manuscript with each author providing context-specific contributions. LET had primary responsibility for the final content. All authors read and approved the final manuscript.Appendix A. Supermarket snack food audit tool. *Please note the audit tool is freely available for other researchers to use . Please acknowledge the audit tool developers when reporting findings based on the use of this audit tool.Click here for fileAppendix B. Raw mean (unadjusted) shelf length of snack food items, soft drinks and fruits and vegetables . Appendix C. Percentage of checkouts in 170 supermarkets from 8 countries displaying individual snack food items and soft drinks. Appendix D. Percentage of end-of-aisles  displaying individual snack food items and soft drinks.Click here for file


The studies performed in laboratory animals and psychiatric patients suggest a possible role of limbic system-associated membrane protein (LAMP) in the mechanisms of psychiatric disorders. Stressful manipulations and genetic invalidation have revealed a role of the Lsamp gene in the regulation of anxiety in rodents. Besides that, Lsamp-deficient mice display reduced aggressiveness and impaired adaptation in novel and stressful environments. The behavioral effects of amphetamine were blunted in genetically modified mice. Recent pharmacological and biochemical studies point toward altered function of GABA-, 5-hydroxytryptamine-, and dopaminergic systems in Lsamp-deficient mice. Moreover, we found an association between the gene polymorphisms of LSAMP and major depressive disorder (MDD). Patients suffering from MDD had significantly increased ratio between risk and protective haplotypes of the LSAMP gene compared to healthy volunteers. However, the impact of these haplotypes for the function of LAMP is not clear and remains to be elucidated in future studies. The limbic system-associated membrane protein (LSAMP) gene gives rise to LAMP, which is a 64- to 68-kDa heavily glycosylated protein, structurally characterized by three immunoglobulin (Ig) domains . LAMP prThe first evidence for a role of the Lsamp gene in the regulation of emotional behavior came from a study where male Wistar rats were selected according to their exploratory behavior in the elevated plus-maze model of anxiety. Animals with lower exploratory activity (increased anxiety) had elevated levels of the Lsamp transcript in the periaqueductal gray . In the Two different Lsamp gene knockout mouse lines have been created. The first  was creaA receptor subunit genes is shifted in favor of the alpha2 subunit compared to the alpha1 subunit in the temporal lobe of Lsamp-deficient mice. This could be a possible reason for the reduced anxiety as well as the increased anxiolytic effect of diazepam in Lsamp-deficient mice , a technique that has often been shown to abolish phenotypic deviations in knockout mice, and to social isolation, a stressful manipulation, after which all the mice were tested in a behavioral battery. EE abolished differences between the genotypes in body weight and anogenital sniffing, a behavior related to aggressiveness, and amplified the anxiolytic-like phenotype of Lsamp-deficient mice both in the plus-maze and motility box . IsolatiHuman data link LSAMP not only with anxiety, but also with a wider spectrum of psychiatric disorders: polymorphisms in the human LSAMP gene have been associated with panic disorder PD;  and maleP = 0.0009; P = 0.066). Therefore, this study (Our recent studies indicate that the LSAMP gene is possibly related to major depressive disorder (MDD) and PD . We deteis study  underlinA receptor subunits in favor of alpha2. This could be a reason for the reduced anxiety and increased anxiolytic action of diazepam in Lsamp-deficient mice (In conclusion, the studies described above, performed in laboratory animals and psychiatric patients, suggest a possible role of LAMP in the mechanisms of psychiatric disorders. The Lsamp gene seems to be involved in the regulation of emotional behavior in rodents as the elevated function of the Lsamp gene is accompanied with increased anxiety, whereas the genetic invalidation of the Lsamp gene leads to the reduction of anxiety in rodents. There is also a shift in the expression of GABAent mice . Furtherent mice . These bent mice . PatientThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Based on the KPCA-mapped feature densities, the MAP classifier successfully distinguished 91.8% voice records, with a sensitivity rate of 0.986, a specificity rate of 0.708, and an area value of 0.94 under the receiver operating characteristic (ROC) curve. The diagnostic performance provided by the MAP classifier was superior to those of the FLDA and SVM classifiers. In addition, the classification results indicated that gender is insensitive to dysphonia detection, and the sustained phonations of PD patients with minimal functional disability are more difficult to be correctly identified.Detection of dysphonia is useful for monitoring the progression of phonatory impairment for patients with Parkinson’s disease (PD), and also helps assess the disease severity. This paper describes the statistical pattern analysis methods to study different vocal measurements of sustained phonations. The feature dimension reduction procedure was implemented by using the sequential forward selection (SFS) and kernel principal component analysis (KPCA) methods. Four selected vocal measures were projected by the KPCA onto the bivariate feature space, in which the class-conditional feature densities can be approximated with the nonparametric kernel density estimation technique. In the vocal pattern classification experiments, Fisher’s linear discriminant analysis (FLDA) was applied to perform the linear classification of voice records for healthy control subjects and PD patients, and the maximum  Dysphonia is a type of phonation disorder with an impairment in the ability to produce