Fasciotomy for chronic exertional compartment syndrome of the leg: clinical outcome in a large retrospective cohort.

BACKGROUND: Chronic exertional compartment syndrome (CECS) is an overuse disorder typically affecting an athletic population. CECS is a diagnosis based on history and intracompartmental pressure (ICP) testing. CECS patients can be treated surgically by fasciotomy; however, research on the relationship between ICP and patient symptoms and also between ICP and patient-reported outcome post-fasciotomy is limited. This study aims to (1) assess functional outcome and patient satisfaction post-fasciotomy and (2) identify any potential correlation between ICP and reported levels of pain. METHODS: 138 CECS patients who had ICP measurements and subsequently underwent fasciotomy were identified from our regional service for exercise-induced lower limb extremity pain between January 2000 and March 2017. Clinical outcomes were recorded at the time of ICP testing and in the post-operative follow-up clinic. Pain was reported using a verbal rating scale (VRS) ('low', 'moderate' or 'high') or as a visual analogue score (VAS) 0-10 (0 = least painful, 10 = most painful). Spearman's ranked correlation test was used to calculate correlation between ICP and reported pain. RESULTS: A total of 138 patients were eligible for inclusion in this study (mean age 29.7 ± 9.7 years, 110 M, 28 F) of which 109 patients (VRS n = 61, VAS n = 48) reported pain level at pre- and post-operative stages. Mean pre-operative VAS score was 8.52 ± 0.71, and decreased to 0.77 ± 0.69 post-operatively. An insignificant positive correlation (r = 0.046, two-tailed p = 0.76) was found between VAS pain and ICP. A significant moderate positive correlation (r = 0.497, two-tailed p = 0.01) was found between VRS pain and ICP. CONCLUSION: Fasciotomy significantly reduces pain and increases activity levels in CECS patients. ICP was found to positively correlate with patient-reported pain.

Attenuating the rate of total body fat accumulation and alleviating liver damage by oral administration of vitamin D-enriched edible mushrooms in a diet-induced obesity murine model is mediated by an anti-inflammatory paradigm shift.

BACKGROUND: Hypovitaminosis D is associated with many features of the metabolic syndrome, including non-alcoholic fatty liver disease. Vitamin D-enriched mushrooms extracts exert a synergistic anti-inflammatory effect. The aim of the present study is to determine the immunomodulatory effect of oral administration of vitamin D-enriched mushrooms extracts on high-fat diet (HFD) animal model of non-alcoholic steatohepatitis (NASH). METHODS: C57BL/6 mice on HFD were orally administered with vitamin D supplement, Lentinula edodes (LE) mushrooms extract, or vitamin D-enriched mushrooms extract for 25 weeks. Mice were studied for the effect of the treatment on the immune system, liver functions and histology, insulin resistance and lipid profile. RESULTS: Treatment with vitamin D-enriched LE extracts was associated with significant attenuation of the rate of total body fat accumulation, along with a decrease in hepatic fat content as measured by an EchoMRI. Significant alleviation of liver damage manifested by a marked decrease in ALT, and AST serum levels (from 900 and 1021 U/L in the control group to 313 and 340; 294 and 292; and 366 and 321 U/L for ALT and AST, in Vit D, LE and LE + Vit D treated groups, respectively). A corresponding effect on hepatocyte ballooning were also noted. A significant decrease in serum triglycerides (from 103 to 75, 69 and 72 mg/dL), total cholesterol (from 267 to 160, 157 and 184 mg/dL), and LDL cholesterol (from 193 mg/dL to 133, 115 and 124 mg/dL) along with an increase in the HDL/LDL ratio, and improved glucose levels were documented. These beneficial effects were associated with a systemic immunomodulatory effect associated with an increased CD4/CD8 lymphocyte ratio (from 1.38 in the control group to 1.69, 1.71 and 1.63), and a pro- to an anti-inflammatory cytokine shift. CONCLUSIONS: Oral administration of vitamin-D enriched mushrooms extracts exerts an immune modulatory hepato-protective effect in NASH model.

A trans-Atlantic examination of haddock Melanogrammus aeglefinus food habits.

