C57BL/6J mice exposed to perfluorooctanoic acid demonstrate altered immune responses and increased seizures after Theiler's murine encephalomyelitis virus infection.

Introduction: Neurological diseases can stem from environmental influences such as antecedent viral infections or exposure to potential toxicants, some of which can trigger immune responses leading to neurological symptoms. Theiler's murine encephalomyelitis virus (TMEV) is used to model human neurological conditions associated with prior viral infections, with outcomes partly attributable to improper induction and regulation of the immune response. Perfluorooctanoic acid (PFOA) can alter pathologies known to influence neurological disease such as inflammatory responses, cytokine expression, and glial activation. Co-exposure to TMEV and PFOA was used to test the hypothesis that early life exposure to the potential immunotoxicant PFOA would affect immune responses so as to render TMEV-resistant C57BL/6J (B6) mice susceptible to viral-induced neurological disease. Methods: Neonate B6 mice were exposed to different treatments: non-injected, sham-infected with PBS, and TMEV-infected, with the drinking water of each group including either 70 ppt PFOA or filtered water. The effects of PFOA were evaluated by comparing neurological symptoms and changes in immune-related cytokine and chemokine production induced by viral infection. Immune responses of 23 cytokines and chemokines were measured before and after infection to determine the effects of PFOA exposure on immune response. Results: Prior to infection, an imbalance between Th1, Th2, and Treg cytokines was observed in PFOA-exposed mice, suppressing IL-4 and IL-13 production. However, the balance was restored and characterized by an increase in pro-inflammatory cytokines in the non-infected group, and a decrease in IL-10 in the PFOA + TMEV group. Furthermore, the PFOA + TMEV group experienced an increase in seizure frequency and severity. Discussion: Overall, these findings provide insight into the complex roles of immune responses in the pathogenesis of virus-associated neurological diseases influenced by co-exposures to viruses and immunotoxic compounds.

Baseline Gait and Motor Function Predict Long-Term Severity of Neurological Outcomes of Viral Infection.

Neurological dysfunction following viral infection varies among individuals, largely due to differences in their genetic backgrounds. Gait patterns, which can be evaluated using measures of coordination, balance, posture, muscle function, step-to-step variability, and other factors, are also influenced by genetic background. Accordingly, to some extent gait can be characteristic of an individual, even prior to changes in neurological function. Because neuromuscular aspects of gait are under a certain degree of genetic control, the hypothesis tested was that gait parameters could be predictive of neuromuscular dysfunction following viral infection. The Collaborative Cross (CC) mouse resource was utilized to model genetically diverse populations and the DigiGait treadmill system used to provide quantitative and objective measurements of 131 gait parameters in 142 mice from 23 CC and SJL/J strains. DigiGait measurements were taken prior to infection with the neurotropic virus Theiler's Murine Encephalomyelitis Virus (TMEV). Neurological phenotypes were recorded over 90 days post-infection (d.p.i.), and the cumulative frequency of the observation of these phenotypes was statistically associated with discrete baseline DigiGait measurements. These associations represented spatial and postural aspects of gait influenced by the 90 d.p.i. phenotype score. Furthermore, associations were found between these gait parameters with sex and outcomes considered to show resistance, resilience, or susceptibility to severe neurological symptoms after long-term infection. For example, higher pre-infection measurement values for the Paw Drag parameter corresponded with greater disease severity at 90 d.p.i. Quantitative trait loci significantly associated with these DigiGait parameters revealed potential relationships between 28 differentially expressed genes (DEGs) and different aspects of gait influenced by viral infection. Thus, these potential candidate genes and genetic variations may be predictive of long-term neurological dysfunction. Overall, these findings demonstrate the predictive/prognostic value of quantitative and objective pre-infection DigiGait measurements for viral-induced neuromuscular dysfunction.

Viral Clearance and Neuroinflammation in Acute TMEV Infection Vary by Host Genetic Background.

