Chikungunya virus infection disrupts MHC-I antigen presentation via nonstructural protein 2.

Infection by chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes severe polyarthralgia and polymyalgia, which can last in some people for months to years. Chronic CHIKV disease signs and symptoms are associated with the persistence of viral nucleic acid and antigen in tissues. Like humans and nonhuman primates, CHIKV infection in mice results in the development of robust adaptive antiviral immune responses. Despite this, joint tissue fibroblasts survive CHIKV infection and can support persistent viral replication, suggesting that they escape immune surveillance. Here, using a recombinant CHIKV strain encoding the fluorescent protein VENUS with an embedded CD8+ T cell epitope, SIINFEKL, we observed a marked loss of both MHC class I (MHC-I) surface expression and antigen presentation by CHIKV-infected joint tissue fibroblasts. Both in vivo and ex vivo infected joint tissue fibroblasts displayed reduced cell surface levels of H2-Kb and H2-Db MHC-I proteins while maintaining similar levels of other cell surface proteins. Mutations within the methyl transferase-like domain of the CHIKV nonstructural protein 2 (nsP2) increased MHC-I cell surface expression and antigen presentation efficiency by CHIKV-infected cells. Moreover, expression of WT nsP2 alone, but not nsP2 with mutations in the methyltransferase-like domain, resulted in decreased MHC-I antigen presentation efficiency. MHC-I surface expression and antigen presentation was rescued by replacing VENUS-SIINFEKL with SIINFEKL tethered to ß2-microglobulin in the CHIKV genome, which bypasses the requirement for peptide processing and TAP-mediated peptide transport into the endoplasmic reticulum. Collectively, this work suggests that CHIKV escapes the surveillance of antiviral CD8+ T cells, in part, by nsP2-mediated disruption of MHC-I antigen presentation.

The Spanish version of the Home Environment Survey (HES) among families of children with overweight/obesity: a validation study.

PURPOSE: The aim of this article was to validate the Spanish version of the Home Environment Survey (HES-S) and was divided in two studies: (1) to assess the reliability, convergent validity of HES-S in a survey of 145 parents of children with overweight/obesity; (2) to study the magnitude of the association between children's BMI status with the latent scores theoretically defined by the HES model. METHODS: To test the scale and the model, a confirmatory factor analysis (CFA) and a path analysis were carried out among a sample of 156 parents of preadolescents (106 overweight/obesity and 50 normal-weight children). No CFA or EFA were carried out in the validation of the original instrument. RESULTS: Study 1, both the Physical Activity and the Eating Habits components of the scale showed adequate levels of internal consistency for the majority of the scales, except for two. One of them, Healthy Eating Parental Policies (HEP) subscale was reduced after excluded two items, although it did not improve substantially. This model indicated that there was a significant association between the two Eating Habits scales and the child's weight status, but child's weight was not associated with the Physical Activity components. Convergent validity was confirmed by correlations with related variables: family eating habits (F-EAT), parent's physical activity (IPAQ), and children's physical activity (assessed via accelerometers during one week). Study 2, our results replicated the original four factor structure proposed for physical activity (CFI = 0.99; RMSEA = 0.03), but the original factor structure of the eating habits component was not supported. In addition, the relationship of the child's weight status, the Physical Activity components, and the two scales of Eating Habits (Parental Modeling and Policies) was explored with a path analysis showing good fit indices (CFI = 0.95; RMSEA = 0.06). Child's BMI was negatively associated with Healthy Eating Parental Role Modeling (r = - 0.21) and with Healthy Eating Parental Policies (r = - 0.19), but not with the factors of Child's Physical Activity model. CONCLUSION: To our knowledge, this is the first instrument to assess obesogenic family environment in Spanish speaking countries, which is a relevant dimension within a health perspective so as to implement new policies and strategies in obesity tertiary prevention. Overall, the confirmatory factor analysis of the HES-S has only provided additional support for one part related to Physical Activity. In addition, Child's BMI was correlated with scales of Eating Habits but not with Child's Physical Activity factor. These results clearly suggest that further research is warranted. LEVEL III: Case-control analytic study.

