T cell-mediated curation and restructuring of tumor tissue coordinates an effective immune response.

Antigen-specific T cells traffic to, are influenced by, and create unique cellular microenvironments. Here we characterize these microenvironments over time with multiplexed imaging in a melanoma model of adoptive T cell therapy and human patients with melanoma treated with checkpoint inhibitor therapy. Multicellular neighborhood analysis reveals dynamic immune cell infiltration and inflamed tumor cell neighborhoods associated with CD8+ T cells. T cell-focused analysis indicates T cells are found along a continuum of neighborhoods that reflect the progressive steps coordinating the anti-tumor immune response. More effective anti-tumor immune responses are characterized by inflamed tumor-T cell neighborhoods, flanked by dense immune infiltration neighborhoods. Conversely, ineffective T cell therapies express anti-inflammatory cytokines, resulting in regulatory neighborhoods, spatially disrupting productive T cell-immune and -tumor interactions. Our study provides in situ mechanistic insights into temporal tumor microenvironment changes, cell interactions critical for response, and spatial correlates of immunotherapy outcomes, informing cellular therapy evaluation and engineering.

NOVEL PS-OME MIRNA130B-3P REDUCES INFLAMMATION AND INJURY AND IMPROVES SURVIVAL AFTER RENAL ISCHEMIA-REPERFUSION INJURY.

ABSTRACT: Introduction : Acute kidney injury (AKI) is a prevalent medical disorder characterized by a sudden decline in kidney function, often because of ischemia/reperfusion (I/R) events. It is associated with significant chronic complications, and currently available therapies are limited to supportive measures. Extracellular cold-inducible RNA-binding protein (eCIRP) has been identified as a mediator that potentiates inflammation after I/R injury. However, it has been discovered that miRNA 130b-3p acts as an endogenous inhibitor of eCIRP. To address the inherent instability of miRNA in vivo , a chemically modified miRNA mimic called PS-OME miR130 was developed. We hypothesize that administration of PS-OME miR130 after renal I/R can lead to reduced inflammation and injury in a murine model of AKI. Methods : C57BL/6 male mice underwent renal I/R by clamping of bilateral renal hilum for 30 min or sham operation. Immediately after closure, mice were intravenously administered vehicle (phosphate-buffered saline) or PS-OME miR130 at a dose of 12.5 nmol/mouse. Blood and kidneys were collected after 24 h for further analysis. Separately, mice underwent renal I/R and administered vehicle or treatment and, survival was monitored for 10 days. Results : After renal I/R, mice receiving vehicle showed a significant increase in serum markers of kidney injury and inflammation including blood urea nitrogen, NGAL, KIM-1, and IL-6. After treatment with PS-OME miR130, these markers were significantly decreased. Kidney tissue mRNA expression for injury and inflammation markers including NGAL, KIM-1, KC, and MIP-2 were increased after renal I/R; however, these markers showed a significant reduction with PS-OME miR130 treatment. Histologically, treatment with PS-OME miR130 showed a significant decrease in neutrophil infiltration and injury severity score, and decreased apoptosis. In the 10-day survival study, mice in the treatment group showed a significant reduction in mortality as compared with vehicle group. Conclusion : In a murine renal I/R model, the administration of PS-OME miR130, a direct eCIRP antagonistic miRNA mimic, resulted in the reduction of kidney inflammation and injury, and improved survival. PS-OME miR130 holds promise to be developed as novel therapeutic for AKI as an adjunct to the standard of care.

Comparación de la violencia y agresiones sufridas por el personal de salud durante la pandemia de COVID-19 en Argentina y el resto de Latinoamérica / Comparison of violence and aggressions suffered by health personnel during the COVID-19 pandemic in Argentina and the rest of Latin America