A wide range of viruses cause neurological manifestations in their hosts. Infection by neurotropic viruses as well as the resulting immune response can irreversibly disrupt the complex structural and functional architecture of the brain, depending in part on host genetic background. The interaction between host genetic background, neurological response to viral infection, and subsequent clinical manifestations remains poorly understood. In the present study, we used the genetically diverse Collaborative Cross (CC) mouse resource to better understand how differences in genetic background drive clinical signs and neuropathological manifestations of acute Theiler's murine encephalomyelitis virus (TMEV) infection. For the first time, we characterized variations of TMEV viral tropism and load based on host genetic background, and correlated viral load with microglial/macrophage activation. For five CC strains (CC002, CC023, CC027, CC057, and CC078) infected with TMEV, we compared clinical signs, lesion distribution, microglial/macrophage response, expression, and distribution of TMEV mRNA, and identified genetic loci relevant to the early acute (4 days post-infection [dpi]) and late acute (14 dpi) timepoints. We examined brain pathology to determine possible causes of strain-specific differences in clinical signs, and found that fields CA1 and CA2 of the hippocampal formation were especially targeted by TMEV across all strains. Using Iba-1 immunolabeling, we identified and characterized strain- and timepoint-specific variation in microglial/macrophage reactivity in the hippocampal formation. Because viral clearance can influence disease outcome, we used RNA in situ hybridization to quantify viral load and TMEV mRNA distribution at both timepoints. TMEV mRNA expression was broadly distributed in the hippocampal formation at 4 dpi in all strains but varied between radiating and clustered distribution depending on the CC strain. We found a positive correlation between microglial/macrophage reactivity and TMEV mRNA expression at 4 dpi. At 14 dpi, we observed a dramatic reduction in TMEV mRNA expression, and localization to the medial portion of field CA1 and field CA2. To better understand how host genetic background can influence pathological outcomes, we identified quantitative trait loci associated with frequency of lesions in a particular brain region and with microglial/macrophage reactivity. These QTL were located near several loci of interest: lysosomal trafficking regulator (Lyst) and nidogen 1 (Nid1), and transmembrane protein 106 B (Tmem106b). Together, these results provide a novel understanding about the influences of genetic variation on the acute neuropathological and immunopathological environment and viral load, which collectively lead to variable disease outcomes. Our findings reveal possible avenues for future investigation which may lead to more effective intervention strategies and treatment regimens.

Serum Cytokines Predict Neurological Damage in Genetically Diverse Mouse Models.

Viral infections contribute to neurological and immunological dysfunction driven by complex genetic networks. Theiler's murine encephalomyelitis virus (TMEV) causes neurological dysfunction in mice and can model human outcomes to viral infections. Here, we used genetically distinct mice from five Collaborative Cross mouse strains and C57BL/6J to demonstrate how TMEV-induced immune responses in serum may predict neurological outcomes in acute infection. To test the hypothesis that serum cytokine levels can provide biomarkers for phenotypic outcomes of acute disease, we compared cytokine levels at pre-injection, 4 days post-injection (d.p.i.), and 14 d.p.i. Each strain produced unique baseline cytokine levels and had distinct immune responses to the injection procedure itself. Thus, we eliminated the baseline responses to the injection procedure itself and identified cytokines and chemokines induced specifically by TMEV infection. Then, we identified strain-specific longitudinal cytokine profiles in serum during acute disease. Using stepwise regression analysis, we identified serum immune markers predictive for TMEV-induced neurological phenotypes of the acute phase, e.g., IL-9 for limb paralysis; and TNF-α, IL-1ß, and MIP-1ß for limb weakness. These findings indicate how temporal differences in immune responses are influenced by host genetic background and demonstrate the potential of serum biomarkers to track the neurological effects of viral infection.

Assessing the Emergency Response Role of Community-Based Organizations (CBOs) Serving People with Disabilities and Older Adults in Puerto Rico Post-Hurricane María and during the COVID-19 Pandemic.

In Puerto Rico, a host of factors makes the role of community-based organizations (CBOs) critically important in emergency preparedness and response (EPR) and disability-inclusive disaster risk reduction (DiDRR) addressing the needs of people with disabilities and older adults. The territory has been the site of recurring hurricanes, earthquakes, medical crises, and human-made disasters. Political, social, and economic problems unique to the archipelago have historically limited the preparedness and response capacity of governmental authorities, especially for its most at-risk populations. In a context of severe constraints on government resources, CBOs are positioned to play an outsized role in providing services for disabled and older adults before, during, and after emergencies. This study assesses the emergency preparedness and response capacity of CBOs (n = 22) for addressing the needs of people with disabilities and the elderly. Semi-structured, largely closed-ended interviews were conducted in Spanish with key informants at Puerto Rican CBOs. The interviews included questions about emergency preparedness and response training, as well as organizational capacity during COVID-19 and post-Hurricane María. This study posits that conditions in Puerto Rico place CBOs at the forefront of critical responsibilities including emergency preparedness and response, warranting assessment of their practices and resources to assist them in fulfilling their mission.

Genetic and immunological contributors to virus-induced paralysis.

Infection by a single virus can evoke diverse immune responses, resulting in different neurological outcomes, depending on the host's genetic background. To study heterogenous viral response, we use Theiler's Murine Encephalomyelitis Virus (TMEV) to model virally induced neurological phenotypes and immune responses in Collaborative Cross (CC) mice. The CC resource consists of genetically distinct and reproducible mouse lines, thus providing a population model with genetic heterogeneity similar to humans. We examined different CC strains for the effect of chronic stage TMEV-induced immune responses on neurological outcomes throughout 90 days post infection (dpi), with a particular focus on limb paralysis, by measuring serum levels of 23 different cytokines and chemokines. Each CC strain demonstrated a unique set of immune responses, regardless of presence or absence of TMEV RNA. Using stepwise regression, significant associations were identified between IL-1α, RANTES, and paralysis frequency scores. To better understand these interactions, we evaluated multiple aspects of the different CC genetic backgrounds, including haplotypes of genomic regions previously linked with TMEV pathogenesis and viral clearance or persistence, individual cytokine levels, and TMEV-relevant gene expression. These results demonstrate how loci previously associated with TMEV outcomes provide incomplete information regarding TMEV-induced paralysis in the CC strains. Overall, these findings provide insight into the complex roles of immune response in the pathogenesis of virus-associated neurological diseases influenced by host genetic background.