How Much Progress Have We Made? Trends in Disparities in Tobacco Use.

INTRODUCTION: Reducing tobacco-related health disparities has been a public health priority for more than 2 decades, yet disparities in cigarette use have remained steady or worsened. Less is known about how disparities in other tobacco products have changed over time. Our study examined trends in cigarette and other tobacco product use in Minnesota with the goal of informing efforts aimed at reducing disparities. METHODS: We examined tobacco use disparities as a function of education, income, and race across the Minnesota Adult Tobacco Survey results in 2010 (N = 7,057), 2014 (N = 9,304), and 2018 (N = 6,055). Tobacco use was captured by assessing past 30-day use of 4 tobacco products: cigarettes, cigars, e-cigarettes, and smokeless tobacco, plus combustibles (ie, cigarettes and/or cigars) and any tobacco (ie, use of any of the 4 products). RESULTS: At each wave, those with lower income and education reported greater use of cigarettes, combustibles, and any tobacco than those with higher income and education. Black respondents were more likely to report cigar and combustibles use than White respondents in 2018, whereas White respondents were more likely to report smokeless tobacco use in 2014. We saw no significant wave-by-demographic interactions, suggesting that the magnitude of the disparity remained unchanged over time for any tobacco product. CONCLUSION: Substantial disparities in tobacco use remain across education, income, and race, even in a state such as Minnesota with a strong tobacco control program. Additional efforts are needed to close disparity gaps and reach endgame tobacco use targets for all subpopulations.

Psychological well-being and weight-related teasing in childhood obesity: a case-control study.

PURPOSE: The prevalence of childhood obesity continues to increase worldwide. The aims of this study were to (1) assess the psychological well-being and rates of teasing of Spanish children with obesity (OG) and compare them with their non-overweight peers (NG), and (2) analyze the mediating role of weight-related teasing on the relation between children's BMI z score and psychological well-being. METHODS: The cross-sectional study included 50 preadolescents with obesity, matched with non-overweight children according to age, sex, and socioeconomic status, who were assessed via self-report instruments measuring anxiety, depression, self-esteem, and teasing. RESULTS: The OG reported higher anxiety, depression, and teasing, and lower self-esteem. SEM revealed that children who scored worse on instruments assessing psychological well-being had higher BMI z scores. Weight-related teasing predicted poor psychological well-being scores and weight-related teasing mediated the relation between BMI and psychological well-being. CONCLUSIONS: The high rates of anxiety, depression, and weight-related teasing, as well as the low self-esteem, which was observed amongst the children with obesity, raise concerns about the quality of life of this population. Furthermore, the finding that weight-related teasing mediated the relationship between BMI and psychological well-being adds to a growing body of research, highlighting the harmful effects of weight-related stigma. Overall, these results highlight the importance of early intervention to assess for, and address, the presence of weight-related teasing and psychological well-being difficulties in preadolescents with obesity. LEVEL OF EVIDENCE: Level III, case-control study.

Observational study of the medical management of patients with peripheral artery disease.

BACKGROUND: Previous research has suggested that patients with peripheral artery disease (PAD) are not offered adequate risk factor modification, despite their high cardiovascular risk. The aim of this study was to assess the cardiovascular profiles of patients with PAD and quantify the survival benefits of target-based risk factor modification. METHODS: The Vascular and Endovascular Research Network (VERN) prospectively collected cardiovascular profiles of patients with PAD from ten UK vascular centres (April to June 2018) to assess practice against UK and European goal-directed best medical therapy guidelines. Risk and benefits of risk factor control were estimated using the SMART-REACH model, a validated cardiovascular prediction tool for patients with PAD. RESULTS: Some 440 patients (mean(s.d.) age 70(11) years, 24·8 per cent women) were included in the study. Mean(s.d.) cholesterol (4·3(1·2) mmol/l) and LDL-cholesterol (2·7(1·1) mmol/l) levels were above recommended targets; 319 patients (72·5 per cent) were hypertensive and 343 (78·0 per cent) were active smokers. Only 11·1 per cent of patients were prescribed high-dose statin therapy and 39·1 per cent an antithrombotic agent. The median calculated risk of a major cardiovascular event over 10 years was 53 (i.q.r. 44-62) per cent. Controlling all modifiable cardiovascular risk factors based on UK and European guidance targets (LDL-cholesterol less than 2 mmol/l, systolic BP under 140 mmHg, smoking cessation, antiplatelet therapy) would lead to an absolute risk reduction of the median 10-year cardiovascular risk by 29 (20-38) per cent with 6·3 (4·0-9·3) cardiovascular disease-free years gained. CONCLUSION: The medical management of patients with PAD in this secondary care cohort was suboptimal. Controlling modifiable risk factors to guideline-based targets would confer significant patient benefit.

