Secret messengers: Extracellular RNA communication in the immune system.

One of the hallmarks of the immune system is a dynamic landscape of cellular communication through the secretion of soluble factors, production of cell-bound ligands, and expression of surface receptors. This communication affects all aspects of immune cell behavior, integrates the responses of immune cells in tissues, and is fundamental to orchestrating effective immunity. Recent pioneering work has shown that the transfer of ribonucleic acids (RNAs) constitutes a novel mode of cellular communication. This communication involves diverse RNA species, with short noncoding RNAs especially enriched in the extracellular space. These RNAs are highly stable and selectively packaged for secretion. Transferred RNAs have functions in target cells that both mirror their cell-intrinsic roles and adopt novel mechanisms of action. These extracellular RNAs both impact the behavior of individual immune cells and participate in local and systemic immune responses. The impacts of RNA communication on immune cells and disease states have important implications for the development of novel clinical biomarkers and innovative therapeutic designs in immune-related disease. In this review, we will discuss the foundation of knowledge that is establishing RNA communication as an active and functional process in the immune system.

Frequency-dependent diffusion kurtosis imaging in the human brain using an oscillating gradient spin echo sequence and a high-performance head-only gradient.

Measuring the time/frequency dependence of diffusion MRI is a promising approach to distinguish between the effects of different tissue microenvironments, such as membrane restriction, tissue heterogeneity, and compartmental water exchange. In this study, we measure the frequency dependence of diffusivity (D) and kurtosis (K) with oscillating gradient diffusion encoding waveforms and a diffusion kurtosis imaging (DKI) model in human brains using a high-performance, head-only MAGNUS gradient system, with a combination of b-values, oscillating frequencies (f), and echo time that has not been achieved in human studies before. Frequency dependence of diffusivity and kurtosis are observed in both global and local white matter (WM) and gray matter (GM) regions and characterized with a power-law model ∼Λ*fθ. The frequency dependences of diffusivity and kurtosis (including changes between fmin and fmax, Λ, and θ) vary over different WM and GM regions, indicating potential microstructural differences between regions. A trend of decreasing kurtosis over frequency in the short-time limit is successfully captured for in vivo human brains. The effects of gradient nonlinearity (GNL) on frequency-dependent diffusivity and kurtosis measurements are investigated and corrected. Our results show that the GNL has prominent scaling effects on the measured diffusivity values (3.5∼5.5% difference in the global WM and 6∼8% difference in the global cortex) and subsequently affects the corresponding power-law parameters (Λ, θ) while having a marginal influence on the measured kurtosis values (<0.05% difference) and power-law parameters (Λ, θ). This study expands previous OGSE studies and further demonstrates the translatability of frequency-dependent diffusivity and kurtosis measurements to human brains, which may provide new opportunities to probe human brain microstructure in health and disease.

The Relationship Between Partial and Full Range of Motion Deadlift 1-Repetition Maximum: A Technical Note.

ABSTRACT: Gillingham, B, Bishop, A, Higa, GK, Adams, KJ, and DeBeliso, M. The relationship between partial and full range of motion deadlift 1-repetition maximum: a technical note. J Strength Cond Res 37(4): 909-914, 2023-The full range of motion (FROM) or partial range of motion (PROM) deadlift (DL) are often included in resistance training (RT) programs and are performed by strength athletes in competition. This study examined the relationship between the FROM and PROM 1-repetition maximum (1RM) DL and if the PROM 1RM DL can be estimated by the FROM 1RM DL. Eighteen National Collegiate Athletic Association wrestlers (20.8 ± 1.2 years, 176.0 ± 5.2 cm, 78.9 ± 10.6 kg) performed a warm-up followed by the assessment of the FROM and PROM 1RM DLs. The FROM DLs were executed with a starting position of the bar resting on the lifting platform. Partial range of motion DLs were executed in a power rack with the bar starting position at ≈2.54 cm above the patella. Regression analysis was employed to estimate PROM 1RM DL based on FROM 1RM DL, body height, and mass. A Pearson's correlation coefficient ( r ) was used to compare the PROM 1RM DL with FROM 1RM DL. A dependent t test was used to compare the PROM 1RM DL and FROM 1RM DL scores (α < 0.05). The PROM 1RM DL scores (226.0 ± 40.6 kg) were significantly greater than the FROM 1RM DL scores (191.7 ± 37.2 kg) ( p < 0.05: effect size = 0.92). The PCC between the PROM and FROM 1RM DL was r = 0.85 ( p < 0.05). The regression coefficient for the FROM 1RM DL was significant ( p < 0.05; R = 0.85, R2 = 0.73). The regression coefficients for body mass and height were not significant ( p > 0.05). The PROM and FROM DL may be interchangeable modalities within an RT program, and the PROM 1RM DL can be accurately predicted by the FROM 1RM DL.

