A Hybrid Model for Cardiac Perfusion: Coupling a Discrete Coronary Arterial Tree Model with a Continuous Porous-Media Flow Model of the Myocardium.

This paper presents a novel hybrid approach for the computational modeling of cardiac perfusion, combining a discrete model of the coronary arterial tree with a continuous porous-media flow model of the myocardium. The constructive constrained optimization (CCO) algorithm captures the detailed topology and geometry of the coronary arterial tree network, while Poiseuille's law governs blood flow within this network. Contrast agent dynamics, crucial for cardiac MRI perfusion assessment, are modeled using reaction-advection-diffusion equations within the porous-media framework. The model incorporates fibrosis-contrast agent interactions and considers contrast agent recirculation to simulate myocardial infarction and Gadolinium-based late-enhancement MRI findings. Numerical experiments simulate various scenarios, including normal perfusion, endocardial ischemia resulting from stenosis, and myocardial infarction. The results demonstrate the model's efficacy in establishing the relationship between blood flow and stenosis in the coronary arterial tree and contrast agent dynamics and perfusion in the myocardial tissue. The hybrid model enables the integration of information from two different exams: computational fractional flow reserve (cFFR) measurements of the heart coronaries obtained from CT scans and heart perfusion and anatomy derived from MRI scans. The cFFR data can be integrated with the discrete arterial tree, while cardiac perfusion MRI data can be incorporated into the continuum part of the model. This integration enhances clinical understanding and treatment strategies for managing cardiovascular disease.

Post-transcriptional regulation of the trypanosome heat shock response by a zinc finger protein.

In most organisms, the heat-shock response involves increased heat-shock gene transcription. In Kinetoplastid protists, however, virtually all control of gene expression is post-transcriptional. Correspondingly, Trypanosoma brucei heat-shock protein 70 (HSP70) synthesis after heat shock depends on regulation of HSP70 mRNA turnover. We here show that the T. brucei CCCH zinc finger protein ZC3H11 is a post-transcriptional regulator of trypanosome chaperone mRNAs. ZC3H11 is essential in bloodstream-form trypanosomes and for recovery of insect-form trypanosomes from heat shock. ZC3H11 binds to mRNAs encoding heat-shock protein homologues, with clear specificity for the subset of trypanosome chaperones that is required for protein refolding. In procyclic forms, ZC3H11 was required for stabilisation of target chaperone-encoding mRNAs after heat shock, and the HSP70 mRNA was also decreased upon ZC3H11 depletion in bloodstream forms. Many mRNAs bound to ZC3H11 have a consensus AUU repeat motif in the 3'-untranslated region. ZC3H11 bound preferentially to AUU repeats in vitro, and ZC3H11 regulation of HSP70 mRNA in bloodstream forms depended on its AUU repeat region. Tethering of ZC3H11 to a reporter mRNA increased reporter expression, showing that it is capable of actively stabilizing an mRNA. These results show that expression of trypanosome heat-shock genes is controlled by a specific RNA-protein interaction. They also show that heat-shock-induced chaperone expression in procyclic trypanosome enhances parasite survival at elevated temperatures.

Expression of the RNA recognition motif protein RBP10 promotes a bloodstream-form transcript pattern in Trypanosoma brucei.

When Trypanosoma brucei differentiates from the bloodstream form to the procyclic form, there are decreases in the levels of many mRNAs encoding proteins required for the glycolytic pathway, and the mRNA encoding the RNA recognition motif protein RBP10 decreases in parallel. We show that RBP10 is a cytoplasmic protein that is specific to bloodstream-form trypanosomes, where it is essential. Depletion of RBP10 caused decreases in many bloodstream-form-specific mRNAs, with increases in mRNAs associated with the early stages of differentiation. The changes were similar to, but more extensive than, those caused by glucose deprivation. Conversely, forced RBP10 expression in procyclics induced a switch towards bloodstream-form mRNA expression patterns, with concomitant growth inhibition. Forced expression of RBP10 prevented differentiation of bloodstream forms in response to cis-aconitate, but did not prevent expression of key differentiation markers in response to glucose deprivation. RBP10 was not associated with heavy polysomes, showed no detectable in vivo binding to RNA, and was not stably associated with other proteins. Tethering of RBP10 to a reporter mRNA inhibited translation, and halved the abundance of the bound mRNA. We suggest that RBP10 may prevent the expression of regulatory proteins that are specific to the procyclic form.

Enhanced optimization-based method for the generation of patient-specific models of Purkinje networks.