normal voice sounds Quantitative measures of speech impairment could help assess the severity levels of speech impairment in PD patients and study the specific impaired speech parameters A number of novel speech measurement methods have been developed to assess dysphonic symptoms in the last decade The data set used in this study was donated by Little et al. The vocal vowels were recorded using a head-mounted microphone positioned at 8 cm from the lips. The microphone was calibrated with a Class 1 sound level meter (Brüel & Kjær Type 2238 Mediator) placed 30 cm in front of each subject The correlation matrix between pairs of vocal measures is shown in In this investigation, we performed the sequential forward selection (SFS) method We also implemented the kernel principal component analysis (KPCA) to project the SFS features onto the two-dimensional mapping space. The PCA makes the orthogonal transformation to convert multivariate measures into some linearly uncorrelated principal components. The KPCA is a kernel-based extension of PCA method that conducts a nonlinear feature mapping in the kernel Hilbert space In the present work, we used the nonparametric kernel density estimation technique in order to provide the vocal pattern distribution of the KPCA-mapped features. The principle of the kernel density estimation uses the finite observed pattern scatters to approximate the nature of class distributions. Let the vector The bivariate Gaussian kernel function is presented asBecause the KPCA produces the orthogonal projection for the principal components, the correlation coefficient between the first and second principal components is equal to zero. Hence, the covariance matrix that determines the spread width of the Gaussian kernel function is a diagonal matrix, written as a posteriori (MAP) rule  a posteriori probability a posteriori probability a priori probability a posteriori probability With the estimated class-conditional densities of KPCA features, we employed the maximum In addition to the MAP classifier, we also implemented the SVM for classification performance comparison. The SVM is a kernel-based artificial neural network, which trains the network parameters to minimize the structural risk We also employed the Fisher’s linear discriminant analysis (FLDA) to perform the binary classification of vocal patterns. The FLDA does not require the assumptions that the patterns of different groups are with the normal distributions or equal class covariances. The FLDA searches the parameter vector In the present study, we implemented the 5-fold cross-validation method to evaluate the classification performance for each classifiers. The whole data set was partitioned into five disjoint subsets. Four subsets were used to train the classifiers, and the remaining subset was used for testing. The procedure was repeated for five trials, each time using a different subset for validation.The SFS method selects the MDVP: F0, MDVP: Jitter (%), DFA, and Spread2 as dominant measurements. It can be observed from It is worth noting from The selected features: MDVP: F0, MDVP: Jitter (%), DFA, and Spread2 provided the useful information about pathological voice in different clinical aspects. The fundamental frequency F0 quantifies the vibration frequency of the vocal folds. The period perturbation measure jitter corresponds to the cycle-to-cycle variation in fundamental frequency. The interruptions caused by Parkinson’s disease in the nervous paths could result in neurogenic paralysis of the recurrent laryngeal nerves, the superior laryngeal nerves, or the vagus nerves. The irregular vibration of the vocal folds would change the mean of F0, frequency variability (jitter), and speech amplitude, which could be measured in the phonation course of a sustained vowel. On the other hand, the DFA is used to describe the stochastic self-similarity properties of the noise caused by turbulent airflow in the vocal tract. Breathiness and other dysphonic voice caused by incomplete vocal fold closure would lead to an increase of the DFA value The present study does not require the input data normalization procedure. Little et al. Effective dysphonia detection provides more quantitative analysis of phonation disorders, toward better medical or behavioral treatments for speech improvement. In the present study, we studied the correlation matrix of the vocal measures that indicate the period, amplitude, and nonlinear perturbations in sustained vowel records. The dominant vocal measures of MDVP: F0, MDVP: Jitter (%), DFA, and Spread2 were selected by the SFS method, which could reduce the dimensions for pattern analysis. The nonparametric kernel density estimation method established the visible bivariate distributions of the KPCA-mapped feature densities. Based on the estimated feature densities, the MAP classifier was able to provide excellent classification performance, superior to that of the FLDA classifier and the SVM with RBF kernels. The experimental results demonstrated the merits of feature dimension reduction and kernel density modeling for vocal pattern analysis. The highest true positive rate (sensitivity) and minimal number of misclassified subjects also showed the effectiveness of the MAP classifier in the detection of phonation disorders. The relatively small size of phonation data limited the nonlinear classification capability of the SVM classifier. From the present work, we also conclude that the gender is not a sensitive factor for phonation disorders, and the PD patients with minimal functional disability are more likely to be incorrectly identified in the dysphonia detection. Noting that half of the SFS-selected vocal measures were generated by the nonlinear dynamics analysis tools, it is believed that the development of nonlinear vocal oscillation measurements has high potential in monitoring the progression of phonatory impairments in future studies.