Cutaneous plaques associated with a putative novel papillomavirus type in a horse.

CASE HISTORY AND CLINICAL FINDINGS: A 6-year-old Thoroughbred mare developed multiple flat plaques, < 1 cm in diameter, on the left front fetlock. These were treated topically using 5-fluorouracil and resolved after 4 weeks. However, additional similar plaques developed on the left front pastern 5 months later. These lesions resolved within 3 months without treatment. PATHOLOGICAL AND MOLECULAR FINDINGS: One plaque that developed initially and one plaque that developed later were examined histologically. Both consisted of well-demarcated foci of moderate epidermal hyperplasia. Scattered throughout both plaques were cells showing evidence of papillomavirus-induced cell changes and the same papillomaviral DNA sequence was amplified from both lesions using PCR. As the novel sequence had 79.1% similarity to a partial sequence previously amplified from an equine cutaneous wart and 67.9% similarity to Equus caballus papillomavirus type 1, these results indicate detection of a putative novel papillomavirus type. DIAGNOSIS: Multiple cutaneous plaques due to infection by a novel papillomavirus type. CLINICAL RELEVANCE: Unlike more typical equine cutaneous warts which generally appear as pedunculated and filiform masses, the lesions in this horse appeared as raised plaques. With the exception of aural plaques that are confined to the ears, localised clusters of papillomaviral plaques have not been previously described in horses. The lesions contained subtle histological evidence of papillomavirus infection and careful examination is required to differentiate these plaques from pre-neoplastic lesions. The plaques contained a putative novel papillomavirus type. These results increase the spectrum of papillomavirus-induced skin disease in horses.

mm-wave Rydberg-Rydberg transitions gauge intermolecular coupling in a molecular ultracold plasma.

Out-of-equilibrium, strong correlation in a many-body system can trigger emergent properties that act to constrain the natural dissipation of energy and matter. Signs of such self-organization appear in the avalanche, bifurcation, and quench of a state-selected Rydberg gas of nitric oxide to form an ultracold, strongly correlated ultracold plasma. Work reported here focuses on the initial stages of avalanche and quench and uses the mm-wave spectroscopy of an embedded quantum probe to characterize the intermolecular interaction dynamics associated with the evolution to plasma. Double-resonance excitation prepares a Rydberg gas of nitric oxide composed of a single selected state of principal quantum number, n0. Penning ionization, followed by an avalanche of electron-Rydberg collisions, forms a plasma of NO+ ions and weakly bound electrons, in which a residual population of n0 Rydberg molecules evolves to a state of high orbital angular momentum, ℓ. Predissociation depletes the plasma of low-ℓ molecules. Relaxation ceases and n0ℓ(2) molecules with ℓ ≥ 4 persist for very long times. At short times, varying excitation spectra of mm-wave Rydberg-Rydberg transitions mark the rate of electron-collisional ℓ-mixing. Deep depletion resonances that persist for long times signal energy redistribution in the basis of central-field Rydberg states. The widths and asymmetries of Fano line shapes witness the degree to which coupling in the arrested bath (i) broadens the allowed transition and (ii) mixes the local network of levels in the ensemble.

Independently validated sex-specific nomograms for predicting survival in patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825.

BACKGROUND/PURPOSE: Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials. METHODS: This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825. RESULTS: Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males. CONCLUSIONS: A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here- https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/ .

Bipolar seesaw control on last interglacial sea level.

