Most ecological models assume that predator and prey populations interact solely through consumption: predators reduce prey densities by killing and consuming individual prey. However, predators can also reduce prey densities by forcing prey to adopt costly defensive strategies.We build on a simple Lotka-Volterra predator-prey model to provide a heuristic tool for distinguishing between the demographic effects of consumption (consumptive effects) and of anti-predator defenses (nonconsumptive effects), and for distinguishing among the multiple mechanisms by which anti-predator defenses might reduce prey population growth rates. We illustrate these alternative pathways for nonconsumptive effects with selected empirical examples, and use a meta-analysis of published literature to estimate the mean effect size of each pathway. Overall, predation risk tends to have a much larger impact on prey foraging behavior than measures of growth, survivorship, or fecundity.While our model provides a concise framework for understanding the many potential NCE pathways and their relationships to each other, our results confirm empirical research showing that prey are able to partially compensate for changes in energy income, mitigating the fitness effects of defensive changes in time budgets. Distinguishing the many facets of nonconsumptive effects raises some novel questions, and will help guide both empirical and theoretical studies of how predation risk affects prey dynamics. In this model, predators and prey interact solely through successful predator attacks. Predators cannot grow without reducing prey density; similarly, any reduction in prey populations must contribute to predator population growth.Predators capture, kill, and consume their prey. This apparently trivial statement has complex and important implications: predators reduce prey population density, which in turn can affect the population growth of prey resources and other predators. The ‘cascading’ effects of consumption propagate throughout ecological communities, and are critically important to community dynamics. Food web models attempt to capture these dynamics using simultaneous population dynamic equations that link predators, prey, and resources via consumption rates a) in predator-prey dynamics . The mere threat of predation can be sufficient to reduce prey growth, survival, or fecundity . Far from being passive players on the ecological stage, prey employ a suite of behavioral and morphological defenses to avoid predation. These defensive strategies often have significant costs that reduce prey fecundity or survival. Predators can thus affect prey populations both by direct consumption  and by inducing costly defensive changes in prey traits .Both theoretical and empirical studies have challenged ecology's focus on consumption . Our intent is not a mathematical analysis of the resulting framework; rather, we examine the different ways in which r might respond to predator density, using the Lotka-Volterra model as a heuristic tool for identifying potential NCE pathways and clarifying the relationships between them. Because different types of prey defenses may have distinct ecological effects, genetic causes, and evolutionary consequences, such a classification scheme may help distinguish between biologically distinct types of interactions, allowing a more comprehensive and more mechanistic description of predator-prey dynamics. We integrate our explication of this framework with a metaanalysis of published literature assessing (where possible) the mean effect sizes of both the individual and combined pathways of nonconsumptive predator effects.The integration of NCE into predator-prey theory is clearly critical for progress towards a comprehensive understanding of predator-prey dynamics. We seek to assist such integration by distinguishing among multiple biologically distinct mechanisms by which predator intimidation can affect prey density and, thus, population dynamics. Our hope is that distinguishing among these mechanisms may make it easier to contrast outcomes from different study systems, draw general inferences, and more effectively connect empirical results with predictive models. We develop this framework by systematically expanding the term in the Lotka-Volterra equation through which the effects of predator NCE are manifest, the intrinsic growth rate (–aNP in eq 2). Prey defenses intended to mitigate this mortality rate may incur costs that reduce population growth in other ways, reflected in changes in the population's intrinsic growth rate (r) which depend on prey behavior, physiology, and life history. The trade-off between r and a has been the subject of numerous theoretical studies indicating that prey may optimize their expected fitness by trading off reduced r for reduced predation .Different mechanisms of nonconsumptive effects can be categorized by either: 1) the type of trait that is changed in response to predation risk; or 2) the way in which trait changes impact prey population growth. While these two systems may often overlap, they are not identical. We chose the latter approach in this review because it has clear and direct implications for prey (and hence community) dynamics. Traditional Lotka-Volterra equations represent decreases in prey density due to consumption . The net energy income is the difference between the rate of gross energy income (grossE) and a rate of energetic expenditure necessary for non-reproductive functions . We further subdivide the gross energy income rate into two components: the foraging effort , and the energy income per unit foraging time (E/t). Equivalently one might measure distance traveled per day while foraging, and energy income per unit distance. Splitting grossE in this way allows the separate consideration of potentially independent facets of foraging biology that can have distinct ecological impacts (see below). This net rate of energy acquisition,netbE. The rate of population growth (r) is the difference between this birth rate (netbE) and losses due to a background mortality rate (m). If we are dealing with a geographically bounded sub-population rather than an entire species, the local population density may also be modified by immigration (i) or emigration rates (e). The proportion of individuals available to emigrate is realistically a function of the number of local individuals, whereas the number of immigrants may be density-independent or density-dependent (we assume the former here). We thus substitute the following in place of the intrinsic population growth:r is a constant, the terms in equation (4) can be variable. Each term (except N) is a function of the prey's behavior, physiology, or biotic or abiotic environment, which in turn depends on the perceived level of risk. Changes in these terms in response to predation risk reduce the attack rate, a, but also yield nonconsumptive effects of predators on prey density.Population growth depends first on the rate of net energy income that can be put towards reproduction  or the rate at which prey are successfully attacked (a). Predators also modify prey growth rates, and life history schedules, which would have to be incorporated into size or age-structured models. While such feedback processes are clearly important, their detailed explication is beyond the scope of a general review such as ours. Finally, a conceptual framework of this sort necessarily glosses over an array of additional parameters (or further subdivisions of existing ones) that may sometimes prove important. Many of these parameters, and their theoretical underpinnings, have already been reviewed in detail ; our framework and the accompanying metaanalysis is intended for a broader audience interested in the most widely documented types of NCE pathways, the connections that exist between them, and their relative magnitudes. However, we believe this model-based argument is helpful for explicitly considering different aspects of NCEs. The distinctions between these pathways are often glossed over in empirical studies, most of which are logistically constrained to measuring only one or a few of the mechanisms by which predators might impact prey dynamics.Our development and discussion of the model presented in equation (4) requires several caveats. First, we use our expansion of the Lotka-Volterra equations as a conceptual framework rather than as a mathematical model E/t) while foraging. They do so by focusing on the subset of potential food resources providing the highest yield (due to energy content and/or handling time). While optimal diet theory can be successful at predicting foraging behavior E/t once predation risk is accounted for Optimal diet theory suggests that animals adopt foraging strategies intended to maximize some fitness-related currency [reviewed in 22]. The most common assumption is that animals act to maximize the rate of energy income (E/t) habitats lower in risk. The tradeoff between optimal foraging effort and risk was formalized by Gilliam and Fraser f rule” – prey should forage in habitats with the lowest ratio of mortality (μ) to foraging rate (f). For example, juvenile bluegill sunfish avoid predatory largemouth bass by shifting from open-water habitat to safer but energetically less profitable shallow habitats E/t food items in favor of less rewarding foods that could be carried to a safe location for consumption E/t, may therefore frequently be a negative function of predator density When energetically profitable habitats are accompanied by a high risk of predation, prey may choose less rewarding (low amount of time spent foraging per day [reviewed in 29]. While E/t and ft can be combined in models to yield a single rate parameter (grossE), they are biologically distinct. For instance, the presence of fish predators induces some freshwater snails to spend less time in the water, minimizing their time in aquatic habitats where they feed but are more vulnerable. The resulting decrease in foraging time can substantially affect the snails' fecundity Solenopsis geminata stops foraging and adopts a defensive posture in the presence of parasitoid phorid flies ft and E/t) is important because prey reducing one term in response to predation risk may compensate by increasing the other. Furthermore, these two components of foraging behavior may have very different ecological consequences. Reduced foraging on existing resources merely reduces top-down control of the focal species' resources. In contrast, prey may completely switch to another less profitable prey species (changing E/t instead of ft), greatly changing top-down control on the two resource types without affecting the activity cycle of the