Resilience in Long-Term Viral Infection: Genetic Determinants and Interactions.

Virus-induced neurological sequelae resulting from infection by Theiler's murine encephalomyelitis virus (TMEV) are used for studying human conditions ranging from epileptic seizures to demyelinating disease. Mouse strains are typically considered susceptible or resistant to TMEV infection based on viral persistence and extreme phenotypes, such as demyelination. We have identified a broader spectrum of phenotypic outcomes by infecting strains of the genetically diverse Collaborative Cross (CC) mouse resource. We evaluated the chronic-infection gene expression profiles of hippocampi and thoracic spinal cords for 19 CC strains in relation to phenotypic severity and TMEV persistence. Strains were clustered based on similar phenotypic profiles and TMEV levels at 90 days post-infection, and we categorized distinct TMEV response profiles. The three most common profiles included "resistant" and "susceptible," as before, as well as a "resilient" TMEV response group which experienced both TMEV persistence and mild neurological phenotypes even at 90 days post-infection. Each profile had a distinct gene expression signature, allowing the identification of pathways and networks specific to each TMEV response group. CC founder haplotypes for genes involved in these pathways/networks revealed candidate response-specific alleles. These alleles demonstrated pleiotropy and epigenetic (miRNA) regulation in long-term TMEV infection, with particular relevance for resilient mouse strains.

Host genetic diversity drives variable central nervous system lesion distribution in chronic phase of Theiler's Murine Encephalomyelitis Virus (TMEV) infection.

Host genetic background is a significant driver of the variability in neurological responses to viral infection. Here, we leverage the genetically diverse Collaborative Cross (CC) mouse resource to better understand how chronic infection by Theiler's Murine Encephalomyelitis Virus (TMEV) elicits diverse clinical and morphologic changes in the central nervous system (CNS). We characterized the TMEV-induced clinical phenotype responses, and associated lesion distributions in the CNS, in six CC mouse strains over a 90 day infection period. We observed varying degrees of motor impairment in these strains, as measured by delayed righting reflex, paresis, paralysis, seizures, limb clasping, ruffling, and encephalitis phenotypes. All strains developed neuroparenchymal necrosis and mineralization in the brain, primarily localized to the hippocampal regions. Two of the six strains presented with axonal degeneration with myelin loss of the nerve roots in the lumbar spinal cord. Moreover, we statistically correlated lesion distribution with overall frequencies of clinical phenotypes and phenotype progression to better understand how and where TMEV targets the CNS, based on genetic background. Specifically, we assessed lesion distribution in relation to the clinical progression of these phenotypes from early to late TMEV disease, finding significant relationships between progression and lesion distribution. Finally, we identified quantitative trait loci associated with frequency of lesions in a particular brain region, revealing several loci of interest for future study: lysosomal trafficking regulator (Lyst) and nidogen 1 (Nid1). Together, these results indicate that the genetic background influences the type and severity of clinical phenotypes, phenotypic resilience to TMEV, and the lesion distribution across strains.

Reporte de un caso de leptospirosis y embarazo / Report of a case of leptospirosis and pregnancy

La leptospirosis es una enfermedad común en Latinoamérica que se transmite hacia los humanos mediante el contacto con agua o tierra contaminada con la orina infectada de roedores, perros o ganado. La transmisión entre humanos es rara y se desconoce de su transmisión perinatal. Son escasos los reportes en la literatura de la asociación de esta entidad y el embarazo, existiendo una elevada tasa de muerte intrauterina y varios reportes de niños que nacen sanos o con signos de enfermedad activa. El manejo de esta enfermedad asociada al embarazo es el apropiado y oportuno diagnóstico clínico y el tratamiento es a base de penicilina. Presentamos a continuación un caso de leptospirosis asociada a un embarazo de 28 semanas...

Retención placentaria como causa de tercer período de labor prolongado / Placentaria retention like cause of third prolonged period of work

Quizás el tercer período de labor representa el más peligroso de todos, en donde ya no está en riesgo el feto sino la madre. La OMS estima que cerca de 500.000 mujeres mueren cada año por causas relacionadas al nacimiento de niños y por accidentes durante el tercer período de labor, más que en los otros dos períodos combinados, siendo la principal causa la hemorragia postparto. La retención de placenta (RP) tiene una incidencia, que varía de acuerdo al estudio y de una incidencia, que varía de acuerdo al estudio y de acuerdo a la definición, de 2-3 por ciento de todos partos vaginales (11,19,53) y del 1.7-2 por ciento si solo se consideran las extraídas manualmente. El 57 por ciento de las hemorragias postparto resultan de ella (11)...