RESUMEN Objetivos. Explorar la frecuencia e impacto de la violencia contra los trabajadores de salud de Argentina y compararlo con el resto de sus pares de Latinoamérica en el contexto de la pandemia por COVID-19. Materiales y métodos. Estudio de corte transversal a través de una encuesta electrónica al personal médico y no médico de Latinoamérica que desempeño tareas asistenciales desde marzo de 2020. Se utilizó una regresión de Poisson para estimar las Razones de Prevalencia crudas (RP) y ajustadas (RPa) con sus respectivos intervalos de confianza al 95%. Resultados. Un total de 3544 participantes de 19 países respondieron la encuesta; 1992 (56,0%) residían en Argentina. Entre los mismos, el 62,9% padeció al menos un hecho de violencia: 97,7% refirió violencia verbal y 11,8% violencia física. El 41,5% de los agredidos padecieron situaciones de violencia al menos una vez por semana. El personal de salud de Argentina vivenció más frecuentemente violencia que los de otros países (62,9% vs. 54,6%, p<0,001), siendo estos eventos más habituales y estresantes (p<0,05). Además, refirieron más frecuentemente haber considerado cambiar sus tareas asistenciales y/o deseos de abandonar su profesión (p<0,001). En la regresión de Poisson, los participantes de Argentina tuvieron una prevalencia de violencia mayor que los trabajadores de salud de la región (14,6%; p<0,001). Conclusiones. Existió una elevada prevalencia de violencia contra el personal de salud de Argentina durante la pandemia por COVID-19. Estos hechos tuvieron un alto impacto negativo entre quienes los padecieron. Nuestros datos sugieren que, esto podría haber sido más frecuente en Argentina respecto de otras regiones del continente.

ABSTRACT Objectives. To explore the frequency and impact of violence against healthcare workers in Argentina and to compare it with the rest of their Latin American peers during the COVID-19 pandemic. Materials and methods. A cross-sectional study was conducted by applying an electronic survey on Latin American medical and non-medical personnel who carried out health care tasks since March 2020. We used Poisson regression to estimate crude (PR) and adjusted (aPR) Prevalence Ratios with their respective 95% confidence intervals. Results. A total of 3544 participants from 19 countries answered the survey; 1992 (56.0%) resided in Argentina. Of these, 62.9% experienced at least one act of violence; 97.7% reported verbal violence and 11.8% physical violence. Of those who were assaulted, 41.5% experienced violence at least once a week. Health personnel from Argentina experienced violence more frequently than those from other countries (62.9% vs. 54.6%, p<0.001), and these events were more frequent and stressful (p<0.05). In addition, Argentinean health personnel reported having considered changing their healthcare tasks and/or desired to leave their profession more frequently (p<0.001). In the Poisson regression, we found that participants from Argentina had a higher prevalence of violence than health workers from the region (14.6%; p<0.001). Conclusions. There was a high prevalence of violence against health personnel in Argentina during the COVID-19 pandemic. These events had a strong negative impact on those who suffered them. Our data suggest that violence against health personnel may have been more frequent in Argentina than in other regions of the continent.

Association between peripheral biomarkers and clinical response to IV ketamine for unipolar treatment-resistant depression: An open label study.

BACKGROUND: Major Depression is the leading cause of disability worldwide. A cohort of patients do not respond adequately to available antidepressants, leading to treatment-resistant depression (TRD). We evaluated the antidepressant efficacy of an acute intravenous ketamine treatment (0.5 mg/kg) for patients with unipolar TRD, and measured peripheral blood-based biomarkers associated with response to treatment. METHODS: Fifteen adults diagnosed with TRD completed an open label study of ten infusions of subanesthetic ketamine over four weeks. Out of fifteen patients, blood was collected from eleven patients at three timepoints to analyze peripheral biomarkers in isolated plasma, including IL-6, IL-10, TNF-α, BDNF, and irisin. Irisin analysis was completed using an ELISA assay, and the remaining biomarkers were analyzed together simultaneously using a multiplex immunoassay. RESULTS: Repeated ketamine infusions produced a significant decrease in total average depressive symptoms (MADRS) at all timepoints. Improvements in depressive symptoms were significant at one week, and continued to significantly decrease until two weeks, where it was maintained. Ketamine was generally well tolerated, and we observed improvements in functional impairment, anhedonia, and psychiatric symptoms, with no increases in manic symptoms. Levels of BDNF throughout treatment inversely correlated to decreases in MADRS scores, and higher levels of baseline BDNF predicted mood responses at one- and four weeks. LIMITATIONS: The study was observational and uncontrolled, with a sample size of 15. Outpatients remained on their course of medications, unless they were pharmacological agents that have previously been identified to block ketamine's effects. CONCLUSIONS: Ketamine may be an efficacious and safe pharmacological option for the acute treatment of patients suffering from severe TRD. BDNF has the potential to function as a prognostic biomarker for predicting response to ketamine treatments.

Combined protein and nucleic acid imaging reveals virus-dependent B cell and macrophage immunosuppression of tissue microenvironments.