Our current understanding of ocean-atmosphere-cryosphere interactions at ice-age terminations relies largely on assessments of the most recent (last) glacial-interglacial transition, Termination I (T-I). But the extent to which T-I is representative of previous terminations remains unclear. Testing the consistency of termination processes requires comparison of time series of critical climate parameters with detailed absolute and relative age control. However, such age control has been lacking for even the penultimate glacial termination (T-II), which culminated in a sea-level highstand during the last interglacial period that was several metres above present. Here we show that Heinrich Stadial 11 (HS11), a prominent North Atlantic cold episode, occurred between 135 ± 1 and 130 ± 2 thousand years ago and was linked with rapid sea-level rise during T-II. Our conclusions are based on new and existing data for T-II and the last interglacial that we collate onto a single, radiometrically constrained chronology. The HS11 cold episode punctuated T-II and coincided directly with a major deglacial meltwater pulse, which predominantly entered the North Atlantic Ocean and accounted for about 70 per cent of the glacial-interglacial sea-level rise. We conclude that, possibly in response to stronger insolation and CO2 forcing earlier in T-II, the relationship between climate and ice-volume changes differed fundamentally from that of T-I. In T-I, the major sea-level rise clearly post-dates Heinrich Stadial 1. We also find that HS11 coincided with sustained Antarctic warming, probably through a bipolar seesaw temperature response, and propose that this heat gain at high southern latitudes promoted Antarctic ice-sheet melting that fuelled the last interglacial sea-level peak.

Minimal Open Hemorrhoidectomy Versus Transanal Hemorrhoidal Dearterialization: The Effect on Symptoms: An Open-Label Randomized Controlled Trial.

BACKGROUND: There is limited evidence on the long-term efficacy of transanal hemorrhoidal dearterialization compared with hemorrhoidectomy. Most studies investigated short-term effects with postoperative pain as the primary outcome. Being a benign disease, the long-term goal of treatment for hemorrhoids is the resolution of symptoms and improvement of quality of life. OBJECTIVE: The purpose of this study was to compare the effect of minimal open hemorrhoidectomy versus transanal hemorrhoidal dearterialization on patient-reported symptoms. DESIGN: This was an open-label randomized controlled trial. SETTINGS: This was a single-center study. PATIENTS: Patients with symptomatic hemorrhoids grade II to IV (Goligher's classification) were included. INTERVENTIONS: Patients were randomly allocated to minimal open hemorrhoidectomy or transanal hemorrhoidal dearterialization. MAIN OUTCOME MEASURES: The primary outcome was symptoms assessed by the Hemorrhoidal Disease Symptom Score 1 year postoperatively. Secondary outcomes included health-related quality of life, patient satisfaction, postoperative pain and recovery, adverse events, recurrence, and hospital costs. RESULTS: Forty-eight patients received minimal open hemorrhoidectomy, and 50 patients received transanal hemorrhoidal dearterialization. No difference in symptom score at 1-year follow-up was found. Median (range) symptom score was 3 (0-17) after minimal open hemorrhoidectomy and 5 (0-17) after transanal hemorrhoidal dearterialization (median difference = -1.0 (95% CI, -3.0 to 0.0); p = 0.15). Residual hemorrhoidal prolapse was reported more frequently (p = 0.008), and more patients had treatment for recurrence after transanal hemorrhoidal dearterialization (7 vs 0 patients; p = 0.013). Patient satisfaction was higher after minimal open hemorrhoidectomy (p = 0.049). No differences were found in the impact on health-related quality of life, average and peak postoperative pain, recovery, or adverse events (p > 0.05). Transanal hemorrhoidal dearterialization was more expensive (median difference = &OV0556;555 (95% CI, &OV0556;472-&OV0556;693); p < 0.001). LIMITATIONS: No blinding was included in this study. CONCLUSION: No difference was found in symptom score 1 year postoperatively. Minimal open hemorrhoidectomy had a better effect on the hemorrhoidal prolapse and higher patient satisfaction. More patients needed treatment for recurrence after transanal hemorrhoidal dearterialization. Minimal open hemorrhoidectomy has an immediate postoperative course similar to transanal hemorrhoidal dearterialization. See Video Abstract at http://links.lww.com/DCR/B152. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02061176. HEMORROIDECTOMíA MíNIMA ABIERTA VERSUS DESARTERIALIZACIóN HEMORROIDAL TRANSANAL: EL EFECTO SOBRE LOS SíNTOMAS: UN ESTUDIO ABIERTO CONTROLADO Y ALEATORIZADO: Hay evidencia limitada sobre la eficacia a largo plazo de la desarterialización hemorroidal transanal en comparación con la hemorroidectomía. La mayoría de los estudios han investigado los efectos a corto plazo con el dolor postoperatorio como el resultado primario. Al ser una enfermedad benigna, el objetivo a largo plazo del tratamiento de la enfermedad hemorroidal es la resolución de los síntomas y la mejora en la calidad de vida.Comparar el efecto de la hemorroidectomía abierta mínima versus la desarterialización hemorroidal transanal en los síntomas reportados por el paciente.Ensayo controlado aleatorizado abierto.Estudio en sede única.Pacientes con enfermedad hemorroidal sintomática de grado II-IV (clasificación de Goligher).Los pacientes fueron asignados aleatoriamente a hemorroidectomía mínima abierta o desarterialización hemorroidal transanal.El resultado primario fueron los síntomas evaluados por el Score de Síntomas de Enfermedad Hemorroidal un año después de la operación. Los resultados secundarios incluyeron calidad de vida relacionada con la salud, satisfacción del paciente, dolor y recuperación postoperatorios, eventos adversos, recurrencia y costos hospitalarios.Cuarenta y ocho pacientes recibieron hemorroidectomía abierta mínima y cincuenta pacientes recibieron desarterialización hemorroidal transanal. No se encontraron diferencias en la puntuación de los síntomas al año de seguimiento. La puntuación mediana (rango) de síntomas fue 3 (0-17) después de una hemorroidectomía mínima abierta y 5 (0-17) después de la desarterialización hemorroidal transanal (diferencia mediana [IC95%]: -1.0 [-3.0-0.0], p = 0.15). El prolapso hemorroidal residual se informó con mayor frecuencia (p = 0.008) y más pacientes recibieron tratamiento por recurrencia después de la desarterialización hemorroidal transanal (7 frente a 0 pacientes, p = 0.013). La satisfacción del paciente fue mayor después de una hemorroidectomía abierta mínima (p = 0.049). No se encontraron diferencias en el impacto sobre la calidad de vida relacionada con la salud, el dolor postoperatorio promedio y máximo, la recuperación o los eventos adversos (p> 0.05). La desarterialización hemorroidal transanal fue más costosa (diferencia mediana [IC95%]: &OV0556; 555 [472-693], p <0.001).Estudio sin cegamiento.No se encontraron diferencias en la puntuación de los síntomas a un año después de la operación. La hemorroidectomía mínima abierta tuvo un mejor efecto sobre el prolapso hemorroidal y una mayor satisfacción del paciente. Más pacientes necesitaron tratamiento para la recurrencia después de la desarterialización hemorroidal transanal. La hemorroidectomía abierta mínima tiene un curso postoperatorio inmediato similar a la desarterialización hemorroidal transanal. Consulte Video Resumen en http://links.lww.com/DCR/B152. (Traducción-Dr. Jorge Silva Velazco).ClinicalTrials.gov Identifier: NCT02061176.