Cardiac Purkinje networks are a fundamental part of the conduction system and are known to initiate a variety of cardiac arrhythmias. However, patient-specific modeling of Purkinje networks remains a challenge due to their high morphological complexity. This work presents a novel method based on optimization principles for the generation of Purkinje networks that combines geometric and activation accuracy in branch size, bifurcation angles, and Purkinje-ventricular-junction activation times. Three biventricular meshes with increasing levels of complexity are used to evaluate the performance of our approach. Purkinje-tissue coupled monodomain simulations are executed to evaluate the generated networks in a realistic scenario using the most recent Purkinje/ventricular human cellular models and physiological values for the Purkinje-ventricular-junction characteristic delay. The results demonstrate that the new method can generate patient-specific Purkinje networks with controlled morphological metrics and specified local activation times at the Purkinje-ventricular junctions.

Potential Biomarkers of impulsivity in mild traumatic brain injury: A pilot study.

Very few studies have investigated cognition and impulsivity following mild traumatic brain injury (mTBI) in the general population. Furthermore, the neurobiological mechanisms underlying post-TBI neurobehavioral syndromes are complex and remain to be fully clarified. Herein, we took advantage of machine learning based-modeling to investigate potential biomarkers of mTBI-associated impulsivity. Twenty-one mTBI patients were assessed within one-month post-TBI and their data were compared to 19 healthy controls on measures of impulsivity (Barratt Impulsiveness Scale - BIS), executive functioning, episodic memory, self-report cognitive failures and blood biomarkers of inflammation, vascular and neuronal damage. mTBI patients were significantly more impulsive than controls in BIS total and subscales. Serum levels of sCD40L, Cathepsin D, IL-4, Neuropilin-1, IFN-α2, and Copeptin were associated with impulsivity in mTBI patients. Besides showing that mTBI are associated with impulsivity in non-military people, we unveiled different pathophysiological pathways potentially implicated in mTBI-related impulsivity.

The RNA helicase DHH1 is central to the correct expression of many developmentally regulated mRNAs in trypanosomes.

In trypanosomes, the predominant mechanisms of regulation of gene expression are post-transcriptional. The DEAD-box RNA helicase DHH1 was identified in a screen for gene products that are necessary for the instability of the GPI-PLC mRNA in insect-stage trypanosomes. Expression of an ATPase-deficient dhh1 mutant caused a rapid growth arrest associated with a decrease in polysomes, an increase in P-bodies and a slight decrease in average mRNA levels. However, the effect of dhh1 mutant expression on both turnover and translational repression of mRNAs was selective. Whereas there was little effect on the stability of constitutive mRNAs, the control of a large cohort of developmentally regulated mRNAs was reversed; many mRNAs normally downregulated in insect-stage trypanosomes were stabilized and many mRNAs normally upregulated decreased in level. One stabilised mRNA, ISG75, was characterised further. Despite the overall decrease in polysomes, the proportion of the ISG75 mRNA in polysomes was unchanged and the result was ISG75 protein accumulation. Our data show that specific mRNAs can escape DHH1-mediated translational repression. In trypanosomes, DHH1 has a selective role in determining the levels of developmentally regulated mRNAs.

Trypanosoma brucei PUF9 regulates mRNAs for proteins involved in replicative processes over the cell cycle.

Many genes that are required at specific points in the cell cycle exhibit cell cycle-dependent expression. In the early-diverging model eukaryote and important human pathogen Trypanosoma brucei, regulation of gene expression in the cell cycle and other processes is almost entirely post-transcriptional. Here, we show that the T. brucei RNA-binding protein PUF9 stabilizes certain transcripts during S-phase. Target transcripts of PUF9--LIGKA, PNT1 and PNT2--were identified by affinity purification with TAP-tagged PUF9. RNAi against PUF9 caused an accumulation of cells in G2/M phase and unexpectedly destabilized the PUF9 target mRNAs, despite the fact that most known Puf-domain proteins promote degradation of their target mRNAs. The levels of the PUF9-regulated transcripts were cell cycle dependent, peaking in mid- to late- S-phase, and this effect was abolished when PUF9 was targeted by RNAi. The sequence UUGUACC was over-represented in the 3' UTRs of PUF9 targets; a point mutation in this motif abolished PUF9-dependent stabilization of a reporter transcript carrying the PNT1 3' UTR. LIGKA is involved in replication of the kinetoplast, and here we show that PNT1 is also kinetoplast-associated and its over-expression causes kinetoplast-related defects, while PNT2 is localized to the nucleus in G1 phase and redistributes to the mitotic spindle during mitosis. PUF9 targets may constitute a post-transcriptional regulon, encoding proteins involved in temporally coordinated replicative processes in early G2 phase.