Controlling tumour margins in head and neck surgery is of the utmost importance in preventing loco-regional spread and distant metastasis, which will ultimately lead to a significant reduction in morbidity and mortality. We comment on the surgical margins in photodynamic therapy and photochemical internalization. Several studies assessing diseased tissues in the head and neck region have identified two clinic-pathological parameters, the surgical margin and nodal involvement, which are of utmost importance in assessing tumour-related progression, recurrence, morbidity and mortality .The surgical margin concept has been around for sometime now. It represents the visible margin of macroscopically tumour-free area during surgery or histopathologically proven tumour-free area during processing of the specimen. The status of this margin has been identified to play a vital role in assessing disease status in the head and neck. For example, the presence of non-cohesive invasive front, dysplasia at margin, lympho-vascular invasion, nerve invasion and bone/cartilage may suggest aggressive cancerous growth which is more likely to resist adjuvant therapy and have high recurrence rate .The traditional treatment for any cancer may include 3 modalities: surgery, radiotherapy and chemotherapy. Development in scientific methodology and clinical research has lead to identification of other modalities that were found superior to the traditional ones for specific diseases of certain stage and grade , also the identification of other non-traditional adjuvant therapy that could improve the efficacy of other treatments or sometimes act independently (i.e. immunotherapy).When managing head and neck disease, surgery continue to be the primary intervention with chemo-radiation as adjuvant therapy; but have been applied as neo-adjuvant in certain cases. Keeping an open mind in cancer management is a must as no "magic bullet" has been identified to date and most interventions are equally effective, leading mostly to poor survival rates in most cancers.Over the last 2 decades, photodynamic therapy (PDT) was introduced as a minimally-invasive surgical modality in cancer management and several studies have proved its usefulness in oncological care .Using different photo-sensitizers, PDT successfully targeted pathologies in the head and neck, skin, brain, lung, pancreas, intra-peritoneal cavity, breast and prostate. The resultant photochemical reaction  lasts for few hours and leads to selective injury to the target tissue. All the clinical studies published on this technology showed that PDT is comparable to all the three conventional modalities  when it comes to disease mortality in the head and neck but identified PDT to be superior as it causes much less morbidity ,3.The growing body of evidence regarding PDT's efficacy suggests that it will have a leading role in minimally-invasive surgical oncology. Long-term studies showed that the outcome improves when PDT is offered on a repeatable basis rather than one time only. A recent study on T1/T2 oral cancer showed that 3 rounds of PDT are as successful as surgery in terms of mortality with minimal morbidity. The repeatability is required as residual or recurrent tumour islands have been identified in previously treated PDT-margins , according to the study . It is wIt is hoped that with the development of third generation photo-sensitizers or advancement in photodynamic applications , a real solution to surgical margins problem in PDT may be found.in vivo approach to site-specific cancer therapy via photochemical internalization. The outcome of the study revealed synergetic effect of combing photo-activation of photosensitizer and gelonin and the resultant PCI reaction [Photochemical internalization (PCI) is a novel technology facilitates the delivery of macromolecules into cytoplasm. It can best be described as sub-lethal PDT facilitating the effect of chemotherapy. The initial mechanism and practical application was described by Berg et al. in 1999 . In 2001reaction . These freaction .in vitro study by Norum et al. [A recent m et al.  had showcytosol by photochemical rupture of the endocytic vesicles and that PCI caused larger necrotic areas and the regrowth in the peripheral zone was almost completely inhibited after PCI. This study suggested that the PCI effect may result in tumour clearance in the peripheries  of the treated cancerous lesions.The first PCI trial in humans, using amphinex as the photosensitiser and bleomycin as the chemotherapeutic agent are taking place at University College London Hospital. The trial clinical results, when published, will help shed light on the real effect of PCI on the surgical margins or peripheries of human pathologies.Controlling tumour margins is of the utmost importance in preventing loco-regional spread and distant metastasis, which will ultimately lead to a significant reduction in morbidity and mortality.Colin Hopper is the principal investigator of the PCI trial on human being carried at University College London Hospital, London. Waseem Jerjes was a sub-investigator of the PCI trial. The other authors declare no competing interests.All authors have contributed intellectually and to the writing of this manuscript. All authors read and approved the final manuscript.