forager. Consequently, the extent and nature of trophic cascades may greatly depend on the distinction between changes in foraging time versus efficiency.In addition to reducing the prey's foraging efficiency (energy gained per unit time), predators often reduce the Daphnia pulex are associated with decreases in longevity and clutch size, both of which affect population growth rate Daphnia requires a significant shift of energetic resources away from reproduction. Over a lifetime, crest induction in Daphnia required resources equivalent to 60 eggs Defenses against predation are not necessarily behavioral; inducible prey responses to predators can include phenotypic changes such as spines, chemical defenses, hormonal stress responses, or autotomy . These energetically costly defenses often divert resources away from reproduction. Predator-induced defensive morphologies in Daphnia herbivores Daphnia cues decrease; the resulting increase in generation time reduces overall population growth rates. In contrast, shorter-lived algal species tested in the same experiment showed no such delay.Reduced net energy income (a function of the three factors discussed above) can directly impact prey fecundity or survival, constituting a nonconsumptive predator effect on prey demography. However, predators can also reduce prey birth rates independent of their effects on energy income. Attracting a mate often entails high-profile activities that may also increase vulnerability to predators, and several studies have found reductions in mating effort when predation risk is high. Water striders reduce the number and duration of matings in the presence of predatory sunfish per se in our meta-analysis.The preceding example of delayed reproduction in algae raises a more general issue that neither our Lotka-Volterra formulation nor our across-taxa metaanalysis (below) adequately addresses. Age-structured population models highlight the fact that a population's intrinsic growth rate depends on both the number of progeny and how quickly they are produced. Predation risk can have a number of conflicting effects on prey life history. While higher predation rates may favor faster maturation as prey try to reproduce before being eaten, reduced energy intake due to restricted foraging activity can slow growth rates, resulting in either smaller (and perhaps less fecund) prey, or delayed maturation. For instance, mayfly larvae exposed to a model of their fish predator took 50–80% longer to reach maturity than larvae in a predator-free control m, equation 6). For instance, non-lethal spiders whose mandibles were glued shut nonetheless had strong starvation-mediated effects on grasshoppers probability of starvation is less than the corresponding marginal decrease in the probability of being captured.Predator effects on prey fecundity are compounded by additional non-consumptive effects on prey survival , it would be inappropriate to calculate a ‘mean’ effect size across studies spanning an array of different spatial scales Methods: The vast majority of published empirical studies of NCE evaluate only one, or a few, of the preceding pathways. We therefore used meta-analysis to evaluate whether the empirical literature reveals whether some NCE pathways have a consistently large or small effect. We built upon the data set described in Preisser et al. ; briefly, we searched for published literature that experimentally assessed the nonconsumptive effect of predators on various prey life-history indices. Because of our interest in the population-level effects of NCE, only papers providing data on one or more of the following prey indices were included in the database: growth , fecundity , and survival . All papers fitting the above criteria were also searched for the following indices: activity , habitat use , and feeding rate . Data were taken directly from the text or tables, or extracted from graphs or figures. If a study provided data on multiple predator-prey pairs, or on the same predator-prey interaction in substantively different conditions , we treated these studies as independent data points in our analyses in order to address the range of possible conditions in which NCE might be important . If a study examined the same predator-prey pair at different sizes or developmental stages , we chose the combination with the largest prey/ predator size ratio.sr, for each dataset in order to test for potential publication bias The final 1034-line dataset was generated using 230 papers and included 135 predator species, 179 prey species, and 299 predator-prey species combinations . There aResults : Predator cues strongly affected prey behavioral indices such as feeding rate, overall activity level, and the use of exposed versus sheltered habitats. In aquatic systems, the presence of predator cues reduced prey feeding rate and overall activity by an average of 57% and 42%, respectively . Although indices of prey fitness such as growth and fecundity were less strongly affected, predator cues decreased prey growth and fecundity by an average of 8% and 10% in aquatic systems . Even though it seems unlikely that predation risk alone would increase prey mortality, predator cues decreased prey survival by 5% in aquatic systems . All of the preceding trends are significantly different from null hypotheses of no effect. There was no significant difference in effect size between terrestrial and aquatic interactions for any of the six variables . Tests for potential publication bias found no significant correlation between effect size and sample size  in all cases, suggesting that file-drawer effects did not strongly bias our results.2−a2PC) is in part a function of the density of the first predator (1C).Equations involving only two species cannot fully account for all potential NCE. This is because predators may also modify prey population dynamics by altering the prey's interactions with other species. ‘Interaction modification’ constitutes a major pathway for NCE and includes the consequences of predator-predator interactions and the effect of predator intimidation on interspecific prey competition. In a Lotka-Volterra context, we might say that the loss of prey to a second predator  provides a heuristic tool for distinguishing among these mechanisms. We see several advantages to using this scheme as a means of distinguishing among the different mechanisms underlying nonconsumptive predator effects.E/t are often associated with prey shifting between resources, releasing some resources from consumption while increasing use of others. In contrast, changes in other parameters  do not shift the burden of consumption between different species of resources. Hence, NCE involving changes in E/t may have fundamentally different community- and ecosystem-level effects than other NCE mechanisms. Changes in ft reduce the total flow of energy through the prey species, whereas changes in m, e, i, or (2PC2−a) simply redirect where the energy flows. The mechanisms may also require different temporal or spatial scales. Although emigration can almost instantly deplete a local prey population, phenotypic plasticity that redirects energy away from reproduction may have effects that are slow relative to direct consumptive effects.First, the mechanisms have different implications for community dynamics and energy flow within a community. Changes in Phenotypic traits affecting foraging strategies, time allocation, resource allocation, and dispersal behavior may have different genetic architectures, which will affect the likelihood of their evolution. It seems likely that, when faced with a novel predator, prey are more likely to adopt highly plastic behavioral defenses than physiologically based defenses. On the other hand, if physiological defenses have higher heritability than behavioral traits, they may be more readily optimized by natural selection.Finally, our classification scheme suggests that studies measuring a single NCE pathway will not accurately reflect the actual cumulative interaction strength. Predator-induced decreases in energy income require measurements of both foraging time, and the rate of energy return per unit time. Short-term studies that examine only energetic changes may unwittingly miss the effects of predators on prey fecundity. Field enclosures used to eliminate prey emigration  also remove an often-significant mechanism by which predators reduce local prey population density. Studies on prey mortality rates may miss effects on fecundity. Finally, changes in one variable may be compensated for by changes in another a) and by changing prey population growth rates (r). These growth rates are in turn a complex function of energy income, energy allocation, mating effort, survivorship, emigration and immigration, all of which depend on prey behavior and physiology. Prey respond to predation risk by changing their behavior and physiology, which in turn can affect population growth rates.We have argued that using Lotka-Volterra equations to address chronic predator effects provides a simple yet fairly general framework for illustrating the fact that predators affect prey dynamics both through consumption  may also positively affect per-capita prey growth through reductions in ‘a’ (capture rate). Finally, there is also increasing evidence that some organisms are capable of partially decoupling foraging activity and growth via changes in digestive physiology The large changes in prey behavior noted above were mirrored by smaller changes in ‘fitness-related’ metrices like growth, fecundity, and even mortality. This finding has several potential (non-exclusive) explanations. First, prey may simply shift their activity budget temporally; predator cues can increase nocturnal activity in a variety of species . Second, reductions in one behavior may be offset by increases in another; prey that reduce overall activity levels may, for example, become more efficient at capturing and consuming resources. Third, organisms facing the looming prospect of substantial reductions in growth, fecundity, and survival are likely to eventually increase foraging activity regardless of predation risk Despite our increased knowledge of the possible pathways and impacts of NCE, several questions remain unresolved. First, what is the functional relationship between each variable in equation (4) and predation risk? Theoretical treatments of NCE have been predominantly focused on a subset of these variables, and few models have considered the joint action of multiple factors. Complicating the matter, these functional relationships may change with ecological conditions such as resource availability Appendix S1(0.04 MB PDF)Click here for additional data file.


