Pesticides and environmental injustice in the USA: root causes, current regulatory reinforcement and a path forward.

Many environmental pollutants are known to have disproportionate effects on Black, Indigenous and People of Color (BIPOC) as well as communities of low-income and wealth. The reasons for these disproportionate effects are complex and involve hundreds of years of systematic oppression kept in place through structural racism and classism in the USA. Here we analyze the available literature and existing datasets to determine the extent to which disparities in exposure and harm exist for one of the most widespread pollutants in the world - pesticides. Our objective was to identify and discuss not only the historical injustices that have led to these disparities, but also the current laws, policies and regulatory practices that perpetuate them to this day with the ultimate goal of proposing achievable solutions. Disparities in exposures and harms from pesticides are widespread, impacting BIPOC and low-income communities in both rural and urban settings and occurring throughout the entire lifecycle of the pesticide from production to end-use. These disparities are being perpetuated by current laws and regulations through 1) a pesticide safety double standard, 2) inadequate worker protections, and 3) export of dangerous pesticides to developing countries. Racial, ethnic and income disparities are also maintained through policies and regulatory practices that 4) fail to implement environmental justice Executive Orders, 5) fail to account for unintended pesticide use or provide adequate training and support, 6) fail to effectively monitor and follow-up with vulnerable communities post-approval, and 7) fail to implement essential protections for children. Here we've identified federal laws, regulations, policies, and practices that allow for disparities in pesticide exposure and harm to remain entrenched in everyday life for environmental justice communities. This is not simply a pesticides issue, but a broader public health and civil rights issue. The true fix is to shift the USA to a more just system based on the Precautionary Principle to prevent harmful pollution exposure to everyone, regardless of skin tone or income. However, there are actions that can be taken within our existing framework in the short term to make our unjust regulatory system work better for everyone.

Relapse versus reinfection: recurrent Clostridium difficile infection following treatment with fidaxomicin or vancomycin.

Our study sought to compare the strain types of Clostridium difficile causing initial and recurrent episodes of C. difficile infection (CDI) in adult patients with a first episode of CDI or 1 prior episode of CDI within the previous 90 days. Strains originated from patients who had been entered into two phase 3 randomized clinical trials of fidaxomicin versus vancomycin. Isolates of C. difficile from the initial and recurrent episodes within 28 (± 2) days of cure of CDI were compared using restriction endonuclease analysis (REA) typing. Paired isolates were available from 90 of 194 (46%) patients with recurrent CDI. Patients with isolates available were significantly younger (P = .008) and more likely to be from Canadian sites (P = .0001), compared with patients without isolates. In 75 of 90 subjects (83.3%), the identical REA type strain was identified at recurrence and the initial episode (putative relapse). Early recurrences (0-14 days after treatment completion) were relapses in 86.7% and a new strain (reinfection) in 13.3%. Later recurrences (15-31 days after treatment) were relapses in 76.7% and reinfections in 23.3%. Mean time (± standard deviation) to recurrence was 12.2 (± 6.4) days for relapses and 14.7 (± 6.8) days for reinfections (P = .177). The most common BI/NAP1/027 group and the previous US epidemic REA group J/NAP2/001 had a significantly higher combined rate of recurrence with the same strain (relapse), compared with the other REA groups (39 of 42 [93%] vs 36 of 48 [75%], respectively; P = .023). We found a higher than historic rate of recurrent CDI caused by the same isolate as the original episode, a finding that may be related to the relatively short observation period in this study and the high frequency of isolation of epidemic strains, such as groups BI and J, for which relapse rates may be higher than for other REA groups. Caution in generalizing these observations is required, because the patients studied were younger and more likely to be from Canadian sites than were patients with recurrence who did not provide isolates.

PIDD-dependent activation of caspase-2-mediated mitochondrial injury in E1A-induced cellular sensitivity to macrophage nitric oxide-induced apoptosis.

Expression of the adenovirus E1A oncogene sensitizes tumor cells to innate immune rejection by apoptosis induced by macrophage-produced tumor necrosis factor (TNF)-α and nitric oxide (NO). E1A sensitizes cells to TNF-α and NO through two distinct mechanisms, by repressing NF-κB-dependent antiapoptotic responses and enhancing caspase-2 activation and mitochondrial injury, respectively. The mechanisms through which E1A enhances caspase-2 activation in response to NO were unknown. Here, we report that E1A-induced sensitization to NO-induced apoptosis is dependent on expression of PIDD (p53-inducible protein with a death domain) and enhancement of primary immunodeficiency diseases (PIDD) processing for formation of the PIDDosome, the core component of the caspase-2 activation complex. NO-induced apoptosis in E1A-expressing cells did not require expression Bak or Bax, indicating that NO-induced caspase-2-mediated mitochondrial injury does not proceed through the activities of typical, proapoptotic Bcl-2 family members that induce mitochondrial cytochrome C release. These results define a PIDD-dependent pathway, through which E1A enhances casapse-2-mediated mitochondrial injury, resulting in increased sensitivity of mammalian cells to macrophage-induced, NO-mediated apoptosis.