The food habits of Melanogrammus aeglefinus were explored and contrasted across multiple north-eastern and north-western Atlantic Ocean ecosystems, using databases that span multiple decades. The results show that among all ecosystems, echinoderms are a consistent part of M. aeglefinus diet, but patterns emerge regarding where and when M. aeglefinus primarily eat fishes v. echinoderms. Melanogrammus aeglefinus does not regularly exhibit the increase in piscivory with ontogeny that other gadoids often show, and in several ecosystems there is a lower occurrence of piscivory. There is an apparent inverse relationship between the consumption of fishes and echinoderms in M. aeglefinus over time, where certain years show high levels of one prey item and low levels of the other. This apparent binary choice can be viewed as part of a gradient of prey options, contingent upon a suite of factors external to M. aeglefinus dynamics. The energetic consequences of this prey choice are discussed, noting that in some instances it may not be a choice at all.

Effect of ethnicity on care pathway and outcomes in patients hospitalized with influenza A(H1N1)pdm09 in the UK.

Data were extracted from the case records of UK patients admitted with laboratory-confirmed influenza A(H1N1)pdm09. White and non-White patients were characterized by age, sex, socioeconomic status, pandemic wave and indicators of pre-morbid health status. Logistic regression examined differences by ethnicity in patient characteristics, care pathway and clinical outcomes; multivariable models controlled for potential confounders. Whites (n = 630) and non-Whites (n = 510) differed by age, socioeconomic status, pandemic wave of admission, pregnancy, recorded obesity, previous and current smoking, and presence of chronic obstructive pulmonary disease. After adjustment for a priori confounders non-Whites were less likely to have received pre-admission antibiotics [adjusted odds ratio (aOR) 0·43, 95% confidence interval (CI) 0·28-0·68, P < 0·001) but more likely to receive antiviral drugs as in-patients (aOR 1·53, 95% CI 1·08-2·18, P = 0·018). However, there were no significant differences by ethnicity in delayed admission, severity at presentation for admission, or likelihood of severe outcome.

Simultaneous neutralization and innate immune detection of a replicating virus by TRIM21.

Tripartite motif-containing 21 (TRIM21) is a cytosolic immunoglobulin receptor that mediates antibody-dependent intracellular neutralization (ADIN). Here we show that TRIM21 potently inhibits the spreading infection of a replicating cytopathic virus and activates innate immunity. We used a quantitative PCR (qPCR)-based assay to measure in vitro replication of mouse adenovirus type 1 (MAV-1), a virus that causes dose-dependent hemorrhagic encephalitis in mice. Using this assay, we show that genetic ablation of TRIM21 or chemical inhibition of either the AAA ATPase p97/valosin-containing protein (VCP) or the proteasome results in a >1,000-fold increase in the relative level of infection in the presence of immune serum. Moreover, the TRIM21-mediated ability of antisera to block replication was a consistent feature of the humoral immune response in immunized mice. In the presence of immune sera and upon infection, TRIM21 also activates a proinflammatory response, resulting in secretion of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). These results demonstrate that TRIM21 provides a potent block to spreading infection and induces an antiviral state.

Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice.

Endogenous glucocorticoids are essential for mobilizing energy resources, restraining inflammatory responses and coordinating behavior to an immune challenge. Impaired glucocorticoid receptor (GR) function has been associated with impaired metabolic processes, enhanced inflammation and exaggerated sickness and depressive-like behaviors. To discern the molecular mechanisms underlying GR regulation of physiologic and behavioral responses to a systemic immune challenge, GR(dim) mice, in which absent GR dimerization leads to impaired GR-DNA-binding-dependent mechanisms but intact GR protein-protein interactions, were administered low-dose lipopolysaccharide (LPS). GR(dim)-LPS mice exhibited elevated and prolonged levels of plasma corticosterone (CORT), interleukin (IL)-6 and IL-10 (but not plasma tumor necrosis factor-α (TNFα)), enhanced early expression of brain TNFα, IL-1ß and IL-6 mRNA levels, and impaired later central TNFα mRNA expression. Exaggerated sickness behavior (lethargy, piloerection, ptosis) in the GR(dim)-LPS mice was associated with increased early brain proinflammatory cytokine expression and late plasma CORT levels, but decreased late brain TNFα expression. GR(dim)-LPS mice also exhibited sustained locomotor impairment in the open field, body weight loss and metabolic alterations measured by indirect calorimetry, as well as impaired thermoregulation. Taken together, these data indicate that GR dimerization-dependent DNA-binding mechanisms differentially regulate systemic and central cytokine expression in a cytokine- and time-specific manner, and are essential for the proper regulation and recovery of multiple physiologic responses to low-dose endotoxin. Moreover, these results support the concept that GR protein-protein interactions are not sufficient for glucocorticoids to exert their full anti-inflammatory effects and suggest that glucocorticoid responses limited to GR monomer-mediated transcriptional effects could predispose individuals to prolonged behavioral and metabolic sequelae of an enhanced inflammatory state.