During the past 20 years, treatments for head and neck squamous cell carcinoma (HNSCC) have changed dramatically owing largely to the advent of novel approaches such as combined modality therapy as well as improvements in surgical and radiotherapeutic techniques. Locally advanced disease in particular, which engendered very high recurrence and mortality rates, is now associated with long-term disease-free survival in the majority of cases. This article will focus on locally advanced HNSCC, which frequently remains a clinical challenge, review state-of-the-art therapy, and introduce promising novel therapies. The field continues to evolve rapidly with new evidence during the past year clearly establishing the benefit of adjuvant chemoradiotherapy (CRT), as well as early evidence showing improved survival with the use of an epidermal growth factor receptor inhibitor in combination with radiotherapy. There are varied regimens in use for patients with locally advanced disease, but at the same time the multitude of options can plague the clinician when trying to select the most appropriate one. This article will attempt to put the various approaches into perspective and propose an evidence-based treatment algorithm. Head and neck cancer has an estimated annual global incidence of 533 100 cases (Surgery followed by adjuvant chemoradiotherapy (CRT) (or radiation)CRT upfront CRTOther primary treatment options: radiotherapy, surgery (±adjuvant therapy)Induction chemotherapy followed by definitive local therapy:epidermal growth factor receptor (EGFR) inhibition in combination with radiotherapy or CRTCurrent management of locally advanced HNSCC  has evolPredictors of recurrence after surgical resection include involved margins of resection, extranodal/extracapsular spread, perineural invasion, and the presence of two or more involved regional lymph nodes (Adjuvant (postoperative) radiotherapy is well studied (Postoperative (adjuvant) CRT offered an approach that could enhance local control with radiosensitising chemotherapeutic agents. Several studies have demonstrated that concurrent CRT is a highly effective therapy for locally advanced HNSCC including tumours that are not amenable to surgery  with the hope of further improving survival. Many centres have adopted this approach, based on phase II evidence indicating safety, feasibility, and potentially improved efficacy, but this remains an unanswered question until phase III data become available.The optimal time frame to start adjuvant treatment postsurgery has not been studied sufficiently. Limited evidence and clinical experience with the time needed for patients to recover suggest that it should be within 4–6 weeks postsurgery.vs upfront chemoradiation with the option of salvage surgery remains controversial and depends on many factors, including local expertise, goals for organ preservation, operability, resectability, and patient preference. No adequate randomised trial has examined this question and, given inherent biases in patient selection and ability to stage patients in a comparable fashion, it is unlikely that we will have a definitive answer in the near future. Both approaches work well, can coexist, and allow matching of treatments to a patient's disease and preferences.During the past decade, an attractive alternative to initial surgery has evolved. Originally pioneered for inoperable patients, upfront concomitant CRT has emerged as a definitive treatment option comparable to upfront surgical management in resectable patients. Given its advantage with regards to organ preservation and excellent reported local control and survival rates, CRT is increasingly used and has become the dominant treatment modality in many centres  disease  and radiotherapy alone . On the other hand, acute high-grade toxicities were more common in both arms involving chemotherapy. Similar to other CRT trials, late toxicities and swallowing function at 2 years were equivalent between the three arms. As a secondary outcome, CRT achieved the highest locoregional control rate. Survival was not significantly different between all three treatment arms, while both chemotherapy arms showed lower distant failure rates compared to radiotherapy alone. In conclusion concurrent CRT should be considered standard of care in this patient population. Sequential CRT is not more efficacious, but more toxic than radiotherapy, and should therefore not be routinely used.Given that concomitant CRT increases locoregional control, and thereby avoids surgical resection of important anatomical structures, it was postulated that CRT may offer superior organ preservation in comparison to surgery, radiation, or sequential chemotherapy and radiation. Initially, two trials using sequential chemotherapy and radiation in comparison to surgery with adjuvant radiation reported improved organ preservation with no difference in survival  VA Lary, establi disease  .Two European studies have shown evidence of a survival benefit with induction chemotherapy: the Italian GSTTC study (Gruppo di Studio sui Tumori della Testa) , cisplatin, and 5-FU (TPF) with doublet cisplatin/5-FU (PF) .A phase III multicentre trial , following induction chemotherapy and followed by gefitinib maintenance, provided insights into a potential role for EGFR inhibitors (Treatment for locally advanced HNSCC has improved dramatically during the past decade, allowing a discussion of cure in many patients, and an evidence-based algorithm to guide treatment can be created . In part


Sub-Saharan Africa carries a massive dual burden of HIV and alcohol disease, and these pandemics are inextricably linked. Physiological and behavioural research indicates that alcohol independently affects decision-making concerning sex, and skills for negotiating condoms and their correct use. More than 20 studies in Africa have reported higher occurrence of HIV among people with problem drinking; a finding strongly consistent across studies and similar among women and men. Conflation of HIV and alcohol disease in these setting is not surprising given patterns of heavy-episodic drinking and that drinking contexts are often coterminous with opportunities for sexual encounters. HIV and alcohol also share common ground with sexual violence. Both perpetrators and victims of sexual violence have a high likelihood of having drunk alcohol prior to the incident, as with most forms of violence and injury in sub-Saharan Africa. Reducing alcohol harms necessitates multi-level interventions and should be considered a key component of structural interventions to alleviate the burden of HIV and sexual violence. Brief interventions for people with problem drinking , must incorporate specific discussion of links between alcohol and unsafe sex, and consequences thereof. Interventions to reduce alcohol harm among HIV-infected persons are also an important element in positive-prevention initiatives. Most importantly, implementation of known effective interventions could alleviate a large portion of the alcohol-attributable burden of disease, including its effects on unsafe sex, unintended pregnancy and HIV transmission. Globally, HIV and other sexually-transmitted infections (STI) account for 6.3% of the burden of disease and alcohol for 4%, similar to that caused by tobacco 4.1%) and high blood pressure (4.4%) % and hig. Overall'how' and 'where' of alcohol consumption, [Alcohol use results in a considerable range of diseases, the occurrence of which is contingent upon three factors: lifetime cumulative volume consumed; patterns of drinking; and drinking contexts ,5. Overaumption,  than by Unlike settings with low-risk drinking patterns , sub-Saharan Africa is characterised by harmful patterns of drinking. This includes the use of large quantities of alcohol per occasion, but also drinking to intoxication in public spaces, heavy drinking during cultural festivals and drinking outside of mealtimes ,13. ThesHIV and alcohol also share common ground with sexual violence. A person's risk of rape or of perpetrating rape increases during heavy drinking episodes. Both perpetrators and victims of sexual violence have a high likelihood of having drunk alcohol prior to the incident, possibly because alcohol intoxication makes the drinker an easier target for potential perpetrators .More than 20 studies in Africa have reported higher occurrence of HIV among people with problem drinking ,20,22,23Challenging evidence for a causal relationship between alcohol, unsafe sex and HIV, are some studies which suggest that personality factors such as impulsivity or sensation seeking, as well as contextual factors confound the alcohol and sex relationship -26. It mAn argument can be made that alcohol is an intermediate factor on the causal pathway between certain personality types and unsafe sex (see figure Reducing alcohol harms necessitates both population and individual-level interventions, which will have marked health and social benefits beyond a reduction in the burden of HIV, sexual violence and unintended pregnancy. Policies such as increased taxation and limitations on the availability of alcohol, which are highly effective in lowering alcohol harm, are often strongly contested by the alcohol industry . Not unlGiven the substantial contribution of the industry to the GDP of many countries , the alcUniversal community-wide interventions can increase knowledge of the harmful effects of alcohol use and change community norms and values ,33. It isafer behaviours and contexts is more effective than promotion of total abstinence.The health sector has a critical role to play in mitigating alcohol-related harm, especially in the form of selective alcohol interventions, such as Brief Interventions for people with problem drinking. The term "Brief Intervention" refers to time-limited, patient-centred counselling that focuses on changing patient behaviour and has been shown to empower people to control their alcohol use and its effects on sexual behaviour . Such seAdolescents, sex workers, migrant labourers and those who work in the transport industry are particularly vulnerable to the effects of alcohol on sexual behaviour and require targeted interventions. Interventions to reduce alcohol harm among HIV-infected persons are also an important element in positive-prevention initiatives. A study in Cape Town, South Africa, showed that almost one in five adults with HIV infection also have alcohol abuse or dependence . SimilarMeasure the proportion of unsafe sex that is attributed to alcohol, and consequently what portion of the burden of HIV and other STI, sexual violence and unintended pregnancy is attributable to alcohol use. Even though global figures already show that alcohol harm is high, they underestimate its effects as they exclude the considerable social harms of alcohol [•  alcohol . Though Establish global mechanisms for alcohol control, similar to those used for tobacco control. Lessons could be learnt from the control of other potentially harmful substances, such as infant formula and tobacco.