E1A enhances cellular sensitivity to DNA-damage-induced apoptosis through PIDD-dependent caspase-2 activation.

Expression of the adenoviral protein, E1A, sensitizes mammalian cells to a wide variety of apoptosis-inducing agents through multiple cellular pathways. For example, E1A sensitizes cells to apoptosis induced by TNF-superfamily members by inhibiting NF-kappa B (NF-κB)-dependent gene expression. In contrast, E1A sensitization to nitric oxide, an inducer of the intrinsic apoptotic pathway, is not dependent upon repression of NF-κB-dependent transcription but rather is dependent upon caspase-2 activation. The latter observation suggested that E1A-induced enhancement of caspase-2 activation might be a critical factor in cellular sensitization to other intrinsic apoptosis pathway-inducing agents. Etoposide and gemcitabine are two DNA damaging agents that induce intrinsic apoptosis. Here we report that E1A-induced sensitization to both of these agents, like NO, is independent of NF-κB activation but dependent on caspase-2 activation. The results show that caspase-2 is a key mitochondrial-injuring caspase during etoposide and gemcitabine-induced apoptosis of E1A-positive cells, and that caspase-2 is required for induction of caspase-3 activity by both chemotherapeutic agents. Expression of PIDD was required for caspase-2 activation, mitochondrial injury and enhanced apoptotic cell death. Furthermore, E1A-enhanced sensitivity to injury-induced apoptosis required PIDD cleavage to PIDD-CC. These results define the PIDD/caspase-2 pathway as a key apical, mitochondrial-injuring mechanism in E1A-induced sensitivity of mammalian cells to chemotherapeutic agents.

Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections.

UNLABELLED: Clostridium difficile is a leading cause of antibiotic-associated diarrhea, a significant animal pathogen, and a worldwide public health burden. Most disease-causing strains secrete two exotoxins, TcdA and TcdB, which are considered to be the primary virulence factors. Understanding the role that these toxins play in disease is essential for the rational design of urgently needed new therapeutics. However, their relative contributions to disease remain contentious. Using three different animal models, we show that TcdA(+) TcdB(-) mutants are attenuated in virulence in comparison to the wild-type (TcdA(+) TcdB(+)) strain, whereas TcdA(-) TcdB(+) mutants are fully virulent. We also show for the first time that TcdB alone is associated with both severe localized intestinal damage and systemic organ damage, suggesting that this toxin might be responsible for the onset of multiple organ dysfunction syndrome (MODS), a poorly characterized but often fatal complication of C. difficile infection (CDI). Finally, we show that TcdB is the primary factor responsible for inducing the in vivo host innate immune and inflammatory responses. Surprisingly, the animal infection model used was found to profoundly influence disease outcomes, a finding which has important ramifications for the validation of new therapeutics and future disease pathogenesis studies. Overall, our results show unequivocally that TcdB is the major virulence factor of C. difficile and provide new insights into the host response to C. difficile during infection. The results also highlight the critical nature of using appropriate and, when possible, multiple animal infection models when studying bacterial virulence mechanisms. IMPORTANCE: Clostridium difficile is a leading cause of antibiotic-associated diarrhea and an important hospital pathogen. TcdA and TcdB are thought to be the primary virulence factors responsible for disease symptoms of C. difficile infections (CDI). However, the individual contributions of these toxins to disease remain contentious. Using three different animal models of infection, we show for the first time that TcdB alone causes severe damage to the gut, as well as systemic organ damage, suggesting that this toxin might be responsible for MODS, a serious but poorly understood complication of CDI. These findings provide important new insights into the host response to C. difficile during infection and should guide the rational development of urgently required nonantibiotic therapeutics for the treatment of CDI.