Hemorrhoidal dearterialization with mucopexy versus hemorrhoidectomy: 3-year follow-up assessment of a randomized controlled trial.

BACKGROUND: A randomized controlled trial showed that patients with grade III or IV internal hemorrhoids had similar symptomatic relief of symptoms up to 3 months following dearterialization with mucopexy or hemorrhoidectomy albeit with less postoperative pain after the former. This study aimed to compare hemorrhoidal recurrence and chronic complications at 3-year follow-up. METHODS: This study was carried out on 40 patients with grade III or IV internal hemorrhoids previously enrolled to a randomized trial comparing dearterialization to hemorrhoidectomy. Recurrence was defined as internal hemorrhoids diagnosed on proctoscopy. Chronic complications were nonresolving adverse events related to surgery. Outcome measures included patient-reported outcomes and quality of life measured by brief pain inventory (BPI), SF-12, and fecal incontinence surveys. RESULTS: At median follow-up of 36 (27-43) months, 13 patients (32.5 %) were lost to follow-up. Patient-reported outcomes suggested no difference between dearterialization and hemorrhoidectomy in persistent symptoms, occurring in 1 (8.3 %) vs. 2 (13.3 %) patients (p = 0.681) and in symptom recurrence, occurring in 6 (50 %) vs. 4 (26.7 %) patients (p = 0.212). On proctoscopy, recurrence was seen in 2 (13.3 %) vs. 1 (6.7 %) patients (p = 0.411), all with index grade IV disease. One patient in each arm required reoperation (p = 0.869). Chronic complications were not seen in the dearterialization arm while they occurred in 2 (13.3 %) hemorrhoidectomy patients (p = 0.189) and included unhealed wound (n = 1), anal fissure (n = 1) and fecal incontinence (n = 1). There was a trend toward more patient reported than actual recurrence on proctoscopy (10 vs. 3, p = 0.259). There was no difference in BPI, SF-12, and fecal incontinence quality of life scores. CONCLUSIONS: Recurrence rates did not differ significantly at 3-year follow-up and occurred in patients with index grade IV hemorrhoids. Chronic complications occurred only after hemorrhoidectomy.

Self-administered mindfulness interventions reduce stress in a large, randomized controlled multi-site study.

Mindfulness witnessed a substantial popularity surge in the past decade, especially as digitally self-administered interventions became available at relatively low costs. Yet, it is uncertain whether they effectively help reduce stress. In a preregistered (OSF https://doi.org/10.17605/OSF.IO/UF4JZ ; retrospective registration at ClinicalTrials.gov NCT06308744 ) multi-site study (nsites = 37, nparticipants = 2,239, 70.4% women, Mage = 22.4, s.d.age = 10.1, all fluent English speakers), we experimentally tested whether four single, standalone mindfulness exercises effectively reduced stress, using Bayesian mixed-effects models. All exercises proved to be more efficacious than the active control. We observed a mean difference of 0.27 (d = -0.56; 95% confidence interval, -0.43 to -0.69) between the control condition (M = 1.95, s.d. = 0.50) and the condition with the largest stress reduction (body scan: M = 1.68, s.d. = 0.46). Our findings suggest that mindfulness may be beneficial for reducing self-reported short-term stress for English speakers from higher-income countries.

Growth of textured thin Au coatings on iron oxide nanoparticles with near infrared absorbance.

A homologous series of Au coated iron oxide nanoparticles with hydrodynamic diameters smaller than 60 nm was synthesized with very low Au-to-iron mass ratios, as low as 0.15. The hydrodynamic diameter was determined by dynamic light scattering and the composition by atomic absorption spectroscopy and energy dispersive x-ray spectroscopy. Unusually low Au precursor supersaturation levels were utilized to nucleate and grow Au coatings on iron oxide relative to the formation of pure Au nanoparticles. This approach produced unusually thin coatings by lowering autocatalytic growth of Au on Au, as shown by transmission electron microscopy. Nearly all of the nanoparticles were attracted by a magnet, indicating a minimal number of pure Au particles. The coatings were sufficiently thin to shift the surface plasmon resonance to the near infrared with large extinction coefficients, despite the small particle hydrodynamic diameters observed from dynamic light scattering to be less than 60 nm.