• HIV-alcohol links must be clearly articulated within national strategies for HIV prevention and for alcohol control. Given the burden of HIV in many African countries and causal links with alcohol, drunk sex should be considered as dangerous as drunk driving or tobacco use and warrants equal preventive efforts. HIV-alcohol links must therefore be clearly articulated within national HIV prevention strategies, but also within alcohol control policies. The South African government HIV and STI National Strategic Plan 2007-2011 places alcohol control among the key interventions required to reduce sexual transmission of HIV [• n of HIV .Develop clear public messaging that unsafe alcohol use can lead to HIV transmission. In addition to alcohol-HIV messaging on warning labels on drinks for example, combining alcohol and sex topics within educational initiatives among youth appears effective [• ffective -50. Soulffective .Restrict advertising of alcohol. This is analogous to bans on tobacco advertising, and could include banning alcohol adverts on billboards, or allowing TV alcohol adverts only after 21:00 to avoid youth being exposed to alcohol marketing [• arketing .Raise taxes on alcohol. This reduces alcohol harm, increases government revenue and assists in recouping the costs of alcohol harm. Levels of alcohol taxation in South Africa are still below international standards, and lower than the neighbouring country Botswana which is pioneering alcohol control in the region [• e region . Increase region  and there region . TaxatioHealth-care providers should screen for hazardous or harmful use of alcohol at the time of diagnosing HIV and in later visits for HIV care and treatment. As an HIV diagnosis commonly leads to changes in sexual behaviour, this is a critical opportunity to provide Brief Interventions or similar services to further support adoption of safer sexual practices. Both HIV testing and receipt of ART are key life stages or transition points for many people, and signify important moments of opportunity for intervention by health workers [•  workers .Large-scale research is needed to document whether HIV incidence is lowered by interventions to reduce high-risk drinking, as well as the feasibility of changing drinking patterns and making drinking contexts safer in sub-Saharan Africa. Though evidence suggests that adoption of safer drinking patterns may reduce unsafe sex [• safe sex -58, addiA substantial proportion of unsafe sex occurs due to alcohol-related disinhibition, diminished rational capacity and impaired decision-making. Reduction in cognitive restraint with alcohol use also hampers skills for condom negotiation and their correct use. For communities and individuals in sub-Saharan Africa, interventions are thus needed to change the way alcohol is used, so that hazardous drinking patterns are shifted to safer patterns.Control of alcohol use, including alcohol-sex linkages, has been prioritised by the World Health Assembly . Interna


Man-made vitreous fibers (MMVFs) are noncrystalline inorganic fibrous material used for thermal and acoustical insulation . Neither epidemiologic studies of human exposure nor animal studies have shown a noticeable hazardous effect of glass wools on health. However, MMVFs have been anecdotally associated with granulomatous lung disease in several case reports.Here, we describe the case of a patient with multiple bilateral nodular opacities who was exposed to glass wool fibers and coating materials for 7 years. Bronchoalveolar lavage fluid revealed an increased total cell count (predominantly macrophages) with numerous cytoplasmic particles. Lung biopsy showed peribronchiolar infiltration of lymphoid cells and many foreign-body–type granulomas. Alveolar macrophages had numerous round and elongated platelike particles inside the cytoplasm. X-ray microanalysis of these particles detected mainly oxygen/aluminum/silicon and oxygen/magnesium/silicon, compatible with kaolinite and talc, respectively. No elemental evidence for glass fibers was found in lung biopsy.The contribution of analytical electron microscopy applied in the lung biopsy was imperative to confirm the diagnosis of pneumoconiosis associated with a complex occupational exposure that included both MMVFs and coating materials.This case study points out the possible participation of other components , beyond MMVFs, in the etiology of pneumoconiosis. Man-made vitreous fibers (MMVFs), also called man-made mineral fibers, represent a group of manufactured fibers that includes rock wool, slag wool, glass wool, glass continuous filaments, glass microfibers, and refractory ceramic fibers . The useIn the present study, we describe a case of diffuse pulmonary nodular lesions caused by exposure to MMVF and coating materials applied in the speedboat industry. A number of coating materials are used in the production of glass-wool fibers and also in paints and varnishes used in the manufacture of boats. Energy-dispersive X-ray analysis (EDXA) associated with transmission electron microscopy (TEM) and scanning electron microscopy (SEM) performed on original fibers, coating materials, and lung biopsy was fundamental to identifying the elemental composition of these materials and diagnosing this pneumoconiosis.A 36-year-old man was admitted to Antonio Pedro University Hospital  in November 2004 with bilateral diffuse pulmonary infiltrates on the chest radiograph and dyspnea on exertion. He had been working as a laminator of glass-wool fibers and coating materials for 7 years, without respiratory protection, suggesting excessive occupational exposures to MMVFs and coating materials. His past medical history was unremarkable, and he was a lifetime nonsmoker.On admission, he was in good clinical condition, and his physical examination was normal. Chest radiograph and high-resolution computed tomography (HRCT) showed small nodular opacities spread throughout the lung fields . RoutineThe patient underwent bronchoalveolar lavage, and the sample was used for cell count, cytologic examination, and specific staining for fungi and acid-fast bacilli. Cellular bronchoalveolar lavage fluid (BALF) observed by light microscopy revealed an increased total cell count, predominantly macrophages . Numerous particles of different sizes were observed within the cytoplasm of alveolar macrophages by differential interferential contrast microscopy . Some ofAn open lung biopsy was performed because of an uncommon radiologic pattern rarely observed in patients with an occupational history of glass fiber exposure. Light microscopy showed peribronchiolar infiltration of lymphoid cells and many foreign-body–type granulomas throughout the examined tissue . AlveolaGlass wool fiber and the resin used in lamination were brought in by the patient and studied. These materials were deposited on a carbon (C)-conductive tape covering SEM stubs and analyzed by EDXA  coupled in a Jeol 1200 EX scanning-transmission electron microscope . The fibers contained the elements oxygen (O), magnesium (Mg), aluminum (Al), silicon (Si), and calcium (Ca), matching with glass wool fibers . The resEpidemiologic studies in humans suggest that there is no direct evidence of chronic lung disease associated with glass exposure . A cohorTo determine the possible association of MMVF exposure and the development of sarcoid-like granulomas, + T lymphocytes in the induced sputum and BALF, the histologic findings and lung CT–scan changes together indicated a possible active inflammatory process, resembling pulmonary fibrosis. The fibers found in the biopsy slides of the patient resembled the morphology and chemical composition of those found in typical glass wool insulation materials. The authors concluded that the disease was probably caused by low-fibrogenic-activity glass wool fibers.In our study, beyond the inhalation of the small glass fibers, the patient also inhaled other materials used in the lamination process, which should be evaluated as possible confounders. EDXA spectra of lung tissue did not indicate exactly the same elements present in original glass fibers. Ca was not detected within the alveolar macrophages, indicating that Ca (and the fibers per se) could be dissolved by lysosomal acid hydrolases. Spectra showed mainly O/Al/Si in platelike fibrillar particles inside alveolar macrophages, compatible with kaolinite, an insoluble nonfibrous silicate. Mg was also detected in the original fibers and in alveolar macrophage particles but, combined with O and Si, should be part of a talc-like material aspirated by the patient, such as kaolinite, which is commonly used as fillers in paints and plastics in boat industry. Several radiologic studies have shown small rounded opacities in kaolin and talc pneumoconiosis, and a number of different lesions have been described in the lungs of persons exposed to talc . The lesInhalation of metal dust or fumes can cause granulomatous lung disease that mimics sarcoidosis. Particular metals that possess antigenic properties, which promote granuloma formation, include Al, barium, beryllium, cobalt, copper, gold, titanium, and zirconium . Al was The biopersistence mechanism of the fibers deposited in the respiratory tract results from a combination of physiologic clearance  and physicochemical events  .We found fibers < 12 μm inside the alveolar macrophages. Human macrophages can phagocytose fibers ≤ 20 mm . The potAccording to Based on our findings and on the few studies available in the literature, the use of X-ray microanalysis provides an accurate identification of the deposits observed within the alveolar macrophages and supports a causal association with the type of exposure reported by the patient and his lung disease. In our case, the contribution of analytical electron microscopy applied in lung biopsy confirmed the diagnosis of this pneumoconiosis associated with a complex occupational exposure, but not clearly due to MMVFs.


An experimental tumour system for the study of metastasis has been developed using a syngeneically transplanted murine squamous carcinoma of spontaneous origin. Implants of the tumour, which does not elicit a significant immune response, grew and metastasized regularly to regional lymph nodes and lungs, in a manner comparable with that of the more malignant types of human epithelioma. The system has been used to test the influece of pre-operative irradiation, regional lymph node excision, tumour biopsy and manipulation, on metastasis. Of these, only pre-operative irradiation with 2000 rad 24 h before tumour excision produced a significant differential effect--a lower incidence of metastasis. By contrast, local radiation therapy sufficient to cause complete tumour regression but insufficient to achieve long-term local cure was shown to result in accelerated metastasis. A highly significant inhibition of metastasis was observed with the drug ICRF 159, but histological features suggested that its anti-metastatic effect in this system did not depend on morphological changes which might prevent dissemination of tumour cells.