Human foodborne listeriosis in England and Wales, 1981 to 2015.

Almost all cases of human listeriosis are foodborne, however the proportion where specific exposures are identified is small. Between 1981 and 2015, 5252 human listeriosis cases were reported in England and Wales. The purpose of this study was to summarise data where consumption of specific foods was identified with transmission and these comprised 11 sporadic cases and 17 outbreaks. There was a single outbreak in the community of 378 cases (7% of the total) which was associated with pâté consumption and 112 cases (2% of the total) attributed to specific foods in all the other incidents. The proportion of food-attributed cases increased during this study with improvements in typing methods for Listeria monocytogenes. Ten incidents (one sporadic case and nine outbreaks of 2-9 cases over 4 days to 32 months) occurred in hospitals: all were associated with the consumption of pre-prepared sandwiches. The 18 community incidents comprised eight outbreaks (seven of between 3 and 17 cases) and 10 sporadic cases: food of animal origin was implicated in 16 of the incidents (sliced or potted meats, pork pies, pâté, liver, chicken, crab-meat, butter and soft cheese) and food of non-animal origin in the remaining two (olives and vegetable rennet).

The use of multiple hypothesis-generating methods in an outbreak investigation of Escherichia coli O121 infections associated with wheat flour, Canada 2016-2017.