Bariatric Surgery Prior to Total Joint Arthroplasty, Does it Decrease the Risk of Obesity Related Perioperative Complications?

PURPOSE OF REVIEW: The purpose of this review paper is to provide an overview of the relationship between obesity, osteoarthritis, arthroplasty outcomes, and the potential use of bariatric surgery to improve these outcomes. RECENT FINDINGS: Unfortunately, the findings in the currently available literature evaluating the role of bariatric surgery prior to arthroplasty surgery largely rely on retrospective data and their results are somewhat conflicting. Future prospective studies are needed to further evaluate whether or not bariatric surgery prior to arthroplasty surgery may be of benefit for patients. Additional research is needed to identify other methods to minimize complications that obese patients are particularly prone to developing following arthroplasty surgery.

Phagocyte-expressed glycosaminoglycans promote capture of alphaviruses from the blood circulation in a host species-specific manner.

The magnitude and duration of vertebrate viremia are critical determinants of arbovirus transmission, geographic spread, and disease severity-yet, mechanisms determining arbovirus viremia levels are poorly defined. Previous studies have drawn associations between in vitro virion-glycosaminoglycan (GAG) interactions and in vivo clearance kinetics of virions from blood circulation. From these observations, it is commonly hypothesized that GAG-binding virions are rapidly removed from circulation due to ubiquitous expression of GAGs by vascular endothelial cells, thereby limiting viremia. Using an in vivo model for viremia, we compared the vascular clearance of low and enhanced GAG-binding viral variants of chikungunya, eastern- (EEEV), and Venezuelan- (VEEV) equine encephalitis viruses. We find GAG-binding virions are more quickly removed from circulation than their non-GAG-binding variant; however individual clearance kinetics vary between GAG-binding viruses, from swift (VEEV) to slow removal from circulation (EEEV). Remarkably, we find phagocytes are required for efficient vascular clearance of some enhanced GAG-binding virions. Moreover, transient depletion of vascular heparan sulfate impedes vascular clearance of only some GAG-binding viral variants and in a phagocyte-dependent manner, implying phagocytes can mediate vascular GAG-virion interactions. Finally, in direct contrast to mice, we find enhanced GAG-binding EEEV is resistant to vascular clearance in avian hosts, suggesting the existence of species-specificity in virion-GAG interactions. In summary, these data support a role for GAG-mediated clearance of some viral particles from the blood circulation, illuminate the potential of blood-contacting phagocytes as a site for GAG-virion binding, and suggest a role for species-specific GAG structures in arbovirus ecology.

4'-Fluorouridine inhibits alphavirus replication and infection in vitro and in vivo.