How viruses are transmitted across the mucosal epithelia of the respiratory, digestive, or excretory tracts, and how they spread from cell to cell and cause systemic infections, is incompletely understood. Recent advances from single virus tracking experiments have revealed conserved patterns of virus movements on the plasma membrane, including diffusive motions, drifting motions depending on retrograde flow of actin filaments or actin tail formation by polymerization, and confinement to submicrometer areas. Here, we discuss how viruses take advantage of cellular mechanisms that normally drive the movements of proteins and lipids on the cell surface. A concept emerges where short periods of fast diffusive motions allow viruses to rapidly move over several micrometers. Coupling to actin flow supports directional transport of virus particles during entry and cell-cell transmission, and local confinement coincides with either nonproductive stalling or infectious endocytic uptake. These conserved features of virus–host interactions upstream of infectious entry offer new perspectives for anti-viral interference. The plasma membrane is a highly dynamic organelle and fences off pathogens with considerable efficiency. Besides segregation, it coordinates cell migration, information processing, and endo- and exocytosis during signalling and homeostasis. It also transmits information between neighboring cells or cells at a distance. Viruses take advantage of the plasma membrane in various ways. They bind to attachment factors, move laterally, and interact with secondary signalling receptors, or engage into endocytosis or fusion with the plasma membrane. All of these events determine if a particular cell gets infected or resists against the pathogen. For many viruses, the interactions with attachment factors and receptors are well characterized, and endocytic pathways have been mapped and in part integrated with cell signalling -like particles Simian virus 40 (SV40) also uses glycolipids as a cell surface attachment site Diffusion of lipids and proteins in the plasma membrane is driven by thermal motion. Tracking of single fluorescent SV40 particles revealed that SV40 particles on the plasma membrane randomly diffuse shortly after warming and are then immobilized on caveolin-GFP patches Aplysia neurons demonstrated that retrograde flow required clustering of the receptors and signal transduction Extracellular particles take advantage of directional movements inside cells by coupling to retrograde flow of F-actin . Early oA direct mechanical link between transmembrane receptors and actin filaments was suggested for retrograde flow of the cell adhesion molecule L1-CAM  on actin-rich microvilli and filopodia F-actin flow, unlike diffusion, may also allow viruses to break free from nonproductive confinements and may couple actin dynamics to signalling and endocytosis. This is supported by the observation that certain forms of vaccinia virus from the poxvirus family, the so-called MVs (intracellular mature viruses), are transported retrogradely on filopodia to the cell body where they induce actin turnover and membrane blebbing Retrograde F-actin flow also increases the dispersion of viral particles from infected cells to noninfected cells and thereby enhances infection. This has been demonstrated with MLV in cell culture experiments where env-expressing infected cells attach to mCAT-1 of filopodia from neighboring noninfected cells Retrograde flow on filopodia is particularly important for viral transmission between polarized cells of respiratory or intestinal epithelia and immune cells, and depends on receptor clustering induced by the multivalent pathogen Poxviruses are large enveloped DNA viruses and are pathogenic to humans and animals. The best studied prototypic strain is vaccinia virus, which infects a large variety of cell types from many different organisms. Two predominant forms of poxviruses are found in the cytosol, MVs and intracellular enveloped viruses (IEVs). Unlike MVs, IEVs contain two membranes that are derived from Golgi or endosomal membranes The first nonenveloped virus shown to use retrograde F-actin flow for infection was human papilloma virus type 16 (HPV16) Although it is not known how HPV16 couples to F-actin flow, the coupling mechanism may depend on the flow strength since particles alternated between drifting and confinement. This could, for example, involve a hierarchical slippage clutch that would mediate “frictional coupling” and differential transmission of F-actin–based forces through a network of transient protein–lipid or protein–protein interactions. Such mechanisms could be similar to F-actin flow in focal adhesions Compared to polyomaviruses, adenoviruses are 2-fold larger and more amenable for single particle tracking. They can be labelled with hundreds of fluorophore molecules, which makes them extremely bright point sources of light, ideal for tracking at high spatial and temporal resolutions How viruses enter into polarized cells is a question of major importance, and has been addressed with several cell culture models Clathrin-mediated endocytosis is a deeply characterized endocytic pathway, and has been linked with particular motions of viral particles on the cell surface. It delivers ligand-receptor complexes to early endosomes and other vesicular compartments, including late endosomes, recycling endosomes, and Golgi membranes In contrast to large viral cargo, transferrin, an iron carrier protein of about 5 nm, is constitutively internalized by short lived clathrin-coated pits within less than one minute, implying that the rate of clathrin-coated pit formation either depends on the size of the ligand, or functional differences in the clustering mechanisms. The latter could be due to signalling from clustered viral receptors, in analogy to the G protein-coupled receptor (GPCR) delta-opioid. This receptor delays its agonist-stimulated uptake from clathrin-coated pits by PDZ-dependent linkage to the actin cytoskeleton Whether functional specialization of clathrin-mediated endocytosis leads to the generation of distinct endosomes or endosomal domains is an open question trans-infection between immune cells and T cells. We expect that most viruses will be found to use retrograde F-actin flow, if they bind to specific cell surface receptors. In instances of nonspecific attachment, for example, viruses binding to heparan sulfate proteoglycans, which are interlinked with plasma membrane proteins or the extracellular matrix, we expect the virus particles not to drift, until they attach to a receptor connected to the plasma membrane. Evidence for this has come from single virus tracking experiments of HIV VLPs in cultured cells Evidence from single particle tracking experiments has demonstrated that particular motion types on the cell surface support infection. These motions include diffusion, drifting motions, and confinement of virus–receptor complexes. Recent data from a variety of unrelated viruses indicate that directional F-actin flow is a powerful gate into cells. It also facilitates transmission of infectious virus particles between infected and noninfected cells, for example by supporting It will be of great importance to define the specific virus–receptor complexes and the membrane domains that support viral surface movements. We already know, for example, that different receptors have different attachment mechanisms to cortical F-actin flow. Specifically, receptor linkages to F-actin can be regulated or stochastically determined, and they can be direct, through adaptor proteins, or indirect through a series of low affinity interactions of clustered protein or lipid receptors. The mechanisms of how particular virus–receptor complexes link to F-actin flow have implications on how long the viruses stay in the drifting mode, and how they recruit effector proteins for downstream events. This is important for viral interactions with immune cells and polarized epithelial or neuronal cells. Future analyses will identify how distinct motion types connect to the infectious endocytic uptake processes, or the noninfectious processes leading to virus destruction or immune presentation.The concept of targeting the host for anti-viral therapy was introduced in the 1990s by giving hepatitis C virus–infected individuals interferon-alpha in combination with ribavirin


We recently found that lithocholic acid (LCA), a bile                        acid, extends yeast longevity. Unlike mammals, yeast do not synthesize bile                        acids. We therefore propose that bile acids released into the environment                        by mammals may act as interspecies chemical signals providing longevity                        benefits to yeast and, perhaps, other species within an ecosystem.                 We recently found that LCA greatly (and some other bile acids to a                            lesser degree) increases the chronological life span of yeast under caloric                            restriction (CR) conditions . Our fin In one mechanism, this bile                            acid targets longevity pathways that control chronological aging irrespective                            of the number of calories available to yeast. Because these pathways modulate                            longevity regardless of calorie availability, we called them "constitutive" or                            "housekeeping" . LCA mod In the other mechanism, LCA targets the adaptable cAMP/PKA                            pathway by unmasking an anti-aging potential of PKA under non-CR conditions,                            perhaps by activating PKA-dependent phosphorylation of the cytosolic pool of                            the key nutrient-sensory protein kinase Rim15p . Hence, lit/lit mice and due to the ability of cholic acid                            administered to food of wild-type mice to activate transcription of numerous                            xenobiotic detoxification genes, it has been proposed that, by promoting                            chemical hormesis in mammals, these mildly toxic molecules with detergent-like                            properties may extend their longevity by acting as endobiotic regulators of aging [Although bile acids in mammals have been traditionally considered                            only as trophic factors for the enteric epithelium and detergents for the                            emulsification and absorption of dietary lipids -11, theyof aging -18.    of aging -21;    Importantly, yeast do not                            synthesize LCA or any other bile acid found in mammals ,11,22. Wi.e., the number of available calories and                            nutrients); and 2) do not overlap  with the                            adaptable TOR and cAMP/PKA longevity pathways that are under the stringent                            control of calorie and nutrient availability.                                        