A Canadian outbreak investigation into a cluster of Escherichia coli O121 was initiated in late 2016. When initial interviews using a closed-ended hypothesis-generating questionnaire did not point to a common source, cases were centrally re-interviewed using an open-ended approach. The open-ended interviews led cases to describe exposures with greater specificity, as well as food preparation activities. Data collected supported hypothesis generation, particularly with respect to flour exposures. In March 2017, an open sample of Brand X flour from a case home, and a closed sample collected at retail of the same brand and production date, tested positive for the outbreak strain of E. coli O121. In total, 76% (16/21) of cases reported that they used or probably used Brand X flour or that it was used or probably was used in the home during their exposure period. Crucial hypothesis-generating techniques used during the course of the investigation included a centralised open-ended interviewing approach and product sampling from case homes. This was the first outbreak investigation in Canada to identify flour as the source of infection.

Sea-level and deep-sea-temperature variability over the past 5.3 million years.

Ice volume (and hence sea level) and deep-sea temperature are key measures of global climate change. Sea level has been documented using several independent methods over the past 0.5 million years (Myr). Older periods, however, lack such independent validation; all existing records are related to deep-sea oxygen isotope (δ(18)O) data that are influenced by processes unrelated to sea level. For deep-sea temperature, only one continuous high-resolution (Mg/Ca-based) record exists, with related sea-level estimates, spanning the past 1.5 Myr. Here we present a novel sea-level reconstruction, with associated estimates of deep-sea temperature, which independently validates the previous 0-1.5 Myr reconstruction and extends it back to 5.3 Myr ago. We find that deep-sea temperature and sea level generally decreased through time, but distinctly out of synchrony, which is remarkable given the importance of ice-albedo feedbacks on the radiative forcing of climate. In particular, we observe a large temporal offset during the onset of Plio-Pleistocene ice ages, between a marked cooling step at 2.73 Myr ago and the first major glaciation at 2.15 Myr ago. Last, we tentatively infer that ice sheets may have grown largest during glacials with more modest reductions in deep-sea temperature.

The painful truth: work-related musculoskeletal disorders in Australian surgeons.

BACKGROUND: Work-related musculoskeletal disorder (WRMD) is a collective term for preventable work-related disorders that cause musculoskeletal symptoms. The growing prevalence of these disorders amongst surgeons has been labelled an 'impending epidemic' and currently there is a lack of awareness and no existing intervention programme. AIMS: To estimate prevalence and identify risk factors for developing work related neck, shoulder and upper back pain in surgeons. METHODS: Cross-sectional questionnaire survey of surgeons and surgical trainees across Australia. We collected data on demographics, nature of regular operative work, hours working/operating per week, and prevalence and severity of musculoskeletal disorders based on the Nordic Musculoskeletal Questionnaire [1]. We assessed associations between categorical predictors and pain over 7 days and 12 months using Pearson's chi-square test. We assessed associations involving continuous variables using Student's t-test. Tests were two-tailed and assessed at the 5% alpha level. RESULTS: From ~2058 recipients, 329 (16%) responded; 137 (42%) surgeons reported shoulder, neck or upper back pain in a 7-day period, 245 (75%) reported pain and 101 (31%) had pain preventing normal work in a 12-month period. Significant predictors of increased prevalence included female sex (P < 0.001), decreasing age (P < 0.01) and fewer years working (P < 0.01). Body mass index (BMI) and mode of practise did not significantly affect prevalence of WRMDs. CONCLUSIONS: The prevalence of WRMDs amongst surgeons is high, females and younger surgeons reporting increased rates. There is a need to build awareness and educate surgical trainees about WRMDs.

Non-displaced Femoral Neck Stress Fractures in Young Adults: 7-Year Outcomes of Prophylactic Fixation Versus Nonoperative Treatment.

Retrospectively compare outcomes of prophylactic fixation to nonoperative treatment of incomplete or non-displaced femoral neck stress fractures (FNSF) in young adults. Outcomes of 82 patients (mean age 21.7 years) who were diagnosed with incomplete or non-displaced FNSFs from 2002 to 2015 were compared. Forty-one underwent prophylactic fixation; the remaining were treated without surgery. Fracture characteristics and complications were recorded. Pain scores, modified Harris Hip Scores (mHHS), and Hip Outcome Scores (HOS) were obtained and compared. The average fracture line in the operative group was 67% of the femoral neck width versus 18% in the nonoperative group (p < 0.001). There was no difference in outcome scores between the two groups. Prophylactic fixation of high-risk non-displaced FNSFs resulted in similar outcome scores to non-operative management of lower-risk variants at an average of 7.3 years follow up. No patient in either group progressed to a displaced femoral neck stress fracture. (Journal of Surgical Orthopaedic Advances 29(3):173-176, 2020).