Chikungunya virus (CHIKV) is an enveloped, positive-sense RNA virus that has re-emerged to cause millions of human infections worldwide. In humans, acute CHIKV infection causes fever and severe muscle and joint pain. Chronic and debilitating arthritis and joint pain can persist for months to years. To date, there are no approved antivirals against CHIKV. Recently, the ribonucleoside analog 4'-fluorouridine (4'-FlU) was reported as a highly potent orally available inhibitor of SARS-CoV-2, respiratory syncytial virus, and influenza virus replication. In this study, we assessed 4'-FlU's potency and breadth of inhibition against a panel of alphaviruses including CHIKV, and found that it broadly suppressed alphavirus production in cell culture. 4'-FlU acted on the viral RNA replication step, and the first 4 hours post-infection were the critical time for its antiviral effect. In vitro replication assays identified nsP4 as the target of inhibition. In vivo, treatment with 4'-FlU reduced disease signs, inflammatory responses, and viral tissue burden in mouse models of CHIKV and Mayaro virus infection. Treatment initiated at 2 hours post-infection was most effective; however, treatment initiated as late as 24-48 hours post-infection produced measurable antiviral effects in the CHIKV mouse model. 4'-FlU showed effective oral delivery in our mouse model and resulted in the accumulation of both 4'-FlU and its bioactive triphosphate form in tissues relevant to arthritogenic alphavirus pathogenesis. Together, our data indicate that 4'-FlU inhibits CHIKV infection in vitro and in vivo and is a promising oral therapeutic candidate against CHIKV infection.IMPORTANCEAlphaviruses including chikungunya virus (CHIKV) are mosquito-borne positive-strand RNA viruses that can cause various diseases in humans. Although compounds that inhibit CHIKV and other alphaviruses have been identified in vitro, there are no licensed antivirals against CHIKV. Here, we investigated a ribonucleoside analog, 4'-fluorouridine (4'-FlU), and demonstrated that it inhibited infectious virus production by several alphaviruses in vitro and reduced virus burden in mouse models of CHIKV and Mayaro virus infection. Our studies also indicated that 4'-FlU treatment reduced CHIKV-induced footpad swelling and reduced the production of pro-inflammatory cytokines. Inhibition in the mouse model correlated with effective oral delivery of 4'-FlU and accumulation of both 4'-FlU and its bioactive form in relevant tissues. In summary, 4'-FlU exhibits potential as a novel anti-alphavirus agent targeting the replication of viral RNA.

Chikungunya virus infection disrupts MHC-I antigen presentation via nonstructural protein 2.

Infection by chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes severe polyarthralgia and polymyalgia, which can last in some people for months to years. Chronic CHIKV disease signs and symptoms are associated with the persistence of viral nucleic acid and antigen in tissues. Like humans and nonhuman primates, CHIKV infection in mice results in the development of robust adaptive antiviral immune responses. Despite this, joint tissue fibroblasts survive CHIKV infection and can support persistent viral replication, suggesting that they escape immune surveillance. Here, using a recombinant CHIKV strain encoding a chimeric protein of VENUS fused to a CD8+ T cell epitope, SIINFEKL, we observed a marked loss of both MHC class I (MHC-I) surface expression and antigen presentation by CHIKV-infected joint tissue fibroblasts. Both in vivo and ex vivo infected joint tissue fibroblasts displayed reduced cell surface levels of H2-Kb and H2-Db MHC proteins while maintaining similar levels of other cell surface proteins. Mutations within the methyl transferase-like domain of the CHIKV nonstructural protein 2 (nsP2) increased MHC-I cell surface expression and antigen presentation efficiency by CHIKV-infected cells. Moreover, expression of WT nsP2 alone, but not nsP2 with mutations in the methyltransferase-like domain, resulted in decreased MHC-I antigen presentation efficiency. MHC-I surface expression and antigen presentation could be rescued by replacing VENUS-SIINFEKL with SIINFEKL tethered to ß2-microglobulin in the CHIKV genome, which bypasses the need for peptide processing and TAP-mediated peptide transport into the endoplasmic reticulum. Collectively, this work suggests that CHIKV escapes the surveillance of antiviral CD8+ T cells, in part, by nsP2-mediated disruption of MHC-I antigen presentation.

Phagocyte-expressed glycosaminoglycans promote capture of alphaviruses from the blood circulation in a host species-specific manner.