Understanding the mechanisms of HIV tissue persistence necessitates the ability to visualize tissue microenvironments where infected cells reside; however, technological barriers limit our ability to dissect the cellular components of these HIV reservoirs. Here, we developed protein and nucleic acid in situ imaging (PANINI) to simultaneously quantify DNA, RNA, and protein levels within these tissue compartments. By coupling PANINI with multiplexed ion beam imaging (MIBI), we measured over 30 parameters simultaneously across archival lymphoid tissues from healthy or simian immunodeficiency virus (SIV)-infected nonhuman primates. PANINI enabled the spatial dissection of cellular phenotypes, functional markers, and viral events resulting from infection. SIV infection induced IL-10 expression in lymphoid B cells, which correlated with local macrophage M2 polarization. This highlights a potential viral mechanism for conditioning an immunosuppressive tissue environment for virion production. The spatial multimodal framework here can be extended to decipher tissue responses in other infectious diseases and tumor biology.

The Safety and Efficacy of Microbial Ecosystem Therapeutic-2 in People With Major Depression: Protocol for a Phase 2, Double-Blind, Placebo-Controlled Study.

BACKGROUND: The gut-brain axis is a bidirectional signaling pathway between the gastrointestinal tract and the brain; it is being studied because of its potential influence in mediating mood, anxiety, and other neuropsychiatric symptoms. Previous research examining the effects of gut microbiota on neuropsychiatric disorders suggests that gut repopulation treatments such as probiotics, microbe therapy, and fecal microbiota transplantation show promising results in treating symptoms of anxiety and depression. This study explores the use of an alternative gut repopulation treatment to fecal microbiota transplantation, known as Microbial Ecosystem Therapeutic (MET)-2, as an intervention against symptoms of depression. MET-2 is a daily, orally administered capsule containing 40 bacterial strains purified from a single healthy donor. OBJECTIVE: The primary aim of this study is to assess changes in mood in people with major depression that occur pre-, post-, and during the administration of MET-2. The secondary aims are to assess changes in anxiety symptoms, blood biomarker concentrations, and the level of repopulation of healthy gut bacteria as a response to treatment. METHODS: In this study, we will recruit 60 adults aged between 18 and 45 years old with major depression and randomly assign them to treatment or placebo groups. Patients in the treatment group will receive MET-2 once a day for 6 weeks, whereas patients in the placebo group will receive a matching placebo for 6 weeks. Participants will complete biweekly visits during the treatment period and a follow-up visit at 2 weeks post treatment. As a primary outcome measure, participants' mood will be assessed using the Montgomery-Asberg Depression Rating Scale. Secondary outcome measures include changes in mood, anxiety, early stress, gastrointestinal symptoms, and tolerability of MET-2 treatment using a series of clinical scales and changes in blood markers, particularly immunoglobulins (Igs; IgA, IgG, and IgM) and inflammatory markers (C-reactive protein, tumor necrosis factor-α, transforming growth factor-ß, interleukin-6, and interleukin-10). Changes in the relative abundance, diversity, and level of engraftment in fecal samples will be assessed using 16S rRNA sequencing. All data will be integrated to identify biomarkers that could indicate disease state or predict improvement in depressive symptoms in response to MET-2 treatment. RESULTS: Given the association between the gut microbiome and depression, we hypothesized that participants receiving MET-2 would experience greater improvement in depressive symptoms than those receiving placebo owing to the recolonization of the gut microbiome with healthy bacteria modulating the gut-brain axis connection. CONCLUSIONS: This study is the first of its kind to evaluate the safety and efficacy of a microbial therapy such as MET-2 in comparison with placebo for major depressive disorder. We hope that this study will also reveal the potential capabilities of microbial therapies to treat other psychiatric illnesses and mood disorders. TRIAL REGISTRATION: ClinicalTrials.gov NCT04602715; https://clinicaltrials.gov/ct2/show/NCT04602715. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31439.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment-emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second- line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence-based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-line treatments for acute mania. First-line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.

Perfiles fenomenológicos de evocación autobiográfica en individuos con depresión / Phenomenological profiles of autobiographical memories in individuals with depression / Perfis fenomenológicos da evocação autobiográfica em indivíduos com depressão