Noteworthy, the bulk quantity of bile acids in mammals exists as                            an organismal pool which cycles between intestine and liver in the                            enterohepatic circulation due to the efficient reabsorption of bile acids in                            the terminal ileum ,11. Howe It should be stressed, however, that the quantity                            of bile acids released into the environment by mammals could vary due to                            changes in the density of mammalian population and, perhaps, due to other                            environmental factors . In fact, the                            organismal pool of bile acids in mammals is under the stringent control of                            regulatory mechanisms operating in the liver during the fasting-refeeding                            transition -11. HencIt remains to be seen if our hypothesis on the essential role of                            bile acids as interspecies chemical signals regulating longevity in yeast is                            applicable to other species routinely exposed to bile acids within an                            ecosystem, such as plants and bacteria.                                        Our hypothesis on longevity regulation by bile acids within ecosystems may explain the evolutionary                            origin of the life-extending effect of another anti-aging compound, called                            rapamycin. Synthesized by soil bacteria to inhibit growth of fungal                            competitors, this macrocyclic lactone provides longevity benefit to yeast,                            fruit flies and mice by specifically inhibiting TOR (Tor1p in yeast), a                            nutrient-sensory protein kinase that operates as a master negative regulator of                            the key adaptable longevity pathway ,4,23-25.e.g., changes in the density                            of soil bacteria population) by modulating the TOR-governed adaptable longevity                            pathways. Of note, recent findings in yeast imply that - in addition to its                            role as a master negative regulator of the key adaptable longevity pathway -                            Tor1p may also operate as a positive longevity regulator, in particular by                            stimulating nuclear import of the transcriptional factors Sfp1p, Rtg1 and Rtg3                            in response to partial mitochondrial dysfunction or changes in the exogenous                            and endogenous levels of glutamate and glutamine [Interestingly, rapamycin has                            been shown to increase life span in fruit flies under dietary restriction                            conditions , when thlutamine -29. The lutamine ,30,31. i.e.,                            UV light, dehydration, infection, predation, cellular damage and nutrient                            deprivation) by synthesizing a compendium of secondary metabolites [i.e., animals and fungi) within the                            ecosystem an advance warning about deteriorating environmental conditions [Our hypothesis on longevity regulation by bile acids and rapamycin                            within ecosystems complements the "xenohormesis" hypothesis, in which plants                            and other autotrophic organisms respond to various environmental stresses  of organisms within this                            ecosystem, thereby killing competitors and/or protecting themselves from                            predators . Due to In the anti-aging side effect                            hypothesis, cytostatic compounds attenuating the TOR pathway operate as                            interspecies chemical signals that provide longevity benefits to a range of heterotrophic                            organisms composing an ecosystem . We propUnlike                            xenohormetic phytochemicals that are non-toxic compounds transiently                            synthesized and released by autotrophs only in response to environmental                            stresses ,34, bilei.e., bacteria, fungi, plants and animals) within an                            ecosystem are able to synthesize chemical                            compounds that 1) are produced and then released into the environment                            permanently or only in response to deteriorating environmental conditions,                            increased population density of competitors and/or                            predators, or changes in food availability and its nutrient and/or caloric                            content; 2) are mildly toxic compounds that trigger a hormetic response                            in an organism that senses them or, alternatively, are not toxic for any organism                            within the ecosystem and do not cause a hormetic response; 3) are cytostatic                            compounds that attenuate the TOR-governed signaling                            network  or, alternatively, do not                            modulate this growth-promoting network  and 4) extend longevity of                            organisms that can sense these compounds, thereby increasing their chances of                            survival and creating selective force aimed at maintaining the ability of                            organisms composing the ecosystem to respond to these compounds by undergoing                            specific life-extending changes to their physiology. Our                            hypothesis implies that the evolution of longevity regulation mechanisms                            in each group of the organisms composing an ecosystem is driven by the ability                            of this group of organisms to undergo specific life-extending physiological                            changes in response to a compendium of "critical" chemical compounds that are                            permanently or transiently released to the ecosystem by other groups of                            organisms.                                         In our unified                            hypothesis Figure , organise.g., a proposed                            selective advantage of the envisioned "altruistic" program [As the first step towards testing the                            validity of our hypothesis of the xenohormetic, hormetic and cytostatic                            selective forces driving the evolution of longevity regulation mechanisms                            within ecosystems, we are currently carrying out the LCA-driven experimental                            evolution of longevity regulation mechanisms in chronologically aging yeast                            cultured under laboratory conditions. If we could select long-lived yeast                            species following a long-term exposure of wild-type yeast to LCA, we would be                            able to begin addressing the following intriguing questions: 1) what genes are                            affected by mutations responsible for the extended longevity of selected                            long-lived yeast species? 2) how these mutations influence a compendium of the                            housekeeping longevity-related processes modulated by LCA in chronologically                            aging yeast ([ program -52 of   program -52 of th


Retinal vaculitis is a sight-threatening inflammatory eye condition that involves the retinal vessels. Detection of retinal vasculitis is made clinically, and confirmed with the help of fundus fluorescein angiography. Active vascular disease is characterized by exudates around retinal vessels resulting in white sheathing or cuffing of the affected vessels. In this review, a practical approach to the diagnosis of retinal vasculitis is discussed based on ophthalmoscopic and fundus fluorescein angiographic findings. Retinal vasculitis is a sight-threatening inflammatory eye condition that involves the retinal vessels. It may occur as an isolated idiopathic condition, as a complication of infective or neoplastic disorders, or in association with systemic inflammatory diseaseDetection of retinal vasculitis is made clinically, and confirmed with the help of fundus fluorescein angiography. Active vascular disease is characterized by exudates around retinal vessels resulting in white sheathing or cuffing of the affected vessels, which may be segmental (skip lesions) or confluent .Although retinal arterioles or branch retinal arteries may be involved in secondary systemic vasculitides such as systemic lupus erythematosus (SLE), as well as primary systemic vasculitides such as Wegener's granulomatosus, polyarteritis nodosa, Churg-Strauss syndrome or cryoglobulinemia,3Retinal vasculitis results in leakage leading to retinal swelling, exudation, and macular edema. Cystoid macular edema is a significant contributing factor for poor vision in retinal vasculitis. Cystoid macular edema, when adequately treated with immunosuppressive therapy, is associated with a good prognosis.5623Characteristic features seen with fluorescein angiography in active vasculitis include leakage of dye due to breakdown of the inner blood-retinal barrier, and staining of the blood vessel wall with fluorescein. Such leakage may be focal as seen in sarcoidosis or multiple sclerosis  or more The ability to identify retinal vasculitis as ischemic by fluorescein angiography has important implications for management and is discussed later. Other angiographic findings include cystoid macular edema  and optiIn this review, we discuss a practical approach to the diagnosis of retinal vasculitis based on ophthalmoscopic and fluorescein angiographic findings .Retinal vasculitis affecting predominantly the veins (phlebitis) has been described in association with Behçet's disease, tuberculosis, sarcoidosis, multiple sclerosis, pars planitis, retinal vasculitis associated with tuberculoprotein hypersensitivity , human immunodeficiency virus infection (HIV) Figures ,2,4, 6. 