The magnitude and duration of vertebrate viremia are critical determinants of arbovirus transmission, geographic spread, and disease severity-yet, mechanisms determining arbovirus viremia levels are poorly defined. Previous studies have drawn associations between in vitro virion-glycosaminoglycan (GAG) interactions and in vivo clearance kinetics of virions from blood circulation. From these observations, it is commonly hypothesized that GAG-binding virions are rapidly removed from circulation due to ubiquitous expression of GAGs by vascular endothelial cells, thereby limiting viremia. Using an in vivo model for viremia, we compared the vascular clearance of low and enhanced GAG-binding viral variants of chikungunya (CHIKV), eastern-(EEEV), and Venezuelan-(VEEV) equine encephalitis viruses. We find GAG-binding virions are more quickly removed from circulation than their non-GAG-binding variant; however individual clearance kinetics vary between GAG-binding viruses, from swift (VEEV) to slow removal from circulation (EEEV). Remarkably, we find phagocytes are required for efficient vascular clearance of some enhanced GAG-binding virions. Moreover, transient depletion of vascular heparan sulfate (HS) impedes vascular clearance of only some GAG-binding viral variants and in a phagocyte-dependent manner, implying phagocytes can mediate vascular GAG-virion interactions. Finally, in direct contrast to mice, we find enhanced GAG-binding EEEV is resistant to vascular clearance in avian hosts, suggesting the existence of species-specificity in virion-GAG interactions. In summary, these data support a role for GAG-mediated clearance of some viral particles from the blood circulation, illuminate the potential of blood-contacting phagocytes as a site for GAG-virion binding, and suggest a role for species-specific GAG structures in arbovirus ecology. Significance Statement: Previously, evidence of arbovirus-GAG interactions in vivo has been limited to associations between viral residues shown to promote enhanced GAG-binding phenotypes in vitro and in vivo phenotypes of viral dissemination and pathogenesis. By directly manipulating host GAG expression, we identified virion-GAG interactions in vivo and discovered a role for phagocyte-expressed GAGs in viral vascular clearance. Moreover, we observe species-specific differences in viral vascular clearance of enhanced GAG-binding virions between murine and avian hosts. These data suggest species-specific variation in GAG structure is a mechanism to distinguish amplifying from dead-end hosts for arbovirus transmission.

Exposure-response relationship between K. brevis blooms and reporting of upper respiratory and neurotoxin-associated symptoms.

In southwest Florida, Karenia brevis (K. brevis) blooms occur frequently, can be very intense and persist over several years. Individuals living in coastal communities around the Gulf of Mexico are particularly vulnerable to brevetoxins released by K. brevis in seawater and carried inland within marine aerosol. Exposure to K. brevis occurs during residential, recreational, and occupational activities and has been associated with upper respiratory tract (URT) symptoms in healthy and medically vulnerable individuals. Additionally, ingestion of brevetoxin-contaminated seafood causes neurotoxic shellfish poisoning (NSP), and severe headaches prompting emergency department visits which occur in excess during K. brevis blooms. The current study examined a dose-response relationship between K. brevis in coastal waters and URT and NSP-like symptoms and headaches among southwest Florida residents. Data on past medical history (PMH) and medical symptoms were collected from the participants (n = 258) in five southwest Florida counties between June 2019 to August 2021. A dose-response relationship was observed between K. brevis blooms and reporting of URT and NSP-like symptoms and headaches. Reporting of NSP-like symptoms was higher among participants with a PMH of migraines, chronic fatigue syndrome (CFS) and mild memory loss, while the association of headaches with K. brevis blooms was accentuated among individuals with a PMH of migraines. These results suggest further investigations into the threshold of aerosolized brevetoxin dose required to elicit URT, headaches and/or NSP-like symptoms. These symptoms ultimately cause significant public health safety concerns, primarily among vulnerable populations with preexisting neurological conditions.

Finding a (pine) needle in a haystack: chloroplast genome sequence divergence in rare and widespread pines.