Los recuerdos autobiográficos se encuentran en íntima relación con los procesos de regulación emocional y con la concepción del sí mismo. Por otro lado, el acceso a los componentes fenomenológicos específicos se vería disminuido de ocurrir alteraciones afectivas. Se llevó a cabo un muestro no probabilístico intencional de 94 individuos con depresión mayor y de 188 individuos sanos de la ciudad de Buenos Aires, Argentina. Fueron comparados los componentes fenomenológicos de los recuerdos autobiográficos significativos en cuanto a su cantidad e intensidad. Asimismo, se comparó el rendimiento dentro del grupo depresivo, de acuerdo a la presencia o ausencia de episodios depresivos previos, tratamiento psicofarmacológico y severidad sintomatológica. Se encontraron diferencias significativas en la Cantidad e Intensidad Total de los componentes fenomenológicos evocados, presentando el grupo clínico una evocación reducida (p<.001). Las dimensiones Valencia, Imaginería Visual, Sensorialidad, Intersubjetividad y Claridad también presentaron diferencias significativas. No se encontraron diferencias al realizar los análisis secundarios de acuerdo a las variables clínicas. Los individuos con depresión manifestaron un patrón distintivo de evocación fenomenológica de sus recuerdos en comparación a individuos sanos. Considerar las modalidades fenomenológicas de evocación autobiográfica a la luz de los modelos cognitivos en Mindfulness e Imaginería posee implicancias clínicas de relevancia.

Autobiographical memories are deeply linked with emotional regulation processes and self-concept. Conversely, in case of affective disorders, the access to specific phenomenological components would be impaired. Intentional non-probabilistic sampling was carried out, involving 94 individuals with major depression and 188 healthy individuals in the city of Buenos Aires, Argentina. The phenomenological components of significant autobiographical recollections were contrasted, considering their quantity and intensity. In addition, the depressive individuals' performances were compared according to the presence or absence of previous depressive episodes, psychopharmacological treatment and severity of symptoms. Statistically significant differences were found in the total amount and intensity of the recalled phenomenological components, in which the clinical group presented reduced memory (p< .001). Besides, the dimensions: Valence, Visual Imagery, Sensoriality, Inter-subjectivity and Clarity also presented significant differences. Notwithstanding, non-significant differences were observed during the secondary analysis in relation to the clinical variables. Individuals with depression showed a distinctive phenomenological memory pattern in comparison to controls. Considering phenomenological memory modalities in the light of cognitive models of Mindfulness and Imagery entails relevant clinical implications.

Os registos autobiográficos encontram-se em relação íntima com os procesoss de regulação emocional e com a concepção de si mesmo. Por outro lado, os procesos de acesso aos componentes fenomenológicos específicos estariam alterados durante a ocorrência de alterações afetivas. A amostra não probabilística intencional foi constituída por 94 indivíduos com depressão maior e 188 indivíduos sãos, provenientes da cidade de Buenos Aires, Argentina. Foram comparados os componentes fenomenológicos das memorias autobiográficas significativas quanto à sua quantidade e intensidade. Ao mesmo tempo, comparou-se o rendimento do grupo depressivo de acordo com a presença ou ausência de episódios depressivos prévios, tratamento psicofarmacológico e severidade dos sintomas. Encontraram-se diferenças significativas na Quantidade e Intensidade Totais dos componentes fenomenológicos evocados, apresentando o grupo clínico uma evocação reduzida (p<0,001). Ao mesmo tempo, as dimensões Valencia, Imagem Visual, Sensorialidade, Intersubjetividade e Claridade também apresentaram diferenças significativas. Contudo, não se encontraram diferenças significativas ao realizar as análises secundárias de acordo com as variáveis clínicas. Os individuos com depressão mostraram um padrão distintivo de evocação fenomenológica de suas memórias em comparação com os controles. Considerar as modalidades fenomenológicas de evocação autobiográfica à luz dos modelos cognitivos em Mindfulness e Imagem tem implicações clínicas relevantes.

Long-term lithium treatment in bipolar disorder: effects on glomerular filtration rate and other metabolic parameters.