Many drugs are available for control of hypertension and its sequels in Nigeria but some are not affordable for majority of the populace. This serious pharmacoeconomic question has to be answered by the nation’s health economists. The objective of this study was to evaluate the cost-effectiveness of drugs from 4 classes of antihypertensive medications commonly used in Nigeria in management of hypertension without compelling indication to use a particular antihypertensive drug.The study employed decision analytic modeling. Interventions were obtained from a meta-analysis. The Markov process model calculated clinical outcomes and costs during a life cycle of 30 years of 1000 hypertensive patients stratified by 3 cardiovascular risk groups, under the alternative intervention scenarios. Quality adjusted life year (QALY) was used to quantify clinical outcome. The average cost of treatment for the 1000 patient was tracked over the Markov cycle model of the alternative interventions and results were presented in 2010 US Dollars. Probabilistic cost-effectiveness analysis was performed using Monte Carlo simulation, and results presented as cost-effectiveness acceptability frontiers. Expected value of perfect information (EVPI) and expected value of parameter perfect information (EVPPI) analyses were also conducted for the hypothetical population.Thiazide diuretic was the most cost-effective option across the 3 cardiovascular risk groups. Calcium channel blocker was the second best for Moderate risk and high risk with a willingness to pay of at least 2000$/QALY. The result was robust since it was insensitive to the parameters alteration.The result of this study showed that thiazide diuretic followed by calcium channel blocker could be a feasible strategy in order to ensure that patients in Nigeria with hypertension are better controlled. Hypertension is a disturbance in hemodynamic function in which there is persistent abnormal elevation of systemic blood pressure, whether it is diastolic or systolic above the level of normal pressure of 140/90 mmHg.There is growing evidence that prevalence of hypertension is on the increase in most sub-Saharan African countries including Nigeria. A Meta Recent hypertension guidelines stress the usefulness of 4 classes of antihypertensive drugs i.e. thiazide diuretic, beta-blockers (BBs), angiotensin converting enzyme inhibitors (ACEIs), and calcium channel blockers (CCBs) which have been shown to be very effective compared to the others. These dThe hypertensive medication selected for evaluation was based on a published systematic review whose aim was to evaluate the medication which should be first-line drug of choice for hypertension. The stuThe model life cycle used to calculate the cost, effect and cost-effectiveness of the alternative interventions to manage hypertension is shown in Figure Quality Adjusted Life Years (QALYs) was used to quantify clinical outcome. The health related quality of life weights for the different states  were obtained from the data of a health utility state assessment carried out in Nigeria. To obtaA Null scenario was included in this model. The null scenario refers to the case where the patients at asymptomatic stage (1000 patients) are not receiving any of the antihypertensive medications under evaluation. The null scenario however, included the cost of management and the cost of hospitalization for the hypertension-related complications (stroke and CHD). The reason for including the null scenario in this model is to calculate the extra cost that will be incurred if the patients began to treat their hypertension at asymptomatic stage with any of the medications under study and also to evaluate if the patients in their asymptomatic stage who began treatment with any of the antihypertensive drugs will have a higher or lower quality of life years (QALYs) when compared to the case where the patients at their asymptomatic stage received no treatment (null scenario) until they had stroke or CHD. The extra cost  and the difference in QALY was used to evaluate which of the antihypertensive agents or null scenario is the most cost-effective.A web-based recalibrated Framingham risk score designed for estimating 10-year risk of stroke and CHD in seven British black and minority group was used to estimate the risk of stroke and CHD of the different age group. Since tCost was estimated from the providers’ perspective (third party payer). Providers’ perspective requires mainly the direct cost to be measured. In thisFor patients at the asymptomatic hypertension stage, their direct costs include cost of any of the antihypertensive medication under study and cost of physician visit. It was assumed that the medications are taken daily for 365 days in a year while physician visit was made to be monthly (i.e. 12 times per annum). For Stroke patients hospitalized, the direct costs used in the model were cost of medical therapy (mannitol and furosemide), in-patient stay, laboratory tests and physiotherapy. For CHD patients hospitalized, the direct costs used in the model were cost of medical therapy (nifedipine and nitroglycerin), in-patient stay and laboratory tests. The costs were calculated as annual costs under the following headings: cost for use of thiazide; cost for use of lisinopril; cost for use of nifedipine; cost for use of propranolol; cost to hospitalize stroke patients; cost to manage stroke patients; cost to hospitalize CHD patients; and cost to manage CHD patients. A triangular distribution was used to calculate the annual costs under the headings listed above.The cost of providing health care to hypertensive patients (asymptomatic) and those with hypertension-related complications in the null was estimated first before determining the incremental cost that will be incurred if the patients from their asymptomatic stage to hypertension-related complications (stroke and CHD) had consume any of the four antihypertensive drugs  under evaluation. The summary of the interventions cost are shown in Table Distributions appropriate for each variable were employed in order to capture the varying degree of inherent uncertainty in the variables used in the analysis Table . ProbabiThe application of net monetary benefit (NMB) approach has its importance in overcoming the problems associated with incremental cost-effectiveness ratios (ICERs). This waWhere NMB = Net monetary benefitQALY = Quality adjusted life yearsλ = Threshold ratioIn the net monetary benefit approach, a strategy or intervention is considered cost-effective if it produces a positive net benefit. On the The cost-effectiveness threshold (CET) used in this evaluation was $15,000 which is the maximum amount the providers’ will be willing to pay, to achieve the best therapeutic outcome for their clients. The CET used was just an arbitrary figure within range that will aid to obtain the final result.Cost-effectiveness acceptability frontiers were