Rapid Tuberculosis Diagnosis Using Reporter Enzyme Fluorescence.

Tuberculosis is the most frequent cause of death in humans from a single infectious agent. Due to low numbers of bacteria present in sputum during early infection, diagnosis does not usually occur until >3 to 4 months after symptoms develop. We created a new more sensitive diagnostic that can be carried out in 10 min with no processing or technical expertise. This assay utilizes the Mycobacterium tuberculosis-specific biomarker BlaC in reporter enzyme fluorescence (REF) that has been optimized for clinical samples, designated REFtb, along with a more specific fluorogenic substrate, CDG-3. We report the first evaluation of clinical specimens with REFtb assays in comparison to the gold standards for tuberculosis diagnosis, culture and smear microscopy. REFtb assays allowed diagnosis of 160 patients from 16 different countries with a sensitivity of 89% for smear-positive, culture-positive samples and 88% for smear-negative, culture-positive samples with a specificity of 82%. The negative predictive value of REFtb for tuberculosis infection is 93%, and the positive predictive value is 79%. Overall, these data point toward the need for larger accuracy studies by third parties using a commercially available REFtb kit to determine whether incorporation of REFtb into the clinical toolbox for suspected tuberculosis patients would improve case identification. If results similar to our own can be obtained by all diagnostic laboratories, REFtb would allow proper treatment of more than 85% of patients that would be missed during their initial visit to a clinic using current diagnostic strategies, reducing the potential for further spread of disease.

Tau drives translational selectivity by interacting with ribosomal proteins.

There is a fundamental gap in understanding the consequences of tau-ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. First, we performed microarrays and nascent proteomics to measure changes in protein synthesis. Using regulatable rTg4510 tau transgenic mice, we determined that tau expression differentially shifts both the transcriptome and the nascent proteome, and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and found that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6), a crucial regulator of translation. Consequently, protein synthesis under translational control of rpS6 was reduced under tauopathic conditions in Alzheimer's disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, since regulation of protein synthesis is critical for learning and memory, aberrant tau-ribosome interactions in disease could explain the linkage between tauopathies and cognitive impairment.

A relationship between the aldosterone-mineralocorticoid receptor pathway and alcohol drinking: preliminary translational findings across rats, monkeys and humans.

Aldosterone regulates electrolyte and fluid homeostasis through binding to the mineralocorticoid receptors (MRs). Previous work provides evidence for a role of aldosterone in alcohol use disorders (AUDs). We tested the hypothesis that high functional activity of the mineralocorticoid endocrine pathway contributes to vulnerability for AUDs. In Study 1, we investigated the relationship between plasma aldosterone levels, ethanol self-administration and the expression of CYP11B2 and MR (NR3C2) genes in the prefrontal cortex area (PFC) and central nucleus of the amygdala (CeA) in monkeys. Aldosterone significantly increased after 6- and 12-month ethanol self-administration. NR3C2 expression in the CeA was negatively correlated to average ethanol intake during the 12 months. In Study 2, we measured Nr3c2 mRNA levels in the PFC and CeA of dependent and nondependent rats and the correlates with ethanol drinking during acute withdrawal. Low Nr3c2 expression levels in the CeA were significantly associated with increased anxiety-like behavior and compulsive-like drinking in dependent rats. In Study 3, the relationship between plasma aldosterone levels, alcohol drinking and craving was investigated in alcohol-dependent patients. Non-abstinent patients had significantly higher aldosterone levels than abstinent patients. Aldosterone levels positively correlated with the number of drinks consumed, craving and anxiety scores. These findings support a relationship between ethanol drinking and the aldosterone/MR pathway in three different species.

Large outbreak of multiple gastrointestinal pathogens associated with fresh curry leaves in North East England, 2013.