Presumed Unilateral Acute Idiopathic Maculopathy following H1N1 Vaccination.

Purpose: To report a case of unilateral acute idiopathic maculopathy (UAIM) following vaccination for type A influenza virus (H1N1).Methods: Clinical, fundus autofluorescence (FAF), fluorescein angiography (FA) and optical coherence tomography (OCT) findings are presented.Results: A 25-year old white male presented with an acute decrease of vision in his left eye eight days after immunization with influenza A vaccine. Clinical evaluation revealed a deep yellowish-white lesion at the macula, early hyperfluorescence at the level of retinal pigment epithelium (RPE), and leakage and staining during the late phase of FA. OCT demonstrated disruption of the photoreceptor ellipsoid zone, as well as heterogeneous reflectivity changes and thickening at the level of the outer retina-RPE. Three months after presentation, fundus examination showed resolution of the yellowish foveal lesion, with persistence of mild RPE atrophic changes.Conclusion: This is the first reported case of UAIM following H1N1 vaccination to date.

Camouflaged Nests of Mischocyttarus mirificus (Hymenoptera, Vespidae).

Social wasps present various architectural patterns for their nests, which may differ in shape, size, color, and material used in construction. The distribution pattern of comb cells presented by Mischocyttarus mirificus (Zikán, 1935) is vertical with a single cell of width, resulting in a filiform shape that camouflages in the middle of the substrate. There are few studies regarding this architectural pattern for social wasps and their role in camouflage, and this study aims to detail the nesting habits of this species. In total, 40 colonies were analyzed in their natural habitat and six were dissected in the laboratory. Aspects about the construction of the nests and nesting environment have been described. A test was carried out with nest photographs, to quantify their camouflage percentage within the nesting substrate. The colonies were found mainly in riparian forests where there were elements in the environment that favored their camouflage. According to the nest photograph analysis, their camouflage levels can vary according to the position from which the photograph is taken. It is evident that M. mirificus founders select sites where they can camouflage their colonies, and this gives them advantages in exploring a new environment.

Double Trouble: Challenges in the Diagnosis and Management of Ocular Syphilis in HIV-infected Individuals.

Syphilis and HIV infection may coexist in the same individual. Ocular syphilis and/or neurosyphilis may develop at any stage of coinfection, with a stronger association between ocular and neurosyphilis in individuals living with HIV, than in HIV-uninfected individuals. The diagnosis of ocular syphilis in HIV-infected and -uninfected patients remains with some controversy due to unspecific clinical manifestations and limited diagnostic tests. Penicillin is the mainstay of treatment of ocular syphilis, but alternative options are warranted. This review describes the epidemiology, pathophysiology, and clinical manifestations, as well as the diagnostic and therapeutic challenges posed by ocular syphilis against the background of HIV coinfection.

Transcriptome analysis of differentiating trypanosomes reveals the existence of multiple post-transcriptional regulons.

BACKGROUND: Trypanosome gene expression is regulated almost exclusively at the post-transcriptional level, with mRNA degradation playing a decisive role. When trypanosomes are transferred from the blood of a mammal to the midgut of a Tsetse fly, they transform to procyclic forms: gene expression is reprogrammed, changing the cell surface and switching the mode of energy metabolism. Within the blood, trypanosomes can pre-adapt for Tsetse transmission, becoming growth-arrested stumpy forms. We describe here the transitions in gene expression that occur during differentiation of in-vitro cultured bloodstream forms to procyclic forms. RESULTS: Some mRNAs showed changes within 30 min of cis-aconitate addition, whereas others responded 12-24 hours later. For the first 12 h after addition of cis-aconitate, cells accumulated at the G1 phase of the cell cycle, and showed decreases in mRNAs required for proliferation, mimicking the changes seen in stumpy forms: many mRNAs needed for ribosomal and flagellar biogenesis showed striking co-regulation. Other mRNAs encoding components of signal transduction pathways and potential regulators were specifically induced only during differentiation. Messenger RNAs encoding proteins required for individual metabolic pathways were often co-regulated. CONCLUSION: Trypanosome genes form post-transcriptional regulons in which mRNAs with functions in particular pathways, or encoding components of protein complexes, show almost identical patterns of regulation.