BACKGROUND: Concerns about potential adverse effects of long-term exposure to lithium as a mood-stabilizing treatment notably include altered renal function. However, the incidence of severe renal dysfunction; rate of decline over time; effects of lithium dose, serum concentration, and duration of treatment; relative effects of lithium exposure vs. aging; and contributions of sex and other factors all remain unclear. METHODS: Accordingly, we acquired data from 12 collaborating international sites and 312 bipolar disorder patients (6142 person-years, 2669 assays) treated with lithium carbonate for 8-48 (mean 18) years and aged 20-89 (mean 56) years. We evaluated changes of estimated glomerular filtration rate (eGFR) as well as serum creatinine, urea-nitrogen, and glucose concentrations, white blood cell count, and body-mass index, and tested associations of eGFR with selected factors, using standard bivariate contrasts and regression modeling. RESULTS: Overall, 29.5% of subjects experienced at least one low value of eGFR (<60 mL/min/1.73 m2), most after ≥15 years of treatment and age > 55; risk of ≥2 low values was 18.1%; none experienced end-stage renal failure. eGFR declined by 0.71%/year of age and 0.92%/year of treatment, both by 19% more among women than men. Mean serum creatinine increased from 0.87 to 1.17 mg/dL, BUN from 23.7 to 33.1 mg/dL, glucose from 88 to 122 mg/dL, and BMI from 25.9 to 26.6 kg/m2. By multivariate regression, risk factors for declining eGFR ranked: longer lithium treatment, lower lithium dose, higher serum lithium concentration, older age, and medical comorbidity. Later low eGFR was also predicted by lower initial eGFR, and starting lithium at age ≥ 40 years. LIMITATIONS: Control data for age-matched subjects not exposed to lithium were lacking. CONCLUSIONS: Long-term lithium treatment was associated with gradual decline of renal functioning (eGFR) by about 30% more than that was associated with aging alone. Risk of subnormal eGFR was from 18.1% (≥2 low values) to 29.5% (≥1 low value), requiring about 30 years of exposure. Additional risk factors for low eGFR were higher serum lithium level, longer lithium treatment, lower initial eGFR, and medical comorbidity, as well as older age.

Influence of Breastfeeding Time on Levels of Organochlorine Pesticides in Human Milk of a Mexican Population.

This study was conducted with the objective of determining whether there is a depuration of organochlorine pesticides in breast milk according to breastfeeding time. In total, 171 samples from mothers that lived in the State of Guerrero, Mexico were analyzed. There was a weak negative relationship between pp'DDE (r = -0.216) and Σ-DDT (r = -0.222) concentrations with the days of lactation. In a comparison analysis, a statistically significant decrease of pp'DDT and pp'DDE levels was observed, as well as the Σ-DDT from the first to the fifth week of lactation. A reduction of 0.188 mg/kg lipid of pp'DDE and 0.181 mg/kg lipid of Σ-DDT per week was obtained. HCB, ß-HCH and op'DDT concentrations were low and had no major fluctuations between subgroups. The low levels found and the observed reduction in time involve less exposure to the infant to these pollutants. Through this methodology changes in levels of certain organochlorine pesticides in various stages of human milk production may be shown.

The M235T single nucleotide polymorphism in the angiotensinogen gene is associated with coronary artery calcium in patients with a family history of coronary artery disease.

Little is known about the contribution of genetics and lipoprotein subclasses to the development of coronary artery calcification (CAC) in asymptomatic, first-degree relatives of patients with CAD. We evaluated 100 asymptomatic, non-smoking, lipid-lowering therapy-naïve, first-degree relatives of patients with obstructive CAD through testing for 27 biomarkers, 15 single nucleotide polymorphisms in 12 candidate genes, and CAC and compared them to matched controls without family history. We compared prevalence of CAC in those with and without family history and biomarkers between those with and without CAC. Mean age was 41.6 ± 9 years; 58% were female. Significantly more subjects with family history had non-zero CAC (median Agatston: 13, range 1-1107) compared to those without family history (median Agatston: 43; range 1-345) (21% vs. 9%; p = 0.028). Among subjects with family history, in subjects with positive vs. negative CAC, multivariable analysis showed significantly lower HDL-2A (999 ± 333 vs. 1262 ± 397 nmol/L) and higher frequency of a substitution of threonine for methionine at codon 235 in the angiotensinogen gene (AGT M235T) (75% vs. 54%; p < 0.05; odds ratio of 2.6 for CAC). Population attributable risk of one copy of the risk allele at the AGT locus was 16%, highest of any variable tested. In conclusion, in this population of healthy, low-risk subjects with a family history of CAD, the AGT M235T variant was the most significant predictor of CAC independent of blood pressure, raising the possibility of an alternative biological pathway.

Optimal cutoff threshold for calcium quantification in isotropic CT calcium scans by validating against registered intravascular ultrasound with radiofrequency backscatter.

3D Computed Tomography (CT) provides noninvasive, low-radiation method of coronary artery calcium (CAC) measurement. Conventional CAC images are acquired on multidetector-row CT scanners without contrast, and reconstructed with 3 mm slice thickness. The calcium volume is quantified by registering voxels with attenuation values greater than or equal to 130 Hounsfield Unit (HU). In isotropic CAC images with 0.5 mm slice thickness obtained from 320-detector row CT, the optimal value of attenuation cutoff threshold is unknown. In this paper we find the optimal cutoff threshold for calcium quantification in isotropic CT calcium scans by validating against registered intravascular ultrasound with radiofrequency backscatter (IVUS/VH). From the statistical analysis of calcium data obtained from the images of 9 patients we found a range of optimal thresholds and the conventional threshold of 130 HU was in the range. Further, the optimal values were different for individual patients.