1Cotton-wool spots representing microinfarcts of the retina due to precapillary retinal arteriolar occlusion are most often found in association with systemic vasculitides such as SLE, plyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, and cryoglobulinemia .et al.Retinal vascular lesions are the most common ophthalmic manifestations of SLE and are due to arterial occlusion. Retinopathy generally consists of cotton-wool spots with or without retinal hemorrhages and may occur in the absence of hypertension . By cont91227Susac syndrome is a rare disease of unknown pathogenesis. It is also caused by microangiopathy affecting the arterioles of the brain, retina, and cochlea, giving the classic triad of encephalopathy, branch retinal arterial occlusions, and sensorineural hearing loss. The underlying process is believed to be a small vessel vasculitis causing microinfarcts of the retina, brain, and cochlea. Susac syndrome usually occurs in young women but can affect men. In those cases in which a brain biopsy was performed, histopathologic examination results showed microinfarcts, perivascular inflammatory infiltrates of small vessels consistent with an active small vessel angiitis. Magnetic resonance imaging of the brain often shows lesions suggestive of multiple sclerosis. Fluorescein angiography shows focal nonperfusion of retinal arterioles and arteriolar wall hyperfluorescence.33Intraretinal infiltrates are characteristic of infectious processes, but in the absence of these, they are pathognomonic of Behçet's disease Figure ,7 and 8.et al.,et al.Retinal vasculitis may be associated with necrotizing retinitis due to ocular toxoplasmosis, acute retinal necrosis, cytomegalovirus (CMV) retinitis, and rarely human T cell lymphoma virus type 1 (HTLV-1) associated uveitis. The hallmark of ocular toxoplasmosis is focal necrotizing retinitis, ultimately resulting in characteristic atrophic scars. Reactivation is frequently situated adjacent to an old atrophic scar with hyper pigmentation along the borders, indicating an old infection (satellite formation). Anterior uveitis, which may be granulomatous, and a secondary rise in intraocular pressure may also be noted. There may be an associated retinal vasculitis, which may be either near to or distant from the focus of active retinochoroiditis . The artAcute retinal necrosis is caused by viruses of the herpes group, mainly varicella zoster, herpes simplex types 1 and 2, and rarely, cytomegalovirus.etal.,In majority of the cases, cytomegalovirus (CMV) retinitis is a manifestation of acquired immunodeficiency syndrome (AIDS), with CMV retinitis being the most common ocular infection in these patients. The classic description of CMV retinitis is one of scattered yellow-white areas of necrotizing retinitis with variable degrees of hemorrhage and mild vitreous inflammation (“cottage cheese with catsup” or “pizza pie” retinopathy). The pathway of expanding lesions can be predicted by the appearance of venous sheathing or white dots distal to the leading edge. CMV retinitis is often accompanied by varying amounts of retinal vasculitis consisting primarily of perivenous sheathing.404244+t-cell. HTLV-1 infection is the established cause of adultt-cell leukemia/lymphoma (ATL), an aggressive malignancy of CD4+ lymphocytes; HTLV-1 associated myelopathy (HAM)/tropical spastic paraparesis (TSP), a demyelinating inflammatory disease of the spinal cord; and HTLV-1 uveitis (HU), defined as uveitis of undetermined etiology in an HTLV-1 carrier. Clinically, HU has been described as an acute granulomatous or nongranulomatous uveal reactions that were accompanied by vitritris and retinal vasculitis. The ocular disease was considered benign, resolving over weeks in response to corticosteroid treatment, with low incidence of complications and good visual prognosis. Gray-white, granular deposits scattered on the retinal vessels in the posterior pole were noted. Similar materials were also found to deposit on the vitreoretinal interface of the foveolar areas. In addition, retinal vasculitis with sheathing of retinal veins in the periphery was described in patients with HTLV-1-associated myelopathy.et al.,HTLV-1 infection is endemic in Japan, the Caribbean islands, and parts of Central Africa and South America. The major target cell of HTLV-1 is the CD4et al.61IRVAN is a rare clinical entity characterized by bilateral retinal arteritis, numerous aneurysmal dilatations of the retinal and optic nerve head arterioles, peripheral retinal vascular occlusion, neuroretinitis, and uveitis . This syet al.),et al.354220Frosted branch angiitis  the development of neovascularization.Ischemic retinal vasculitis is frequently seen secondary to tuberculosis and retinal vasculitis associated with tuberculoprotein hypersensitivity  which is typically an obliterative periphlebitis affecting the retina in multiple quadrants, starting at or anterior to the equator and progressing posteriorly. Occasionally, it can begin close to the optic nerve head, mimicking a vein occlusion. Ophthalmoscopic findings vary and depend on the stage of the disease. Initially, it presents as active retinal periphlebitis with thick exudates around the retinal veins associated with retinal hemorrhages, and hemorrhagic infarctions of the retina Figure ,4,16–18.149Ischemic retinal vasculitis may also be secondary to Behçet's disease and multiple sclerosis. The diagnosis is made using criteria proposed by the International Study Group for Behçet's disease in 1990.23Various ocular inflammatory changes have been described in patients with multiple sclerosis and may be the presenting sign of the disease. They include nongranulomatous and granulomatous iridocyclitis, intermediate uveitis, retinitis, periphlebitis  and opti171783Retinal periphlebitis associated with sarcoidosis is usually nonocclusive, sometimes subclinical and only visible on fluorescein angiography, associated with typical segmental cuffing or more extensive sheathing and perivenous exudates, which are usually indicated as “candle wax drippings” . Multipl8489Idiopathic recurrent branch retinal arterial occlusion is a clinical syndrome characterized by recurrent multiple branch retinal arterial occlusions of unknown cause in one or both eyes of healthy middle-aged patients. Ophthalmoscopic and fluorescein angiographic findings suggested focal arteritis and arteriolitis as the cause of the obstructions. Eyes that have large areas of retinal ischemia may subsequently develop preretinal neovascularization. The prognosis for maintaining good visual acuity is good. Detailed investigation of these patients has failed to reveal a systemic etiology. Vestibuloauditory and/or transient sensorimotor symptoms were detected in 50% of patients. It is postulated that many of the patients have mild or partial manifestations of the microangiopathic syndrome of encephalopathy, hearing loss, and retinal arteriolar occlusions.9094The search for a cause in patients with retinal vasculitis often involves a multidisciplinary approach and laboratory investigation2The laboratory work-up of a patient with retinal vasculitis should be based on a differential diagnosis derived from a detailed history, review of systems, and physical examination. If the patient's medical history, review of systems, or ocular examination suggests an underlying systemic disease, then the diagnostic work-up should be tailored for that disease. The absence of any diagnostic clues from history makes idiopathic retinal vasculitis most likely. If, however, the patient has no signs or symptoms suggestive of an associated disease then the work-up of the patient is limited to a fluorescein angiogram, complete blood count, erythrocyte sedimentation rate, VDRL, FTA-ABS, blood chemistry, urinalysis, tuberculin skin testing, HIV serology, and chest radiograph. Numerous studies have shown that little additional information is gained by “blind” investigation of the patient and that pursuing this is neither time nor cost effective.


Low-density lipoprotein (LDL) cholesterol lowering is a primary goal in clinical management of patients with cardiovascular disease, but traditional cholesterol levels may not accurately reflect the true atherogenicity of plasma lipid profiles. The size and concentration of lipoprotein particles, which transport cholesterol and triglycerides, may provide additional information for accurately assessing cardiovascular risk. This study evaluated changes in plasma lipoprotein profiles determined by nuclear magnetic resonance (NMR) spectroscopy in patients participating in a prospective, nonrandomized lifestyle modification program designed to reverse or stabilize progression of coronary artery disease (CAD) to improve our understanding of lipoprotein management in cardiac patients.The lifestyle intervention was effective in producing significant changes in lipoprotein subclasses that contribute to CAD risk. There was a clear beneficial effect on the total number of LDL particles , small dense LDL particles , and LDL particle size . Likewise, participants showed significant improvement in traditional CAD risk factors such as body mass index , total cholesterol , physical fitness , and future risk for CAD . Men and women responded differently to the program for all clinically-relevant variables, with men deriving greater benefit in terms of lipoprotein atherogenicity. Plasma lipid and lipoprotein responses to the lifestyle change program were not confounded by lipid-lowering medications.at risk patients motivated to participate, an intensive lifestyle change program can effectively alter traditional CAD risk factors and plasma lipoprotein subclasses and may reduce risk for cardiovascular events. Improvements in lipoprotein subclasses are more evident in men compared to women.In  The causal role of high blood cholesterol in the pathogenesis of coronary artery disease (CAD) is well established. A large body of research indicates that plasma cholesterol levels are important risk factors for CAD, and a number of clinical trials have shown that aggressive cholesterol management in patients with heart disease leads to significant reductions in cardiovascular events ,2. At prA more accurate way to assess cardiovascular risk may be to measure the size and concentration of lipoprotein particles . Early sLifestyle interventions have shown the substantial health benefits of a low fat diet, increased physical activity, and stress management in reducing traditional risk factors for cardiovascular disease ,13 and iThe Institutional Review Board at Windber Medical Center approved the research protocol and informed consent documents. All subjects enrolled in the program volunteered to participate and gave written informed consent. Data reporting follows recommendations of the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) group .The study population consisted of 73 Caucasian participants (34 women and 39 men) who completed a prospective, nonrandomized intervention designed to stabilize or reverse progression of CAD through dietary changes, exercise, stress management, and group support. Entry criteria were (1) a diagnosis of CAD, which included stable angina, angioplasty, evidence of ≥ 50% luminal narrowing on coronary angiogram, acute myocardial infarction, bypass surgery, or stent placement; or (2) two or more CAD risk factors: high blood pressure (BP) – systolic pressure > 140 mm Hg or diastolic pressure > 90 mm Hg, high total cholesterol (> 200 mg/dL), physician diagnosed diabetes, obesity defined as body mass index (BMI) ≥ 30, or family history of heart disease in parents or siblings.Prospective participants were recruited by advertisements in regional news media and were accepted into the program only with physician approval. Motivation to commit to following the guidelines of the program for the entire year was part of the acceptance criteria and was assessed by in-depth interviews before admission. Because tobacco use is a significant risk factor for CAD, and breaking a nicotine addiction often requires interventions beyond the scope of the lifestyle change program, patients were required to successfully abstain from smoking for at least three months prior to enrollment.Control participants  receiving only standard care from their primary physicians were matched to lifestyle participants based on gender, age at baseline within a five-year window, and CAD status (diagnosis of CAD or risk factors) using a prospective individual matching