Critical to conservation efforts and other investigations at low taxonomic levels, DNA sequence data offer important insights into the distinctiveness, biogeographic partitioning and evolutionary histories of species. The resolving power of DNA sequences is often limited by insufficient variability at the intraspecific level. This is particularly true of studies involving plant organelles, as the conservative mutation rate of chloroplasts and mitochondria makes it difficult to detect polymorphisms necessary to track genealogical relationships among individuals, populations and closely related taxa, through space and time. Massively parallel sequencing (MPS) makes it possible to acquire entire organelle genome sequences to identify cryptic variation that would be difficult to detect otherwise. We are using MPS to evaluate intraspecific chloroplast-level divergence across biogeographic boundaries in narrowly endemic and widespread species of Pinus. We focus on one of the world's rarest pines - Torrey pine (Pinus torreyana) - due to its conservation interest and because it provides a marked contrast to more widespread pine species. Detailed analysis of nearly 90% ( approximately 105 000 bp each) of these chloroplast genomes shows that mainland and island populations of Torrey pine differ at five sites in their plastome, with the differences fixed between populations. This is an exceptionally low level of divergence (1 polymorphism/ approximately 21 kb), yet it is comparable to intraspecific divergence present in widespread pine species and species complexes. Population-level organelle genome sequencing offers new vistas into the timing and magnitude of divergence within species, and is certain to provide greater insight into pollen dispersal, migration patterns and evolutionary dynamics in plants.

Racial disparities in pre-operative pain, function and disease activity for patients with rheumatoid arthritis undergoing Total knee or Total hip Arthroplasty: a New York based study.

BACKGROUND: Black and Hispanic patients with osteoarthritis have more pain and worse function than Whites at the time of arthroplasty. Whether this is true for patients with rheumatoid arthritis (RA) is unknown. METHODS: This cross-sectional study used data on RA patients acquired between October 2013 and November 2018 prior to elective total knee (TKA) or hip arthroplasty (THA). Pain, function, and disease activity were assessed using the visual analogue scale (VAS), the Multidimensional Health Assessment Questionnaire (MDHAQ), and the Disease Activity Score (DAS28-ESR). We linked the cases to census tracts using geocoding to determine the community poverty level. Race, education, income, insurance and medications were collected via self-report. Using multivariable linear and logistic models we examined whether minority status predicted pain, function and RA disease activity at the time of arthroplasty. RESULTS: Thirty seven (23%) of the 164 patients were Black or Hispanic (minorities). The MDHAQ and DAS28-ESR were not significantly worse while VAS pain score was significantly worse in minority patients (p = 0.03). There was no significant difference in education between the groups. Insurance varied significantly; 29% of minority patients had Medicaid vs. 0% of Whites (p < 0.0001). In the multivariable analyses minority status was not significantly associated with DAS28-ESR [p = 0.66], MDHAQ [p = 0.26], or VAS pain [p = 0.18]. CONCLUSIONS: For Black and/or Hispanic patients with RA undergoing THA or TKA at a high-volume specialty hospital, unlike Black or Hispanic patients with osteoarthritis (OA), there was no association with worse pain, function, or RA disease activity at the time of elective arthroplasty.

Post-eruptive flooding of Santorini caldera and implications for tsunami generation.

Caldera-forming eruptions of island volcanoes generate tsunamis by the interaction of different eruptive phenomena with the sea. Such tsunamis are a major hazard, but forward models of their impacts are limited by poor understanding of source mechanisms. The caldera-forming eruption of Santorini in the Late Bronze Age is known to have been tsunamigenic, and caldera collapse has been proposed as a mechanism. Here, we present bathymetric and seismic evidence showing that the caldera was not open to the sea during the main phase of the eruption, but was flooded once the eruption had finished. Inflow of water and associated landsliding cut a deep, 2.0-2.5 km3, submarine channel, thus filling the caldera in less than a couple of days. If, as at most such volcanoes, caldera collapse occurred syn-eruptively, then it cannot have generated tsunamis. Entry of pyroclastic flows into the sea, combined with slumping of submarine pyroclastic accumulations, were the main mechanisms of tsunami production.

A detailed angiographic analysis of patients with ambulatory electrocardiographic ischemia: results from the Asymptomatic Cardiac Ischemia Pilot (ACIP) study angiographic core laboratory.