Relationship between chest lateral width, tube current, image noise, and radiation exposure associated with coronary artery calcium scanning on 320-detector row CT.

BACKGROUND: The relationship between chest lateral width, tube current, image noise, and radiation exposure on 320-detector row CT has not been reported. OBJECTIVE: We investigated the relationships between chest lateral width, estimated radiation exposure (DLPe), and image noise in 300 patients undergoing clinical coronary calcium scanning. METHODS: Patients undergoing coronary calcium scanning with 320-detector row CT (prospective, volumetric mode, 120 kV of tube voltage, 100-550 mA of tube current, 0.5-mm detector width) were grouped by chest lateral width (small, medium, and large) from anteroposterior topograms and 100 consecutive patients were selected from each group (n = 300). Tube current, DLPe, and noise were compared among groups with Kruskal-Wallis or one-way ANOVA. Phantom experiments were performed to evaluate the accuracy of calcium quantification as a function of size and tube current. RESULTS: Median tube current in small, medium, and large patients was 130, 200, and 250 mA, respectively (P < 0.0001). Despite the use of higher tube current settings, noise levels also increased with size (20.2 ± 4.5 HU, 22.0 ± 3.9 HU, and 25.1 ± 4.9 HU, respectively; global P < 0.001). DLPe was significantly higher with increasing size (54, 83, and 104 mGy · cm, respectively; P < 0.0001). Phantom experiments showed that 50-100 mA, 150-200 mA, and approximately 300 mA in small, medium, and large phantoms were associated with stable estimate of calcium. CONCLUSIONS: Increasing chest lateral width is associated with increasing radiation exposure and image noise. The use of 50-100 mA in small and 150-200 mA in medium patients is associated with acceptable noise and stable estimate of coronary artery calcium. In large patients, precise identification of individual calcified lesions remains difficult despite increasing tube current and radiation exposure.

Coronary atherosclerosis imaging by coronary CT angiography: current status, correlation with intravascular interrogation and meta-analysis.

Coronary computed tomography angiography (CTA) allows coronary artery visualization and the detection of coronary stenoses. In addition; it has been suggested as a novel, noninvasive modality for coronary atherosclerotic plaque detection, characterization, and quantification. Emerging data show that coronary CTA-based semiquantitative plaque characterization and quantification are sufficiently reproducible for clinical purposes, and fully quantitative approaches may be appropriate for use in clinical trials. Furthermore, several lines of investigation have validated plaque imaging by coronary CTA against other imaging modalities such as intravascular ultrasound/"virtual histology" and optical coherence tomography, and there are emerging data using biochemical modalities such as near-infrared spectroscopy. Finally, clinical validation in patients with acute coronary syndrome and in the outpatient setting has shown incremental value of CTA-based plaque characterization for the prediction of major cardiovascular events. With recent developments in image acquisition and reconstruction technologies, coronary CTA can be performed with relatively low radiation exposure. With further technological innovation and clinical research, coronary CTA may become an important tool in the quest to identify vulnerable plaques and the at-risk patient.

Abnormal lipoprotein(a) levels predict coronary artery calcification in Southeast Asians but not in Caucasians: use of noninvasive imaging for evaluation of an emerging risk factor.

Subclinical atherosclerosis can be quantified by coronary artery calcium (CAC) scoring. Due to its high specificity for atherosclerosis, CAC is an excellent phenotypic tool for the evaluation of emerging risk markers. Lipoprotein(a) [Lp(a)] is atherogenic due to the presence of apoB and may be thrombogenic through its apo(a) component. Lp(a) has been linked to cardiovascular events in Caucasians; however, its link to atherosclerosis in various ethnicities remains unclear. We evaluated the ability of Lp(a) mass to predict subclinical atherosclerosis in Southeast Asians and Caucasians, as measured by CAC. Traditional lipid measurements, Lp(a) measurements, and CAC by 64-slice multidetector computed tomography was performed in 103 consecutive patients in the USA and in 104 consecutive patients in Jakarta, Indonesia. Proportion of positive CAC and median CAC in Southeast Asians and in Caucasians was 61.5% and 63.1%, and 23.5 (interquartile range, 0-270) and 13 (interquartile range, 0-388), respectively. Significantly higher proportion of Southeast Asians had elevated Lp(a) levels, compared to Caucasians (51.0% vs. 29.2%; p = 0.005). In Southeast Asians, Lp(a) remained an independent predictor of CAC with an odds ratio of 4.97 (95% confidence interval, 1.56-15.88; p < 0.0001), but not in Caucasians. Receiver operating characteristic analysis showed an improvement in area under the curve from 0.81 to 0.86 (p = 0.05) when including Lp(a) in the predictive model in Southeast Asians. This translated to 7% of Southeast Asians reclassified to correct CAC status. Lp(a) measurements may have a role in risk stratification of Southeast Asians. Ethnic variation should be taken into account when considering the use of Lp(a) measurements in risk assessment.