used to present the result of cost-effectiveness for the 3 different cardiovascular risk scenarios. The cost-effectiveness acceptability frontiers illustrate the probability of any intervention being optimal compared to all other competing alternatives. Cost-effectiveness frontier also illustrates the crossover when one intervention is substituted by the other as the one with the highest probability of being optimal and therefore provides useful information for policy makers. The majPopulation Expected Value of Perfect Information (EVPI) was carried out for the three cardiovascular risk scenarios to determine the opportunity cost surrounding the conclusion of the analysis. The popAcross the four anti-HTs under evaluation including null scenario, the highest NMB for each iteration was selected. The highest NMBs for all the iterations were averaged. The difference between this average value obtained and the highest averaged NMB across the different interventions was noted. In calculating the Discount Population for the 1000 patients over a period of 30 years, a discount rate of 3% (range of 0% - 5%) was used. The sum of the discount population over 30 years is the Effective Population. The Population EVPI was obtained by multiplying the Effective Population with the difference in NMB noted.The expected value of perfect information for parameters (EVPPI) was obtained by multiplying the effective population with the difference between the net-benefit with perfect information and the expected value with current information about the parameter(s). The EVPAll analyses  were carried out using Microsoft Excel .For the three cardiovascular risk groups, the yearly cost in the null scenario was the least. The null scenario also had the least QALYs in the three groups. In all the cardiovascular risk states (CVRSs), ACEI has the highest annual cost if used followed by calcium-channel blocker. ACEI has a low QALY in the medium and high risk state but the highest QALY in the low CVRS. Thiazide diuretic has a very low annual cost in the three states, the highest QALYs in the medium and high risk state but not in the low CVRS. In the low CVRS, at any threshold ratio , ACEI has the highest NMB followed by thiazide but in the medium and high CVRSs, thiazide has the highest NMB followed by calcium-channel blocker at any threshold ratio. For instance, in the medium risk, at threshold ratio of $15,000, the NMB of the various interventions are as follows: null scenario ($89799); thiazide ($101927); beta-blocker ($94094); ACEI ($98619); Calcium-channel blocker ($101780).The null scenario in the three cardiovascular risk groups has a 0 (zero) probability of being cost effective. In the low CVRS, ACEI has the highest probability of being cost effective (about 0.526) followed by thiazide diuretic (about 0.278). In the medium and high CVRSs, calcium-channel blocker has the highest probability of being cost effective (about 0.47 and 0.53) followed by thiazide diuretic (about 0.45 and 0.41) respectively.The application of cost-effectiveness acceptability frontier is to help determine which antihypertensive agent has the highest probability of being cost-effective when compared with other alternative drugs. For low cardiovascular risk state Figure , at no wPopulation expected value of perfect information analysis (EVPI) in Table Analysis for the expected value of perfect information for parameters (EVPPI) in Table From the result, thiazide diuretic among the four alternatives was the most cost-effective. This finding was consistent for the 3 cardiovascular risk scenarios. For low risk patients, lisinopril was the second most cost-effective option to implement but additional fund needs to be committed in order to achieve better health outcomes over thiazide diuretic. CCB was the second most cost-effective option for medium and high risk patients if additional fund is committed in order to achieve better health outcomes over thiazide diuretic. In the graphs, the probability that thiazide diuretic is cost-effective decreases as the CE threshold increases. This is so because beyond a willingness-to-pay of about $2,600/QALY, committing more funds does not yield a corresponding increase in QALY for thiazide. So, additional fund beyond $15,000/QALY is a waste of resource since there is no increase in clinical outcome. Beyond that limit, CCB should be considered.From the report of a recent Meta analysis aimed to quantify the benefits and harm of the major first-line anti-hypertensive drug classes, thiazide diuretic was the best choice for hypertension. Most ofThat an intervention is most cost-effective depends on what the providers are willing to pay per outcome. As a guide, WHO considers interventions to be cost-effective if they have incremental cost-effectiveness ratios (ICERs) that are less than three times the gross national income (GNI) per capita. It is pFrom the University of Toronto, in a published cost-effectiveness analysis of routine echocardiography in patients starting antihypertensive drug therapy, the result of the model showed that ACE-inhibitors cannot be recommended as antihypertensive first-line therapy in the patients under study. This waHowever, the result of this study does not completely support the guideline by the Sixth Report of the Joint National committee on prevention, detection, evaluation and treatment of high blood pressure (JNC- 6) which recommends the use of diuretics and beta-blockers as first-line antihypertensive drugs in the absence of compelling reasons to use other antihypertensive drugs. The resIn the context of research, with respect to this study, EVPI represent the maximum that providers can willingly pay for additional research, to inform the decision they make. The EVPThis analysis has some limitations which have to be considered when interpreting the results. In our Markov model to show a typical timeline of events consequent on hypertension, we made use of an algorithm designed from data obtained from Africans in Britain, which may not hold true for indigenous Africans and Nigerians in particular. The reason for use of those data in the model was because there was no published study that predicted cardiovascular events over time in Africans that could be used for this model.In conclusion, the result of this study shows that thiazide diuretic followed by calcium-channel blocker especially for medium and high risk patients is a cost-effective option in the management of patients with high blood pressure in Nigeria.Funding for this research, a project in partial fulfillment of the requirement for the award of a Bachelor of Pharmacy (B.Pharm) was provided partly by parents and friends of Okafor, C.E. The authors declare no conflict of interest.OIE, CEO and CCE designed the study. OIE designed the model while CEO and PO helped in gathering data. CEO wrote the first draft of the manuscript. All authors read and approved the final manuscript.