OBJECTIVES: The purpose of this Asymptomatic Cardiac Ischemia Pilot (ACIP) data bank study was to characterize angiographic features of coronary pathology of patients enrolled in the ACIP study. BACKGROUND: Ischemia during ambulatory electrocardiographic (AECG) monitoring is associated with increased morbidity and mortality. Reports relating AECG ischemia to severity or complexity of coronary artery disease are few in number and small in size and have produced conflicting results. METHODS: Coronary angiograms from patients with asymptomatic AECG ischemia enrolled in the ACIP study were reviewed at a central core laboratory. Quantitative measurement of percent stenosis and Thrombolysis in Myocardial Infarction flow grades were used to assess the severity of coronary artery disease. Lesions were also evaluated for the presence of intracoronary thrombus, ulceration and lumen contour as indicators of stenosis complexity. In addition, comparisons were made with 27 patients screened for the ACIP study, but who were found ineligible because they did not have AECG ischemia on 48-h Holter monitoring. RESULTS: A total of 329 (75%) of 439 patients with AECG ischemia had multivessel coronary artery disease. Proximal stenoses > or = 50% diameter reduction were common in patients with AECG ischemia (62.2%), as were proximal stenoses > or = 70% (38.7%). Features suggesting complex plaque were found in 50.1% of patients with AECG ischemia. CONCLUSIONS: Multivessel coronary artery disease, severe proximal stenoses and features of complex plaque were observed frequently in patients who exhibited AECG ischemia. The presence of severe and complex coronary artery disease may explain, in part, the increased risk for adverse outcome associated with ischemia during activities of daily life.

Ancient population genomics and the study of evolution.

Recently, the study of ancient DNA (aDNA) has been greatly enhanced by the development of second-generation DNA sequencing technologies and targeted enrichment strategies. These developments have allowed the recovery of several complete ancient genomes, a result that would have been considered virtually impossible only a decade ago. Prior to these developments, aDNA research was largely focused on the recovery of short DNA sequences and their use in the study of phylogenetic relationships, molecular rates, species identification and population structure. However, it is now possible to sequence a large number of modern and ancient complete genomes from a single species and thereby study the genomic patterns of evolutionary change over time. Such a study would herald the beginnings of ancient population genomics and its use in the study of evolution. Species that are amenable to such large-scale studies warrant increased research effort. We report here progress on a population genomic study of the Adélie penguin (Pygoscelis adeliae). This species is ideally suited to ancient population genomic research because both modern and ancient samples are abundant in the permafrost conditions of Antarctica. This species will enable us to directly address many of the fundamental questions in ecology and evolution.

Fibrinolytic activity of plaques and white matter in multiple sclerosis.

Recent work has implicated plasminogen activator released from macrophages as a possible mediator of the demyelinating process in experimental allergic encephalomyelitis and multiple sclerosis (MS). We have studied the capacity of white matter and plaques from MS patients to break down fibrin clots, using a histochemical technique. Fibrinolytic activity was localized exclusively to areas around blood vessels and capillaries in both patients and controls. While there was marked variation between individuals, the unaffected white matter from MS patients was, on the average, not more active than that of controls, but plaques tended to show more numerous foci of lysis, often also more intense, than adjacent white matter; there was no correlation with disease activity or age of the plaques as determined by histological criteria. The localization and degree of fibrinolysis observed were not related to the presence of lymphocytic infiltrates, gliosis, or macrophages. However, the findings do not exclude an involvement of fibrinolytic enzymes (although originating from vascular endothelium rather than macrophages) in the genesis of the MS plaque, which commonly starts around a small vein.

Results of elective stenting of branch-ostial lesions.

Coronary stenting using both Palmaz-Schatz and Gianturco-Roubin stents for branch ostial lesions was performed in 48 patients with high success and low complication rates. The 6-month event-free survival rates were high in these patients.

Dominant syndrome with isolated cryptophthalmos and ocular anomalies.

We report on a mother and daughter with nonsyndromal cryptophthalmos. Both patients have additional ocular anomalies, including microphthalmia, retinal dysplasia, and Peters anomaly. The periocular and lid changes seen in these individuals are distinct from those seen in typical cryptophthalmos. The apparent dominant mode of inheritance in this family distinguishes this condition from autosomal recessive isolated cryptophthalmos and from the Fraser or cryptophthalmos syndrome.