Prospective validation of standardized, 3-dimensional, quantitative coronary computed tomographic plaque measurements using radiofrequency backscatter intravascular ultrasound as reference standard in intermediate coronary arterial lesions: results from the ATLANTA (assessment of tissue characteristics, lesion morphology, and hemodynamics by angiography with fractional flow reserve, intravascular ultrasound and virtual histology, and noninvasive computed tomography in atherosclerotic plaques) I study.

OBJECTIVES: This study sought to determine the accuracy of 3-dimensional, quantitative measurements of coronary plaque by computed tomography angiography (CTA) against intravascular ultrasound with radiofrequency backscatter analysis (IVUS/VH). BACKGROUND: Quantitative, 3-dimensional coronary CTA plaque measurements have not been validated against IVUS/VH. METHODS: Sixty patients in a prospective study underwent coronary X-ray angiography, IVUS/VH, and coronary CTA. Plaque geometry and composition was quantified after spatial coregistration on segmental and slice-by-slice bases. Correlation, mean difference, and limits of agreement were determined. RESULTS: There was significant correlation for all pre-specified parameters by segmental and slice-by-slice analyses (r = 0.41 to 0.84; all p < 0.001). On a segmental basis, CTA underestimated minimal lumen diameter by 21% and overestimated diameter stenosis by 39%. Minimal lumen area was overestimated on CTA by 27% but area stenosis was only underestimated by 5%. Mean difference in noncalcified plaque volume and percent and calcified plaque volume and percent were 38%, -22%, 104%, and 64%. On a slice-by-slice basis, lumen, vessel, noncalcified-, and calcified-plaque areas were overestimated on CTA by 22%, 19%, 44%, and 88%. There was significant correlation for percentage of atheroma volume (0.52 vs. 0.54; r = 0.51; p < 0.001). Compositional analysis suggested that high-density noncalcified plaque on CTA best correlated with fibrous tissue and low-density noncalcified plaque correlated with necrotic core plus fibrofatty tissue by IVUS/VH. CONCLUSIONS: This is the first validation that standardized, 3-dimensional, quantitative measurements of coronary plaque correlate with IVUS/VH. Mean differences are small, whereas limits of agreement are wide. Low-density noncalcified plaque correlates with necrotic core plus fibrofatty tissue on IVUS/VH.

Lesion- and vessel-specific coronary artery calcium scores are superior to whole-heart Agatston and volume scores in the diagnosis of obstructive coronary artery disease.

BACKGROUND: The whole-heart coronary artery calcium (CAC) score has poor predictive value for obstructive coronary artery disease (CAD). We hypothesized that vessel- and lesion-specific CAC scores are more accurate. OBJECTIVES: To evaluate the usefulness of vessel- and lesion-specific CAC in predicting obstructive CAD and to assess the incremental value added by the vessel- and lesion-specific CAC to the conventional whole-heart CAC approach. METHODS: Ninety-one patients with CAC scores and invasive angiography (XRA) data were enrolled. Besides whole-heart CAC, Agatston score (AgSc) and volume score (VolSc) were measured individually for each lesion in the 4 major epicardial coronary arteries. Maximum and average lesion-specific scores in each vessel were also determined. For the primary analysis, obstructive CAD was defined as 50% diameter stenosis by XRA. RESULTS: Whole-heart AgSc and VolSc were not different between patients with and without obstructive CAD (P = .23 and P = .18), whereas vessel- and lesion-specific scores were (maximum lesion specific AgSc, P < .0001). Maximum lesion-specific AgSc had superior diagnostic performance compared with whole-heart AgSc (area under receiver operating characteristics, 0.71 vs 0.58). Overall sensitivity, specificity, and diagnostic accuracy were improved. When specificity was fixed at 80%, sensitivity of maximum lesion-specific AgSc was superior to whole-heart AgSc (56.6% vs 35.1%). Most importantly, with lesion-specific AgSc, fewer patients were classified as "indeterminate" compared with whole-heart AgSc (17.9% vs 50%). CONCLUSIONS: Vessel- and lesion-specific CAC scores are superior to the whole-heart AgSc and VolSc in predicting obstructive CAD. This simple refinement in CAC scoring may significantly improve the clinical predictive role of CAC imaging.