With the force something like a tsunami wave, a surge of genome-wide association studies (GWASs) in common complex diseases has flooded the recent literature and left us awash with data regarding the identification of causative genetic risk factors for cardiovascular disease such as hypertension. Nevertheless, the more slowly moving tide of the classical candidate gene approach also makes steady progress to clarify the interaction between gene function and pathogenesis of hypertension. Like most other common conditions the estimated effects of each genetic variant on blood pressure and the predisposition to hypertension is quite small, yet the delineation of genetic contribution could reveal new targets for risk reduction in cardiovascular disease.The main focus of this special issue is to highlight the genetic basis of hypertension and cardiovascular disease and outline recent progress in genomics. In addition, several successful investigations in common diseases are introduced as good examples of the potential for better understanding of hypertension using genomic approaches.In the first part of this issue, two papers provide clear reviews of the recent progress in the GWAS approach for hypertension and coronary artery disease. These papers elucidate not only the common findings in studies that, to a certain extent, disparate but also interprete these findings in the context of the advantages and limitations of GWAS. This context includes the contrast between the very strong (genome-wide) significance of associations and the relatively small phenotypic effects of each SNP. In terms of discovery potential, unexpected candidate genes obtained from GWAS provide fresh perspectives in hypertension research.But the genomic picture is for more complex than isolated SNPs. It involves the ways in which the sophisticated organization of the operational elements of the genome interdigitates to provide tissue and development stage-specific regulation and integration of gene expression. It also aligns these factors with phenotypic changes that can result. Two subsequent review articles illustrate these principles by showcasing a new cutting edge of cardiovascular research in the form of microRNAs (miRNAs) and scavenger receptors. Both papers disclose the potentials of these newcomers as therapeutic targets of cardiovascular disease.In a more focused review of candidate genes, the next 2 papers focus on gene polymorphisms of adrenergic receptors. K. Masuo examines the critical role of beta2- and beta3-adrenoceptors gene polymorphisms on hypertension or metabolic syndrome unequivocally. K. B. Boström et al. report that a polymorphism (Arg389Gly) of beta1-adrenoceptor gene is significantly associated with increased risk of obstructive sleep apnea (OSA) with hypertension.In the research using candidate gene approach, precise and appropriate phenotyping is important to identify small but significant genetic effect. G. D. Kitsios and E. Zintzaras reveal the protective effect of a haplotype of endothelial nitric oxide synthase gene (NOS3) for predisposition to hypertension. K. Sugimoto et al. point out that a polymorphism in the promoter region of regulator of G protein signaling-2 (RGS2) gene affects the difference of antihypertensive medication in a clinical trial. The last two papers extend the consideration of novel and unexpected concepts for cardiovascular research. A recent topic is the awareness of shared physiological mechanisms between osteoporosis and cardiovascular disease. F. Marini and M. L. Brandi elegantly review the genetic aspects of osteoporosis and touch on the shared mechanisms. The last manuscript by G. Mertens offers a unique perspective on these issues by zooming out to take an evolutionary view. To consider the underlying mechanisms of atherosclerosis, we have to take a larger view without becoming lost in details of the immediate.We hope that this special issue is useful for your research and is conducive to the incorporation of new concepts and methods in your own laboratory.Tomohiro KatsuyaTomohiro KatsuyaStephen B. HarrapStephen B. HarrapToshio OgiharaToshio Ogihara


The innate ability of the human cell to silence endogenous retroviruses through RNA sequences encoding microRNAs, suggests that the cellular RNAi machinery is a major mean by which the host mounts a response against contemporary retroviruses, such as HIV-1 and HTLV-1. Several recent publications have identified cellular miRNAs that target and hybridize to specific sequences of both the HIV-1 and HTLV-1 transcripts. However, much like the variety of host immune responses to retroviral infection, the virus itself contains mechanisms that assist in the evasion of viral inhibition through manipulation of the cellular RNAi pathway. Retroviruses can hijack both the enzymatic and catalytic components of the RNAi pathway, in some cases to produce novel viral miRNAs that can either assist in active viral infection or promote a latent state of infection. Here, we propose that HTLV-1 viral proteins contribute to the dysregulation of the RNAi pathway by altering expression of key components of the pathway. A survey of uninfected and infected cell lines revealed that Drosha was present at lower levels in all HTLV infected lines. Additionally, transfection of HeLa cells with Tax shows colocalization of Tax and Drosha in the nucleus (speckles), suggesting that the HTLV-1 viral transactivator physically interacts with Drosha and targets it to specific areas of the cell. This data suggests the direct interaction of HTLV-1 viral components with RNAi machinery proteins which may lead to their dysregulation in infected cells.