The impact of intravenous fluid administration on complication rates in bowel surgery within an enhanced recovery protocol: a randomized controlled trial.

AIM: A randomized controlled trial was conducted to test the hypothesis that there is no difference in complications in patients receiving intravenous (iv) water and electrolyte, based on either stroke volume or clinical indicators at bowel surgery. METHOD: Eligible patients were randomized either to intra-operative iv administration of fluid boluses based on stroke volume measured by oesophageal Doppler (probe arm) or to iv fluid based on clinical indicators (no-probe arm). The end-point was the complication rate, defined as deviation from an uneventful postoperative course. Surgery was defined as elective bowel resection with primary anastomosis. All patients were on an enhanced recovery protocol. A randomized controlled trial suggested a sample size of 91 patients. RESULTS: Ninety-one patients were randomized. Seventeen were excluded because of withdrawal of consent, failure of the procedure or cancellation of surgery. Patients were comparable for age (P = 0.89), gender (P = 0.14), body mass index (BMI) (P = 0.7), American Society of Anesthesiology (ASA) score (P > 0.9), race (P = 0.55), colorectal POSSUM score (P = 0.11), comorbidity (P = 0.4), previous operations (P = 0.45) and diagnosis (P = 0.50). Physiological and Operative Severity Score for the Enumeration of Morbidity and Mortality (POSSUM)-predicted mortality was higher in the test (probe) arm (P = 0.011). No differences were observed in epidural analgesia (P = 0.16), type of resection (P = 0.43), incision length (P = 0.40), type of incision (P = 0.47), operation time (P = 0.92), estimated blood loss (EBL) (P = 0.56), time to ambulation (P = 0.95), flatus (P = 0.37), diet (P = 0.17), removal of the epidural anaesthesia (P = 0.26) and length of hospital stay (LOS) (P = 0.575). Intra-operative fluids administered were 3.1 (0.7-77) vs 4 (0.9-6.2) liters (P = 0.53). Postoperative fluids administered were 12.5 (5.5-84.6) vs 11.3 (3.4-49.8) (P = 0.42). Overall and septic complication rates were significantly decreased in the test arm (7/32 (22%) vs 19/40 (49%) (P = 0.022) and 2/32 (6.2%) vs 12/40 (30%) (P = 0.05), respectively). CONCLUSION: Intra-operative administration of iv water and electrolyte during bowel surgery, based on stroke volume measured using oesophageal Doppler, was associated with decreased complication rates.

A YAC-based physical map of the mouse genome.

A physical map of the mouse genome is an essential tool for both positional cloning and genomic sequencing in this key model system for biomedical research. Indeed, the construction of a mouse physical map with markers spaced at an average interval of 300 kb is one of the stated goals of the Human Genome Project. Here we report the results of a project at the Whitehead Institute/MIT Center for Genome Research to construct such a physical map of the mouse. We built the map by screening sequenced-tagged sites (STSs) against a large-insert yeast artificial chromosome (YAC) library and then integrating the STS-content information with a dense genetic map. The integrated map shows the location of 9,787 loci, providing landmarks with an average spacing of approximately 300 kb and affording YAC coverage of approximately 92% of the mouse genome. We also report the results of a project at the MRC UK Mouse Genome Centre targeted at chromosome X. The project produced a YAC-based map containing 619 loci (with 121 loci in common with the Whitehead map and 498 additional loci), providing especially dense coverage of this sex chromosome. The YAC-based physical map directly facilitates positional cloning of mouse mutations by providing ready access to most of the genome. More generally, use of this map in addition to a newly constructed radiation hybrid (RH) map provides a comprehensive framework for mouse genomic studies.

Energetic Electron Precipitation Driven by Electromagnetic Ion Cyclotron Waves from ELFIN's Low Altitude Perspective.