strategy similar to that described by Charpentier et al. . The objDetails on the Dr. Dean Ornish Program for Reversing Heart Disease have been published elsewhere ,25. The All participants in the program were required to submit a personal awareness log each week, which summarized for each day their diet , exercise (frequency and duration), stress management (frequency and duration), and group support (frequency of meeting attendance). For each component, adherence to the program guidelines was calculated as a percentage of the recommended goals achieved by each patient. Program staff reviewed the compliance forms weekly and provided immediate feedback to patients on their progress and guidance for improving adherence in specific areas as necessary.Throughout the year-long program, we experienced a drop-out rate of ~32% (n = 46) among participants in the healthy lifestyle program. In addition, 22 participants were excluded from the analysis because no suitable matching control was identified.Clinical examinations were performed at baseline, 12 weeks, and 52 weeks to assess changes in CAD risk factors and to collect blood for standard lipid and lipoprotein analysis. All examinations were conducted by physicians or trained personnel and followed identical protocols.Fasting blood samples were obtained at each examination and placed directly on ice. Within one hour of collection, plasma aliquots were isolated from whole blood by centrifugation and stored at -80°C. Lipoprotein subclass profiles were measured on freshly-thawed plasma samples by NMR spectroscopy at LipoScience  following previously published methods . ConcentA random sample of patients, selected to assess reproducibility of lipoprotein particle measurements, showed coefficients of variation (CV) between 78 blind duplicate samples that were similar to previously reported values . Coeffic2 max; ml/kg/min) based on exercise intensity, duration, and body weight (Bruce score) [Participants in the lifestyle change program and prospective controls were interviewed to collect information on age, gender, ethnicity, smoking status, cardiovascular history, and medication use. Height and weight measurements were used to calculate BMI. Blood pressure was recorded using a mercury sphygmomanometer on the arm of seated, relaxed subjects. General endurance was determined by a graded treadmill exercise test that estimated the volume of oxygen each participant could consume (VOe score) . Assays Future CAD risk was calculated for each subject as the probability of experiencing a subsequent coronary event in patients with cardiovascular disease or an initial event in disease-free participants within the next four years . The FraStatistical analyses were conducted using SPSS version 15.0; p values < 0.05 were considered statistically significant. Prior to analysis, Lilliefors test was used to determine normality of the outcome data, and natural log-transformations were used for variables with non-normal distributions. Potential differences in baseline measures among the lifestyle program and control group cohorts were examined by analysis of variance (ANOVA). As no significant cohort-to-cohort variability at baseline was detected, all intervention and control cohorts were respectively combined in subsequent analyses.Baseline characteristics between lifestyle participants and control subjects were compared by an independent samples Student-t test, or by a nonparametric Mann-Whitney U test if the data remained non-normally distributed after natural log transformation. Statistical comparisons of changes in CAD risk factors at 12 weeks and 52 weeks between the intervention and control groups were done using repeated-measures ANOVA with group (intervention versus control) as the between-subjects factor. Independent samples t-tests (two-tailed) then identified differences in CAD risk factor response from baseline to week 52 between the intervention and control groups. For each outcome variable, differences in response between men and women were assessed by two-factor repeated measures ANOVA  with group and gender within groups as the between-subjects factors, using a Bonferroni adjustment for multiple comparisons by time point, group, and gender within group. As above, independent samples t-tests (two-tailed) compared baseline to week 52 changes between groups, by gender. To examine the potential confounding effects of lipid-lowering medications on response to the program, a sub-group analysis was conducted that included only participants who continued taking the same brand and dosage of lipid-lowering medications as well as those not taking any lipid-lowering drugs.Baseline characteristics of participants in the lifestyle change program and matched controls are presented in Table Lipoprotein subclass measurements did not differ significantly between participants who completed the lifestyle intervention (graduates) and those who dropped out. For traditional CAD risk factors, dropouts tended to be younger  and have lower systolic BP  than graduates. Participants excluded from the analysis due to non-matching were older  and had larger HDL particles  and higher HDL-cholesterol  than participants included in the study.The lifestyle intervention led to significant changes in NMR-defined lipoprotein subclasses, in particular, clinically important LDL variables that contribute to CAD risk Figure . There wParticipation in the lifestyle change program had significant beneficial effects on traditional  CAD risk factors Table . PatientFor variables that showed a significant difference in outcome between participants and controls, we used repeated measures ANOVA by group and gender nested within group to investigate gender specific responses. Gender was not a significant factor for changes in lipoprotein subclasses from baseline to 52 weeks among controls; however, men and women participating in the program responded differently for all clinically-relevant variables Table . Among fFor physiological variables, both men and women showed a significant decrease in BMI and increase in physical fitness scores (p < 0.001) compared to controls after one year. Similar to lipoproteins, however, HDL-cholesterol , triglycerides , and total cholesterol  improved significantly in male participants compared to male controls, but no significant changes compared to controls were seen in women.Lipid-lowering therapy did not have significant effects on lipid and lipoprotein responses to the lifestyle change program. There were 56 participants (77%) and 47 controls (64%) who were not taking lipid-lowering drugs or whose medication levels did not change during the study. Results of the sub-group analysis examining lipid and lipoprotein responses in these patients were largely similar to analyses encompassing all participants (Table Participants who completed a comprehensive year-long lifestyle change program designed to reverse or stabilize progression of CAD showed significant improvement in traditional cardiovascular risk factors and a significant decrease in future cardiovascular risk. The lifestyle intervention also was effective in improving lipoprotein profiles that contribute to CAD risk. When analyses were stratified by gender, men appeared to derive greater vascular health benefit than women due to significant changes in important lipoprotein subclasses, including decreases in LDL particle number, sdLDL particles, and large VLDL, and increases in HDL and LDL particle size. Women showed no significant improvement for any of the measured lipoprotein parameters. Changes in clinically-relevant LDL particle attributes were comparable to other behavioral and pharmacologic interventions for lipoprotein management and were not significantly influenced by changes in lipid-lowering medications.Lifestyle modification programs are known to improve cardiovascular risk profiles through significant reductions in LDL- and total cholesterol, but the effects of lifestyle interventions on lipoprotein profiles and vascular health are not well known. To date, only limited research has examined the impact of lifestyle behaviors, such as exercise and diet, on lipoprotein subclass distributions. Meta-analyses suggest that aerobic exercise has modest effects on blood cholesterol levels ,30, but To make lifestyle interventions more comprehensive, programs have been developed to focus on numerous aspects of lifestyle including weight management, physical activity, nutrition, smoking cessation, and stress management. These multidisciplinary programs have been shown to improve modifiable cardiovascular risk factors -19, but Lipoproteins play an important role in the development and progression of atherosclerotic disease because lipoprotein particles transport cholesterol and triglycerides throughout the body. In particular, low density lipoproteins are the primary carriers of cholesterol in plasma, but are not readily cleared from the circulation. Longer residence time in the vasculature leads to increased uptake by the arterial walls and greater susceptibility to oxidization. LDL particles modified by oxidation accelerate disease progression by promoting foam cell formation, inflammation, and endothelial dysfunction .In patients with an atherogenic lipoprotein profile characterized by a high number of LDL particles, an abundance of sdLDL particles, and small LDL size, the vascular intima is constantly exposed to high concentrations of lipoproteins, which interact with the arterial walls and initiate the cascade of events leading to atherosclerosis . NumerouDespite evidence that behavioral changes can lead to significant improvements in atherogenic lipid profiles, certain at-risk patients may not show comparable benefit . Women iSuccessful stabilization and regression of established atherosclerotic plaques may be achievable clinical goals, but many interventions fail to induce regression of advanced lesions containing necrotic, fibrotic, and calcified tissues because patients cannot achieve the drastic changes in plasma lipoproteins necessary to stabilize the plaque environment . PharmacLowering LDL cholesterol is crucial to reducing cardiovascular morbidity and mortality , but LDLANOVA: analysis of variance; BMI: body mass index; BP: blood pressure; CAD: coronary artery disease; HDL: high-density lipoprotein; IDL: intermediate-density lipoprotein; LDL: low-density lipoprotein; NMR: nuclear magnetic resonance; sdLDL: small, dense LDL; TZD: thiazolidinedione; VLDL: very-low-density lipoprotein.The authors declare that they have no competing interests.DJD drafted the manuscript as a research physician; DMN established the program database, conducted statistical analysis, and assisted with data interpretation; AB directed the lifestyle change program, oversaw subject recruitment, and coordinated data collection; MJH recruited participants and was involved in data collection/entry; HLP obtained and processed blood samples from participants and drafted the manuscript; MNV critically reviewed the manuscript and contributed valuable expertise in clinical medicine; DLE conceived and designed the study, interpreted the data, and supervised manuscript preparation. All authors read and approved the final manuscript.