Simulation of the Perfusion of Contrast Agent Used in Cardiac Magnetic Resonance: A Step Toward Non-invasive Cardiac Perfusion Quantification.

This work presents a new mathematical model to describe cardiac perfusion in the myocardium as acquired by cardiac magnetic resonance (CMR) perfusion exams. The combination of first pass (or contrast-enhanced CMR) and late enhancement CMR is a widely used non-invasive exam that can identify abnormal perfused regions of the heart via the use of a contrast agent (CA). The exam provides important information to the diagnosis, management, and prognosis of ischemia and infarct: perfusion on different regions, the status of microvascular structures, the presence of fibrosis, and the relative volume of extracellular space. This information is obtained by inferring the spatiotemporal dynamics of the contrast in the myocardial tissue from the acquired images. The evaluation of these physiological parameters plays an important role in the assessment of myocardial viability. However, the nature of cardiac physiology poses great challenges in the estimation of these parameters. Briefly, these are currently estimated qualitatively via visual inspection of images and comparison of relative brightness between different regions of the heart. Therefore, there is a great urge for techniques that can help to quantify cardiac perfusion. In this work, we propose a new mathematical model based on multidomain flow in porous media. The model is based on a system of partial differential equations. Darcy's law is used to obtain the pressure and velocity distribution. CA dynamics is described by reaction-diffusion-advection equations in the intravascular space and in the interstitial space. The interaction of fibrosis and the CA is also considered. The new model treats the domains as anisotropic media and imposes a closed loop of intravascular flow, which is necessary to reproduce the recirculation of the CA. The model parameters were adjusted to reproduce clinical data. In addition, the model was used to simulate different scenarios: normal perfusion; endocardial ischemia due to stenosis in a coronary artery in the epicardium; and myocardial infarct. Therefore, the computational model was able to correlate anatomical features, stenosis and the presence of fibrosis, with functional ones, cardiac perfusion. Altogether, the results suggest that the model can support the process of non-invasive cardiac perfusion quantification.

The ghost of the great imitator: prognostic factors for poor outcome in syphilitic uveitis.

BACKGROUND: Syphilitic uveitis is reemerging globally, may lead to any type of intraocular inflammation, and is potentially sight-threatening. We aim to characterize clinical features and prognostic factors in patients with syphilitic posterior uveitis. METHODS: Retrospective chart review at two tertiary university-based referral centers in Brazil. Clinical data, laboratory results, and treatment outcomes were analyzed. Statistical analysis was performed using Fisher's exact test for categorical variables and Mann-Whitney U test for continuous variables. RESULTS: Forty-four patients (81 eyes) were consecutively diagnosed with syphilitic posterior uveitis between March 2011 and April 2013.Thirty-one were male (70.5%) and the mean age was 43.8 years (range 15-81). HIV confection was disclosed in 12 patients (29.3%). The most prevalent finding was vitritis (85.2%), followed by retinal involvement (76.4%) and optic disc abnormalities (63.5%). After treatment, mean visual acuity improved from 1.2 (20/320) to 0.6 (20/80; median 20/30), but 19 eyes (23.5%) persisted with ≤ 1.0 (20/200). Factors associated with final visual acuity ≤ 1.0 despite therapy were prior use of systemic corticosteroids (p = 0.001), higher Venereal Disease Research Laboratory titers (p = 0.004), longer duration of symptoms (p = 0.024), and worse initial VA (p < 0.001). CONCLUSIONS: Syphilitic uveitis is reemerging. Delayed diagnosis and inadvertent use of systemic corticosteroids are potentially modifiable prognostic factors to be considered for possibly improving outcomes.

Intravenous Ceftriaxone for Syphilitic Uveitis.

PURPOSE: Report of clinical/multimodal imaging outcomes of patients with syphilitic uveitis alternatively treated with intravenous(IV) ceftriaxone, due to unavailability of penicillin G. METHODS: Chart review of all cases of syphilitic uveitis presenting to Hospital São Geraldo/HC-UFMG and treated with intravenous ceftriaxone, between January and August 2014. Clinical, serological and ophthalmological data were collected. RESULTS: Twelve consecutive patients with syphilitic uveitis receiving IV ceftriaxone were identified. All 24 eyes had active intraocular inflammation on clinical examination. All patients received IV ceftriaxone (2-4 g daily) for 14-21 days, supplemented with oral corticosteroid as needed in 9 patients (75%), after documented clinical response. Improvement in intraocular inflammation was seen in all 24 eyes, with median best-corrected visual acuity (BCVA) increasing from 20/50 to 20/20, after a mean follow-up of 5.3 months. CONCLUSION: IV ceftriaxone may be an effective alternative for treatment of syphilitic uveitis, in the setting of unavailability of penicillin G.