Insuficiencia renal aguda en ancianos atendidos en cuidados intensivos del Hospital Territorial Docente Julio M. Arístegui Villamil. Cárdenas. 2006-2011 / Acute renal insufficiency in elder people attended at the Intensive Care Unit of the Teaching Territorial Hospital Julio M. Aristegui Villamil. Cárdenas. 2006-2011

La insuficiencia renal aguda es un problema médico habitual en la práctica clínica, tanto fuera como dentro del hospital, en la unidad de cuidados intensivos está asociado a un incremento de la morbimortalidad. Con el fin de caracterizar su comportamiento, se realizó un estudio descriptivo, transversal, en pacientes mayores de 60 años ingresados en la Unidad de Cuidados Intensivos del Hospital Julio Arístegui Villamil, de Cárdenas, en el período comprendido desde 1 enero de 2006 hasta 1 de enero de 2011, los cuales, según la clasificación RIFLE, desarrollaron fallo renal agudo. La muestra estuvo conformada por 68 pacientes (52 %); existió un predominio del sexo masculino con respecto al femenino, (3:1) y del color de piel blanca (72 %). La localización de la lesión predominante fue la parenquimatosa (63 %) seguida de la postrenal. El 45,5 % recibió tratamiento sustitutivo de la función renal. La mortalidad fue elevada (57 %), siendo las principales causas de muerte: el fallo múltiple de órganos y la sepsis.

The acute renal insufficiency is a customary medical problem in the medical practice as much inside as out the hospital; in the Intensive Care Unit it is associated to an increase of the morbimortality. With the objective of characterizing its behavior, we carried out a descriptive, crossed study in more-than-60-years-old patients who entered the Intensive Care Unit of the Hospital Julio Aristegui Villamil, of Cardenas, in the period from January 1st 2006 to January 1st 2011, and developed an acute renal failure according to the RIFLE classification. The sample was formed by 68 patients (52 %); there it was a predomination of the male sex over the female (3:1) and of the white race (72 %). The predominant location of the lesion was the parenchymatous one (63 %) followed by the post-renal one. 45,5 % of the patients received a substitutive treatment of the renal function. The mortality was high (57 %), being the multiple organic failure and sepsis the main death causes.

Hepatitis C en pacientes hemodializados: una mirada actual / Hepatitis C in hemodialized patients: a contemporary look

La hepatitis viral C es un problema de salud pública. En la década del 90 su prevalencia en las unidades de hemodiálisis era significativa, y desde entonces ha disminuido gracias al advenimiento de la eritropoyetina, al control de los donantes y a la mejoría en el cumplimiento de las medidas de bioseguridad. No obstante, se mantiene una elevada incidencia y prevalencia, que supera de 5 a 10 veces la de la población en general. La infección generalmente es asintomática, evoluciona a la cronicidad en el 80 por ciento de los casos y está relacionada con un aumento de la morbimortalidad en hemodializados y trasplantados renales. Su tratamiento es la monoterapia con Interferón, seguro, eficaz y capaz de inducir respuesta bioquímica y virológica, es costoso y produce reacciones adversas frecuentes. No existe actualmente una vacuna que prevenga su infección, por lo que el mejor tratamiento es su prevención mediante el estricto cumplimiento de las medidas universales de bioseguridad. En el Centro de Hemodiálisis, de Cárdenas, constituye un problema de salud, por lo cual el propósito de este trabajo fue realizar una actualización sobre esta temática. Se revisaron numerosos trabajos científicos obtenidos a través de revistas extranjeras y otros; procedentes de centros de hemodiálisis cubanos. Este análisis ha permitido profundizar en factores de riesgo, evaluación clínica, epidemiológica, de laboratorio y avances en su terapéutica; posibilitando ofrecer guías para su mejor abordaje, y poder contribuir con estos conocimientos a elevar la calidad de la atención médica a los pacientes.

The virus C hepatitis is a problem of public health. In the decade of the 90ties its prevalence in the hemodialysis units was significant, and since those times it has diminished thanks to the coming of the erythropoietin, to the donors' control, and the fulfillment of the biosecurity measures. Nonetheless, it has maintained a high incidence and prevalence, surpassing the general population in 5-10 times. The infection is generally asymptomatic and indolent, evolving to chronicity in 80 percent of the cases, and is related with an increase of the morbidity and mortality in hemodialized and renal transplanted patients. The treatment is the monotherapy with Interferon, secure, efficacious and able to introduce a virological and biochemical answer. It is expensive and produces frequent adverse reactions. Currently there is not a vaccine preventing its infection, so, the best treatment is the prevention through the strict fulfillment of the universal biosecurity measures. In the Hemodialysis Centre of Cardenas, it is a health problem; therefore the purpose of this work was making an up-dating on this theme. We reviewed several scientific works obtained from foreign journals and from other Cuban hemodialysis centers. This analysis has allowed us to go deeper in the risk facts, the clinical, epidemiologic and laboratory evaluation, and the therapeutic advances, making it possible to offer guidelines for its better management and to contribute with this knowledge to increase the quality of patients' medical care.