We review comprehensive observations of electromagnetic ion cyclotron (EMIC) wave-driven energetic electron precipitation using data collected by the energetic electron detector on the Electron Losses and Fields InvestigatioN (ELFIN) mission, two polar-orbiting low-altitude spinning CubeSats, measuring 50-5000 keV electrons with good pitch-angle and energy resolution. EMIC wave-driven precipitation exhibits a distinct signature in energy-spectrograms of the precipitating-to-trapped flux ratio: peaks at >0.5 MeV which are abrupt (bursty) (lasting ∼17 s, or ΔL∼0.56) with significant substructure (occasionally down to sub-second timescale). We attribute the bursty nature of the precipitation to the spatial extent and structuredness of the wave field at the equator. Multiple ELFIN passes over the same MLT sector allow us to study the spatial and temporal evolution of the EMIC wave - electron interaction region. Case studies employing conjugate ground-based or equatorial observations of the EMIC waves reveal that the energy of moderate and strong precipitation at ELFIN approximately agrees with theoretical expectations for cyclotron resonant interactions in a cold plasma. Using multiple years of ELFIN data uniformly distributed in local time, we assemble a statistical database of ∼50 events of strong EMIC wave-driven precipitation. Most reside at L∼5-7 at dusk, while a smaller subset exists at L∼8-12 at post-midnight. The energies of the peak-precipitation ratio and of the half-peak precipitation ratio (our proxy for the minimum resonance energy) exhibit an L-shell dependence in good agreement with theoretical estimates based on prior statistical observations of EMIC wave power spectra. The precipitation ratio's spectral shape for the most intense events has an exponential falloff away from the peak (i.e., on either side of ∼1.45 MeV). It too agrees well with quasi-linear diffusion theory based on prior statistics of wave spectra. It should be noted though that this diffusive treatment likely includes effects from nonlinear resonant interactions (especially at high energies) and nonresonant effects from sharp wave packet edges (at low energies). Sub-MeV electron precipitation observed concurrently with strong EMIC wave-driven >1 MeV precipitation has a spectral shape that is consistent with efficient pitch-angle scattering down to ∼ 200-300 keV by much less intense higher frequency EMIC waves at dusk (where such waves are most frequent). At ∼100 keV, whistler-mode chorus may be implicated in concurrent precipitation. These results confirm the critical role of EMIC waves in driving relativistic electron losses. Nonlinear effects may abound and require further investigation.

Cross-cultural neuropsychological assessment in Europe: Position statement of the European Consortium on Cross-Cultural Neuropsychology (ECCroN).

Over the past decades European societies have become increasingly diverse. This diversity in culture, education, and language significantly impacts neuropsychological assessment. Although several initiatives are under way to overcome these barriers - e.g. newly developed and validated test batteries - there is a need for more collaboration in the development and implementation of neuropsychological tests, such as in the domains of social cognition and language.To address these gaps in cross-cultural neuropsychological assessment in Europe, the European Consortium on Cross-Cultural Neuropsychology (ECCroN) was established in 2019.ECCroN recommends taking a broad range of variables into account, such as linguistic factors, literacy, education, migration history, acculturation and other cultural factors. We advocate against race-based norms as a solution to the challenging interpretation of group differences on neuropsychological tests, and instead support the development, validation, and standardization of more widely applicable/cross-culturally applicable tests that take into account interindividual variability. Last, ECCroN advocates for an improvement in the clinical training of neuropsychologists in culturally sensitive neuropsychological assessment, and the development and implementation of guidelines for interpreter-mediated neuropsychological assessment in diverse populations in Europe.ECCroN may impact research and clinical practice by contributing to existing theoretical frameworks and by improving the assessment of diverse individuals across Europe through collaborations on test development, collection of normative data, cross-cultural clinical training, and interpreter-mediated assessment.

Enhanced uptake and photoactivation of topical methyl aminolevulinate after fractional CO2 laser pretreatment.

BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) of thick skin lesions is limited by topical drug uptake. Ablative fractional resurfacing (AFR) creates vertical channels that may facilitate topical PDT drug penetration and improve PDT-response in deep skin layers. The purpose of this study was to evaluate whether pre-treating the skin with AFR before topically applied methyl aminolevulinate (MAL) could enable a deep PDT-response. MATERIALS AND METHODS: Yorkshire swine were treated under general anesthesia with a fractional CO(2) laser using stacked single pulses of 3 milliseconds, 91.6 mJ per pulse and subsequent topical MAL application for 3 hours (Metvix®). Red light (LED arrays) was then delivered at fluences of 37 and 200 J/cm(2). Fluorescent photography and microscopy was used to quantify MAL-induced porphyrin distribution and PDT-induced photobleaching at the skin surface and five specific depths down to 1,800 µm. RESULTS: Laser-ablated channels were approximately 1,850 µm deep, which significantly increased topical MAL-induced porphyrin fluorescence (hair follicles, dermis, P < 0.0001) and PDT response, both superficially and deep, versus topical MAL application alone. The fraction of porphyrin fluorescence lost by photobleaching was slightly less after 37 J/cm(2) than after 200 J/cm(2) (overall median values 67-90%; 37 vs. 200 J/cm(2), P > 0.05 for all but one comparison). Photobleaching was steady throughout skin layers and did not vary significantly with skin depth at either LED fluence (P > 0.05). CONCLUSIONS: AFR greatly facilitates topical MAL-induced porphyrins and the fraction of photobleached porphyrins is similar for superficial and deep skin. These observations are consistent with AFR-enhanced uptake of MAL, increased porphyrin synthesis, and photodynamic activation of deep porphyrins even at the lower fluence of 37 J/cm(2), widely used in clinical practice. AFR appears to be a clinically practical means for improving PDT deep into the skin. Clinical studies are suggested to evaluate selectivity in targeting dysplastic cell types.

The effectiveness of clinical pathway software in inpatient settings: A systematic review.

BACKGROUND: Various studies have assessed the effectiveness of clinical pathways (CPs) in inpatient settings and provided systematic evidence that they positively affect patient outcomes and efficiency of care, thus lowering costs. In recent years, CP implementation is often combined or extended with clinical pathway software (CPS). Until now, no systematic literature review appears to exist which synthesizes the evidence on the effectiveness of CPS in inpatient settings, in relation to the CPs they support. OBJECTIVES: The purpose of this study was to systematically review evidence on (perceived) effectiveness of clinical pathway software (CPS) and investigate mechanisms explaining the effects of CPS implementation on outcomes. METHODS: We searched MEDLINE via PubMed and Scopus, for English-language original articles. Articles were included if they examined the effectiveness and/or the perceived effectiveness of CPS in the inpatient setting. They were analyzed for evidence on structure, process and outcome effects, as well as for mechanisms explaining such effects in relation to contextual factors. RESULTS: From 2904 articles, 12 studies met our inclusion criteria. The seven studies reporting on adherence provide conclusive evidence that CPSs can improve adherence. We also found conclusive evidence of improvement of process related measures regarding appropriate diagnostics, timeliness of care, and length of stay (LOS). Evidence on costs and outcomes is weak and/or less conclusive. This holds true both for patient outcomes (e.g. mortality/patient satisfaction) and caregiver outcomes (e.g. user satisfaction). The studies presented no direct evidence on mechanisms explaining how CPS relate to process and outcome improvements. CONCLUSIONS: The primary effects of CPS to increase adherence may in turn positively impact other process indicators such as LOS, timeliness of care, and diagnostic effectiveness. Subsequent effects on costs, outcomes for patients, physicians and nurses remain inconclusive and call for further research. Further research should explicitly take context into account. The scarce and weak evidence-base relating CPS implementation to process and outcome effects needs development along the same lines.

Evidences and drivers of ocean deoxygenation off Peru over recent past decades.

Deoxygenation is a major threat to the coastal ocean health as it impacts marine life and key biogeochemical cycles. Understanding its drivers is crucial in the thriving and highly exploited Peru upwelling system, where naturally low-oxygenated subsurface waters form the so-called oxygen minimum zone (OMZ), and a slight vertical shift in its upper limit may have a huge impact. Here we investigate the long-term deoxygenation trends in the upper part of the nearshore OMZ off Peru over the period 1970-2008. We use a unique set of dissolved oxygen in situ observations and several high-resolution regional dynamical-biogeochemical coupled model simulations. Both observation and model present a nearshore deoxygenation above 150 m depth, with a maximum trend of - 10 µmol kg-1 decade1, and a shoaling of the oxycline depth (- 6.4 m decade-1). Model sensitivity analysis shows that the modeled oxycline depth presents a non-significant (+ 0.9 m decade-1) trend when remote forcing is suppressed, while a significant oxycline shoaling (- 3 m decade-1) is obtained when the wind variability is suppressed. This indicates that the nearshore deoxygenation can be attributed to the slowdown of the near-equatorial eastward currents, which transport oxygen-rich waters towards the Peruvian shores. The large uncertainties in the estimation of this ventilation flux and the consequences for more recent and future deoxygenation trends are discussed.

Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span.

Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function. Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented age-associated capillary loss, improved organ perfusion and function, and extended life span. Healthier aging was evidenced by favorable metabolism and body composition and amelioration of aging-associated pathologies including hepatic steatosis, sarcopenia, osteoporosis, "inflammaging" (age-related multiorgan chronic inflammation), and increased tumor burden. These results indicate that VEGF signaling insufficiency affects organ aging in mice and suggest that modulating this pathway may result in increased mammalian life span and improved overall health.

Mechanisms of mouse spleen dendritic cell function in the generation of influenza-specific, cytolytic T lymphocytes.

We have evaluated the capacity of dendritic cells to function as antigen-presenting cells (APCs) for influenza and have examined their mechanism of action. Virus-pulsed dendritic cells were 100 times more efficient than bulk spleen cells in stimulating cytotoxic T lymphocyte (CTL) formation. The induction of CTLs required neither exogenous lymphokines nor APCs in the responding T cell population. Infectious virus entered dendritic cells through intracellular acidic vacuoles and directed the synthesis of several viral proteins. If ultraviolet (UV)-inactivated or bromelain-treated viruses were used, viral protein synthesis could not be detected, and there was poor induction of CTLs. This indicated that dendritic cells were not capable of processing noninfectious virus onto major histocompatibility complex (MHC) class I molecules. However, UV-inactivated and bromelain-treated viruses were presented efficiently to class II-restricted CD4+ T cells. The CD4+ T cells crossreacted with different strains of influenza and markedly amplified CTL formation. Cell lines that lacked MHC class II, and consequently the capacity to stimulate CD4+ T cells, failed to induce CTLs unless helper lymphokines were added. Similarly, dendritic cells pulsed with the MHC class I-restricted nucleoprotein 147-155 peptide were poor stimulators in the absence of exogenous helper factors. We conclude that the function of dendritic cells as APCs for the generation of virus-specific CTLs in vitro depends measurably upon: (a) charging class I molecules with peptides derived from endogenously synthesized viral antigens, and (b) stimulating a strong CD4+ helper T cell response.

Detection of transforming growth factor alpha in normal, malignant, and hyperproliferative human keratinocytes.

Transforming growth factor alpha (TGF-alpha) is a 50-amino acid peptide, previously demonstrated only in transformed cell lines and human tumors, which is structurally homologous to epidermal growth factor (EGF). TGF-alpha expression in keratinocytes from normal individuals, patients with psoriasis, and patients with malignant skin diseases was investigated using an mAb raised against synthetic human TGF-alpha. mAb A1.5 reacted with TGF-alpha, but not EGF, in a sensitive ELISA. Keratinocytes in eight nodular basal cell carcinomas, one morpheic basal cell carcinoma, and one squamous cell carcinoma demonstrated intense membranous immunoperoxidase staining with mAb A1.5. Of even greater interest was the observation that the overlying normal epidermis, as well as the epidermis from five normal skin specimens, were stained by the mAb. Keratinocytes in plaques from 18 psoriasis patients were more intensely stained than those from normal skin. Cultured normal keratinocytes demonstrated membranous staining with mAb A1.5. Absorption of mAb A1.5 with synthetic human TGF-alpha completely removed the reactivity of mAb A1.5 with both basal cell tumors and normal epidermis. The demonstration of TGF-alpha in normal keratinocytes suggests that it plays a role in normal keratinocyte growth, wound healing, and in the pathogenesis of acanthosis.

Synthetic peptides from the circumsporozoite proteins of Plasmodium falciparum and Plasmodium knowlesi recognize the human hepatoma cell line HepG2-A16 in vitro.

Several lines of evidence have emphasized the importance of the malaria circumsporozoite (CS) protein as a factor in sporozoite invasion of the hepatocyte; however, the specific mechanism of cell recognition and invasion has not been explained. In this study we present evidence that a highly conserved region of the CS protein immediately adjacent to the repeat region, the N1 region, specifically recognizes receptors on the human hepatoma cell line HepG2-A16 under conditions where invasion by sporozoites can occur. Peptides consisting of sequences from the repeat region or of the more extensive N2 region showed no such specific association. Antibody against the N1 peptide could inhibit sporozoite invasion in vitro. Covalent coupling of radiolabeled N1 peptide to HepG2-A16 cells identified two hepatic cell proteins to be closely associated with the peptide. We suggest that these proteins could act as receptors or mediators, via the N1 region of the CS protein, for the P. falciparum sporozoite in the process of invasion of the hepatocyte.