An Optimization-Based Algorithm for the Construction of Cardiac Purkinje Network Models.

OBJECTIVE: This work presents a new algorithm for the construction of a model for the Purkinje network (PN) of the heart. METHODS: The algorithm is based on a method called constructive constrained optimization (CCO), which was reformulated for the specific case of automatic PN generation. The proposed optimization-based algorithm is referred to as constructive optimization (CO). The CO method iteratively constructs the PN by minimizing the total length of the generated PN tree. In addition, it can take into account some important topological information of the PN, such as the location of the Purkinje-muscle junctions and the average bifurcation angle found in the literature. RESULTS: To validate the model, the new method was compared with the classical L-system method for generating PN models and to a recently proposed image-based technique. CONCLUSION: The results show that the CO is able to construct PNs with geometric features and activation times that are in good agreement with those reported in the literature and to those obtained by the other aforementioned alternatives.

Author Correction: Clinical Manifestations and Ophthalmic Outcomes of Ocular Syphilis at a Time of Re-Emergence of the Systemic Infection.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Clinical Manifestations and Ophthalmic Outcomes of Ocular Syphilis at a Time of Re-Emergence of the Systemic Infection.

Recent reports from different world regions suggest ocular syphilis is re-emerging, in parallel with an increasing incidence of the systemic infection globally. We conducted a large observational study of 127 persons consecutively treated for ocular syphilis at public medical centers in Brazil over a 2.5-year period ending July 2015. Of 104 individuals serologically tested for human immunodeficiency virus (HIV), 34.6% were positive. Ophthalmological evaluations included measurement of Snellen visual acuity and intraocular pressure, and assessment of inflammation by slit lamp examination and dilated posterior eye examination. Involvements in 214 eyes were anterior (6.1%), intermediate (8.4%), posterior (76.2%) and pan- (8.4%) uveitis, and scleritis (0.9%). Multiple anterior and posterior eye complications were observed, including cataract in the anterior eye (incidence rate, 0.18/eye-year) and epiretinal membrane in the posterior eye (incidence rate, 0.09/eye-year); incidence rates of reduction in best-corrected visual acuity to ≤20/50 and ≤20/200 were 0.10 and 0.06/eye-year, respectively. Rates of complications and visual acuity loss did not differ significantly between HIV- positive and negative individuals. In an era of re-emergence, syphilis has ocular complications that may compromise vision, despite treatment with appropriate anti-microbial drugs.

Fulminant proliferative vitreoretinopathy in syphilitic uveitis.

BACKGROUND: Syphilis is a reemerging sexually transmitted disease that can lead to any type of intraocular inflammation. Prognosis of syphilitic uveitis after appropriate therapy is classically regarded as favorable. However, visual threatening complications may develop, rarely including rhegmatogenous/tractional retinal detachment (R/T RD) and proliferative vitreoretinopathy. FINDINGS: We report 4 patients presenting with complex R/T RD and fulminant proliferative vitreoretinopathy despite treatment among 19 patients with syphilitic posterior uveitis consecutively seen at our uveitis service. Most of these complications occurred during or shortly after antibiotic therapy. All patients presented with significant intraocular inflammation, including vitritis, occlusive retinal vasculitis, and retinal infiltrates (necrotizing retinochoroiditis in six eyes of four patients). Two patients (50 %) tested HIV positive, and the same proportion had inadvertently received high dose oral ± intravenous corticosteroids prior to diagnosis of syphilis. Two patients (three eyes) underwent RD surgical repair. Histopathology of an excised epiretinal membrane disclosed fibroglial tissue, with immature glial cells and metaplastic retinal pigment epithelium, admixed with lymphoplasmacytic infiltrate. CONCLUSIONS: Syphilitic uveitis may be complicated by complex RD/fulminant fibroglial proliferation, occurring during/after treatment. Predisposing factors are currently unknown but may include prior use of corticosteroid, necrotizing retinitis and/or high spirochaetal load. A significant inflammatory component may underlie this fulminant fibroglial proliferation, being possibly amenable to modulation by aggressive anti-inflammatory therapy delivered concurrently with parenteral antibiotics.