A total of 592 people reported gastrointestinal illness following attendance at Street Spice, a food festival held in Newcastle-upon-Tyne, North East England in February/March 2013. Epidemiological, microbiological and environmental investigations were undertaken to identify the source and prevent further cases. Several epidemiological analyses were conducted; a cohort study; a follow-up survey of cases and capture re-capture to estimate the true burden of cases. Indistinguishable isolates of Salmonella Agona phage type 40 were identified in cases and on fresh curry leaves used in one of the accompaniments served at the event. Molecular testing indicated entero-aggregative Escherichia coli and Shigella also contributed to the burden of illness. Analytical studies found strong associations between illness and eating food from a particular stall and with food items including coconut chutney which contained fresh curry leaves. Further investigation of the food supply chain and food preparation techniques identified a lack of clear instruction on the use of fresh uncooked curry leaves in finished dishes and uncertainty about their status as a ready-to-eat product. We describe the investigation of one of the largest outbreaks of food poisoning in England, involving several gastrointestinal pathogens including a strain of Salmonella Agona not previously seen in the UK.

Rapid coupling between ice volume and polar temperature over the past 150,000 years.

Current global warming necessitates a detailed understanding of the relationships between climate and global ice volume. Highly resolved and continuous sea-level records are essential for quantifying ice-volume changes. However, an unbiased study of the timing of past ice-volume changes, relative to polar climate change, has so far been impossible because available sea-level records either were dated by using orbital tuning or ice-core timescales, or were discontinuous in time. Here we present an independent dating of a continuous, high-resolution sea-level record in millennial-scale detail throughout the past 150,000 years. We find that the timing of ice-volume fluctuations agrees well with that of variations in Antarctic climate and especially Greenland climate. Amplitudes of ice-volume fluctuations more closely match Antarctic (rather than Greenland) climate changes. Polar climate and ice-volume changes, and their rates of change, are found to covary within centennial response times. Finally, rates of sea-level rise reached at least 1.2 m per century during all major episodes of ice-volume reduction.

Translating slow-binding inhibition kinetics into cellular and in vivo effects.

Many drug candidates fail in clinical trials owing to a lack of efficacy from limited target engagement or an insufficient therapeutic index. Minimizing off-target effects while retaining the desired pharmacodynamic (PD) response can be achieved by reduced exposure for drugs that display kinetic selectivity in which the drug-target complex has a longer half-life than off-target-drug complexes. However, though slow-binding inhibition kinetics are a key feature of many marketed drugs, prospective tools that integrate drug-target residence time into predictions of drug efficacy are lacking, hindering the integration of drug-target kinetics into the drug discovery cascade. Here we describe a mechanistic PD model that includes drug-target kinetic parameters, including the on- and off-rates for the formation and breakdown of the drug-target complex. We demonstrate the utility of this model by using it to predict dose response curves for inhibitors of the LpxC enzyme from Pseudomonas aeruginosa in an animal model of infection.

MAOA expression predicts vulnerability for alcohol use.

The role of the monoamines dopamine (DA) and serotonin (5HT) and the monoamine-metabolizing enzyme monoamine oxidase A (MAOA) have been repeatedly implicated in studies of alcohol use and dependence. Genetic investigations of MAOA have yielded conflicting associations between a common polymorphism (MAOA-LPR) and risk for alcohol abuse. The present study provides direct comparison of tissue-specific MAOA expression and the level of alcohol consumption. We analyzed rhesus macaque MAOA (rhMAOA) expression in blood from males before and after 12 months of alcohol self-administration. In addition, nucleus accumbens core (NAc core) and cerebrospinal fluid (CSF) were collected from alcohol access and control (no alcohol access) subjects at the 12-month time point for comparison. The rhMAOA expression level in the blood of alcohol-naive subjects was negatively correlated with subsequent alcohol consumption level. The mRNA expression was independent of rhMAOA-LPR genotype and global promoter methylation. After 12 months of alcohol use, blood rhMAOA expression had decreased in an alcohol dose-dependent manner. Also after 12 months, rhMAOA expression in the NAc core was significantly lower in the heavy drinkers, as compared with control subjects. The CSF measured higher levels of DA and lower DOPAC/DA ratios among the heavy drinkers at the same time point. These results provide novel evidence that blood MAOA expression predicts alcohol consumption and that heavy alcohol use is linked to low MAOA expression in both the blood and NAc core. Together, the findings suggest a mechanistic link between dampened MAOA expression, elevated DA and alcohol abuse.