This Research Topic assembles for the first time a comprehensive selection of articles  on the bioluminescence resonance energy transfer (BRET) technology. BRET is a natural phenomenon known in several marine organisms. It relies on the non-radiative transfer of energy from an appropriate energy donor to an energy acceptor, provided that both are located at a distance lower than 10 nm [see Ref. . Since tin vivo studies are likely to provide new insights to the existence and physiological relevance of GPCR oligomerization. Not surprisingly, GPCR oligomerization is the main issue of four articles of this Research Topic (Many BRET assays have been developed to study the oligomerization of seven-transmembrane-spanning G protein-coupled receptors (GPCRs). The BRET technology provides an attractive way to study this phenomenon in intact cells without the need of solubilization of receptors from their natural membrane environment. The overwhelming majority of BRET-based studies conclude that GPCRs do indeed exist as dimers or higher-order oligomers when transfected into cells at physiological levels. Three of the articles of this Research Topic discuss BRET assays that have been developed to properly address the specificity of BRET signals obtained upon expression of different GPCRs , 4, 5. Tch Topic  ranging Apart from performing the proper control experiments, another important issue in the BRET field concerns the proper interpretation of stimulus-induced BRET signals. In the context of GPCR oligomerization, agonist-induced BRET signals can be generated by an agonist-driven oligomerization or agonist-induced conformational changes within preassembled oligomers. Discrimination between these two possibilities is not trivial but has become possible due to the development of BRET donor saturation experiments in the absence and presence of receptor stimulation , 9. ThisThe BRET technology has been extended toward other receptor families like tyrosine kinase receptors and cytokine receptors. This diversification demonstrates the general feature of this technique. These studies did not only address the question of receptor oligomerization but also monitored the real-time interaction of receptors with various effector molecules such as Grb2, PTP1-B, PLC-γ1, etc. This important aspect is discussed in the review article of Siddiqui et al. . ReceptoA more recent application of BRET concerns the development of biosensors to monitor downstream events of cellular signaling like the generation of second messengers and activation of intracellular kinases. These sensors are typically composed of the energy donor and acceptor separated by an assay-specific domain that changes its conformation upon second messenger binding or phosphorylation, thus modifying the position of the donor and acceptor and consequently the BRET signal. Similar sensors have been developed for FRET applications, which served as source of inspiration for the development of the BRET sensors. The articles from Salahpour et al.  and Xu eThe high reproducibility of BRET and the robustness of the measurements make BRET an interesting option for the design of high throughput screening assays. Two applications are discussed in this Research Topic. The first concerns the design of an assay for the identification of compounds that specifically activate GPCR heteromers  based onTaken together, this Research Topic provides an illustrative overview of the principles and applications of the BRET technology that should be of interest for any scientist interested in monitoring PPI in intact cells.


Intra-articular hardware penetration can occur during osteosynthesis of ankle fractures, jeopardizing patients' outcomes. The intraoperative recognition of misplaced screws may be difficult due to the challenge of adequate interpretation of specific radiographic views. The present study was designed to investigate the diagnostic accuracy of standardized radiographic ankle views to determine the accuracy of diagnosis for intra-articular hardware placement of medial malleolar screws in a cadaveric model.Nine preserved human cadaveric lower extremity specimens were used. Under direct visualization, two 4.0 mm cancellous screws were inserted into the medial malleolus. Each specimen was analyzed radiographically using antero-posterior (AP) and mortise views. The X-rays were randomly uploaded on a CD-ROM and included in a survey submitted to ten selected orthopaedic surgeons. The "Standards for Reporting of Diagnostic Accuracy" (STARD) questionnaire was used to determine the surgeons' perception of accuracy of screw placement in the medial malleolus. The selection of items was based on evidence whenever possible, therefore the "inconclusive" category was added. Inter and intraobserver variations were analyzed by kappa statistics to measure the amount of agreement.There was a poor level of agreement (kappa 0.4) both in the AP and in the mortise view among all the examiners. Associating the two x-rays, the agreement remained poor (kappa 0.4). In the cases in which there was a diagnosis of articular penetration, there was a poor agreement related to which of the screws was intra-articular. The number of "inconclusive" responses was low and constant, without a statistically significant difference between the subspecialistsThe routine intraoperative radiographic imaging of the ankle is difficult to interpret and unreliable for detection of intra-articular hardware penetration. We therefore recommend to reposition medial malleolar screws intraoperatively if there is any doubt regarding inadequate screw placement. Transverse fractures of the medial malleolus present in several different patterns affecting all ages. The importance of anatomic reduction and rigid internal fixation in displaced fractures of the medial malleolus has been emphasized in order to achieve rapid return of normal function and to reduce the incidence of complications related to this fracture . Stable However, intra-articular hardware penetration and cartilage damage are potential disadvantages related to lag screwing, therefore reducing the chances of successful outcome . In thisIt is generally agreed that three standard views (antero-posterior (AP), mortise, and lateral) should be used routinely in the preoperative evaluation of ankle acute traumas -11. HoweThe present study was designed to investigate the diagnostic accuracy of standardized radiographic ankle views to determine the accuracy of diagnosis for intra-articular hardware placement of medial malleolar screws in a cadaveric model.Nine preserved human cadaveric lower extremity specimens were obtained from the Department of Legal Medicine (DLM) of our institution. This was the amount of the existing specimens in the DLM at the moment of the investigation. There was no gross evidence of deformities, previous injuries, or surgeries involving the lower extremities of these cadavers. There were seven male specimens and the mean estimated age was 67 years old.Arbeitsgemeinschaft für Osteosynthesefragen) small fragments set  were inserted into the medial malleolus. Four specimens had both lag screws placed extra-articularly, three had one lag screw placed intra-articularly, and two had both lag screws placed intra-articularly. All intra-articular screws penetrated the lamina splendens layer of the articular cartilage (approximately 50% of its diameter penetrated the joint itself) , using standard technique  , randomly included in CD-ROMs, and viewed independently by ten orthopaedic surgeons: five Trauma Surgeons and five Foot and Ankle Surgeons  . The selRadiographic view - there was good agreement between the five Trauma Surgeons. The number of "inconclusive" responses was low and constant during the two readings. There was good agreement (kappa 0.8) among the five Foot and Ankle Surgeons, with values that were discretely lower than those of the Trauma Surgeons, without statistical significance  [VA test) . The numIntra-articular screw penetration - there was poor agreement (kappa 0.4) among Trauma Surgeons and Foot and Ankle Surgeons when the radiographic views were independently evaluated. Both subspecialists had difficulty in the diagnosis of joint penetration and in the definition of which screw was intra-articular.The number of "inconclusive" responses was significantly lower between the Trauma Surgeons (p < 0.05) .Radiographic view - there was good agreement (kappa 0.8) among all of the examiners. The number of "inconclusive" responses was slightly lower among the Trauma Surgeons, without statistical representation (p > 0.05) [ > 0.05) .Intra-articular screw penetration - there was a poor level of agreement (kappa 0.4) both in the AP and in the mortise view among all the examiners. Associating the two x-rays, the agreement remained poor. In the cases in which there was a diagnosis of articular penetration, there was a poor agreement related to which of the screws was intra-articular. The number of "inconclusive" responses was low and constant, without a statistically significant difference between the subspecialists (p > 0.05) [ > 0.05) .Malleolar ankle fractures are extremely common injuries. The therapeutic decision in these cases is based primarily on simple and well-defined radiographic evaluations, which include AP, mortise, and lateral views. However, little has been said about intraoperative evaluation in these situations, either in relation to the quality of the reduction or in relation to the intra-articular penetration of the implants used to fix these fractures . In addiMotta et al used three radiographic views on anteroposterior plane to retrospectively analyze the x-rays of 17 patients with the objective of evaluating the position of the screws used to fix the medial malleolar fractures of the ankle . They obIn the present experiment, we observed a low level of intra and interobserver agreement with relation to the diagnosis of articular penetration by the screws used to fix the medial malleolar fractures, both in terms of the AP and the mortise views. The agreement remained low when associating the two views. Furthermore, in the cases in which there was a diagnosis of articular penetration, there was a poor level of agreement in relation to which of the screws was intra-articular. When asked which radiographic view they were seeing, all examiners responded with good agreement. The number of "inconclusive" responses was low and constant during the two readings, showing that the drawing and the performance of the study were well done. Trauma surgeons showed a significantly lower number of "inconclusive" responses than Foot and Ankle Surgeons (p < 0.05), maybe reflecting the need of fast decisions of the prior specialists leading with trauma situations in the Emergency Departments.There are some strengths in our study. In relation to the model used in this study, we followed the STARD Committee standards, which recommend the comparison of the results of one or more tests under evaluation with the results of the reference standard for diagnostically sensitive studies . In the We were unable to identify which intraoperative imaging is the best to determine whether screws are in or out of the joint. This can be seen as one weakness in our experiment. However this was not our aim and we feel it can be investigated in a future study.The rigorous evaluation of the two studied radiographic views allows us to suggest that they are not reliable for intraoperative diagnosis of the articular penetration of implants used to fix transverse medial malleolar fractures of the ankle. We recommend that one does not waste time performing radiographies on different rotations of the foot when invasion of the medial articular space is suspected. In these cases, the best to do in our opinion is to reposition the screw(s) in question.Nevertheless, we advocate the routine use of all standard ankle views  during the surgical procedure, either with fluoroscopy or plain films. This is not our aim to change this investigation pattern, but to alert for the poor detection of articular penetration with these views.The authors declare that they have no competing interests.VG and AFSG designed the study and performed the experiments. VG, RPA and RESP evaluated the results and drafted the first version of the manuscript. NPA contributed to revisions of the manuscript. All authors read and approved the final version of the manuscript.