Proteomic, microarray, and signature-tagged mutagenesis analyses of anaerobic Pseudomonas aeruginosa at pH 6.5, likely representing chronic, late-stage cystic fibrosis airway conditions.

Patients suffering from cystic fibrosis (CF) commonly harbor the important pathogen Pseudomonas aeruginosa in their airways. During chronic late-stage CF, P. aeruginosa is known to grow under reduced oxygen tension and is even capable of respiring anaerobically within the thickened airway mucus, at a pH of approximately 6.5. Therefore, proteins involved in anaerobic metabolism represent potentially important targets for therapeutic intervention. In this study, the clinically relevant "anaerobiome" or "proteogenome" of P. aeruginosa was assessed. First, two different proteomic approaches were used to identify proteins differentially expressed under anaerobic versus aerobic conditions. Microarray studies were also performed, and in general, the anaerobic transcriptome was in agreement with the proteomic results. However, we found that a major portion of the most upregulated genes in the presence of NO(3)(-) and NO(2)(-) are those encoding Pf1 bacteriophage. With anaerobic NO(2)(-), the most downregulated genes are those involved postglycolytically and include many tricarboxylic acid cycle genes and those involved in the electron transport chain, especially those encoding the NADH dehydrogenase I complex. Finally, a signature-tagged mutagenesis library of P. aeruginosa was constructed to further screen genes required for both NO(3)(-) and NO(2)(-) respiration. In addition to genes anticipated to play important roles in the anaerobiome (anr, dnr, nar, nir, and nuo), the cysG and dksA genes were found to be required for both anaerobic NO(3)(-) and NO(2)(-) respiration. This study represents a major step in unraveling the molecular machinery involved in anaerobic NO(3)(-) and NO(2)(-) respiration and offers clues as to how we might disrupt such pathways in P. aeruginosa to limit the growth of this important CF pathogen when it is either limited or completely restricted in its oxygen supply.

Interactions of uranium with polyphosphate.

Inorganic polyphosphates (PolyP) are simple linear phosphate (PO(4)(3-)) polymers which are produced by a variety of microorganisms. One of their functions is to complex metals resulting in their precipitation. We investigated the interaction of phosphate and low-molecular-weight PolyP (1400-1900Da) with uranyl ion at various pHs. Potentiometric titration of uranyl ion in the presence of phosphate showed two sharp inflection points at pHs 4 and 8 due to uranium hydrolysis reaction and interaction with phosphate. Titration of uranyl ion and PolyP revealed a broad inflection point starting at pH 4 indicating that complexation of U-PolyP occurs over a wide range of pHs with no uranium hydrolysis. EXAFS analysis of the U-HPO(4) complex revealed that an insoluble uranyl phosphate species was formed below pH 6; at higher pH (> or = 8) uranium formed a precipitate consisting of hydroxophosphato species. In contrast, adding uranyl ion to PolyP resulted in formation of U-PolyP complex over the entire pH range studied. At low pH (< or = 6) an insoluble U-PolyP complex having a monodentate coordination of phosphate with uranium was observed. Above pH 6 however, a soluble bidentate complex with phosphate and uranium was predominant. These results show that the complexation and solubility of uranium with PO(4) and PolyP are dependent upon pH.

Algunas características biológicas de ratones balb/C del bioterio de la Facultad de Ciencias Médicas de Ciego de Avila / Some characteristics biologics of mouse's balb/C of the animal colony of the School of Sciences Medics of Blind Person of Avila

En este trabajo se exponen los resultados alcanzados en el estudio de algunas características biológicas de una sublínea de ratones balb/c mantenida por más de dos años en bioterio de la Facultad de Ciencias Médicas de ciego de Avila. Las características estudiadas fueron: talla y peso desde el nacimiento hasta la semana 13, comportamiento reproductivo, cuadro hematológico y proteínas plamáticas, los resultados nos brindan información sobre el comportamiento del crecimiento de estas sublínea. No se observaron diferencias con los resultados de otros reportes, sin embargo, en el cuadro hematológico si se presentan diferencias, fundamentalmente leucopenia. se reportan los valores de la fracciones de proteínas plasmáticas