HCV eradication with DAAs differently affects HIV males and females: A whole miRNA sequencing characterization.

Gender-specific consequences after HCV eradication are unexplored. MicroRNAs (miRNAs) play a crucial role in the immune response against viral infections. However, few have highlighted miRNA role in sex-biased disease or therapy response. We aim to assess gender differences reflected in the miRNA expression of HIV/HCV-coinfected patients who achieve sustained virological response (SVR) with direct acting antivirals (DAAs). We conducted a prospective study of miRNA expression in PBMCs from 28 chronic HIV/HCV-coinfected patients (HIV/HCV) at baseline and after achieving SVR with DAAs. Sixteen HIV-monoinfected patients (HIV) and 36 healthy controls (HC) were used as controls. Identification of significant differentially expressed (SDE) miRNAs was performed with generalized linear model and mixed GLMs. We also explored putative dysregulated biological pathways. At baseline, the HIV/HCV patients showed differences in the miRNA profile concerning the HIV group (165 and 102 SDE miRNAs for males and females, respectively). Gender-stratified analysis of HIV/HCV group at baseline versus at SVR achievement showed higher differences in males (80 SDE miRNAs) than in females (55 SDE miRNAs). After SVR, HIV/HCV group showed similar values to HIV individuals, especially in females (1 SDE miRNA). However, ten miRNAs in males remained dysregulated, which were mainly involved in cancer, fatty acid, and inflammatory pathways. Taken together, our results show gender-biased dysregulation in the miRNA expression profile of PBMCs after HCV eradication with DAAs. These differences were normalized in females, while miRNA profile and their target-related pathways in males lack of normalization, which may be related to a high-risk of developing liver-related complications.

Different HCV Exposure Drives Specific miRNA Profile in PBMCs of HIV Patients.

Micro RNAs (miRNAs) are essential players in HIV and HCV infections, as both viruses modulate cellular miRNAs and interact with the miRNA-mediated host response. We aim to analyze the miRNA profile of HIV patients with different exposure to HCV to explore specific signatures in the miRNA profile of PBMCs for each type of infection. We massively sequenced small RNAs of PBMCs from 117 HIV+ infected patients: 45 HIV+ patients chronically infected with HCV (HIV/HCV+), 36 HIV+ that spontaneously clarified HCV after acute infection (HIV/HCV-) and 36 HIV+ patients without previous HCV infection (HIV). Thirty-two healthy patients were used as healthy controls (HC). Differential expression analysis showed significantly differentially expressed (SDE) miRNAs in HIV/HCV+ (n = 153), HIV/HCV- (n = 169) and HIV (n = 153) patients. We found putative dysregulated pathways, such as infectious-related and PI3K signaling pathways, common in all contrasts. Specifically, putatively targeted genes involved in antifolate resistance (HIV/HV+), cancer-related pathways (HIV/HCV-) and HIF-signaling (HIV) were identified, among others. Our findings revealed that HCV strongly influences the expression profile of PBMCs from HIV patients through the disruption of its miRNome. Thus, different HCV exposure can be identified by specific miRNA signatures in PBMCs.

Dronabinol en manejo de apetito y pérdida de peso en pacientes con cáncer terminal, VIH, cuidados paliativos y vejez. Revisión de la literatura / Dronabinol in appetite management and weight loss in patients with terminal cancer, HIV, palliative care and old age. Literature review

Resumen: Introducción: La caquexia es un síndrome asociado al cáncer avanzado, VIH, pacientes en quimioterapia y quienes tienen seguimiento en cuidados paliativos. La prevalencia es de 25% de los pacientes con diagnóstico de cáncer, 26% en quienes reciben quimioterapia y de 14 a 38% de pacientes con VIH. Un pilar para el manejo es el cannabis debido al efecto del delta-9-tetrahidrocanabinol (THC), del cual se derivó el dronabinol, un fármaco desarrollado para estimular apetito y ganancia de peso. El objetivo de esta revisión bibliográfica es obtener la información sobre los cannabinoides y la evidencia más sólida existente con respecto al uso del dronabinol en pacientes que han presentado pérdida de peso y apetito. Material y métodos: Revisión de la bibliografía con buscador PubMed con las palabras clave Palliative care (cuidados paliativos), Cannabinoids (cannabinoides), cachexia (caquexia), Dronabinol (dronabinol), Appetite (apetito), de 1990 a 2018, limitado a humanos, obteniendo 259 artículos, eliminando 222 por repetirse o tener poca relevancia, dejando 37 artículos para análisis. Resultados: De 37 artículos revisados, nueve fueron estudios experimentales, 10 revisiones sistematizadas, un metaanálisis y 16 artículos de recomendaciones y sugerencias de manejo. Conclusión: El manejo del apetito y pérdida de peso en pacientes en cuidados paliativos, VIH, ancianos o en quimioterapia debe ser multidisciplinario, involucrando nutriólogos, psicólogos y médicos, ajustando el manejo a las características individuales que manifiesten. El dronabinol es un fármaco de primera elección para el manejo de dichos síntomas cuando la historia natural de la enfermedad se acompaña de náusea, vómito o dolor.

Abstract: Introduction: Cachexia is a syndrome associated with advanced cancer, HIV, patients on chemotherapy and those who are followed in palliative care. The prevalence is 25% of patients diagnosed with cancer, 26% in those receiving chemotherapy and 14 to 38% of patients with HIV. A mainstay for management is cannabis, due to the effect of delta-9-tetrahydrocannabinol (THC) from which dronabinol, a drug developed to stimulate appetite and weight gain, was derived. The aim of this literature review is to obtain information on cannabinoids and the strongest existing evidence regarding the use of dronabinol in patients who have presented weight and appetite loss. Material and methods: Literature review with PubMed search engine with the keywords Palliative care, Cannabinoids, cachexia, Dronabinol, Appetite, from 1990 to 2018, limited to humans, obtaining 259 articles, eliminating 222 for repetition or low relevance, leaving 37 articles for analysis. Results: Out of 37 articles reviewed 9 were experimental studies, 10 systematized reviews, 1 meta-analysis and 16 articles of recommendations and management suggestions. Conclusion: The management of appetite and weight loss in palliative care, HIV, elderly or chemotherapy patients should be multidisciplinary, involving nutritionists, psychologists and physicians, adjusting the management to the individual characteristics manifested. Dronabinol is a drug of first choice for the management of these symptoms when the natural history of the disease is accompanied by nausea, vomiting or pain.

Exposure to hydrocarbons and chlorpyrifos alters the expression of nuclear receptors and antioxidant, detoxifying, and immune response proteins in the liver of the rainbow trout, Oncorhynchus mykiss.

The development of oil and gas production together with the fruit production in nearby areas of North Patagonia, Argentina, suggests aquatic pollution scenarios which include permanent oil pollution combined with short events of pesticides application. It has been reported that oil hydrocarbons activate the aryl hydrocarbon receptor (AhR) pathway in the rainbow trout, Oncorhynchus mykiss, and that the insecticide Chlorpyrifos (CPF) interacts with these effects. Thus, it is interesting to investigate whether hydrocarbons and insecticides, applied by separate or combined, can affect fish health and reproductive signaling by acting on different nuclear receptors' regulatory pathways. To study this kind of interactions, we exposed juvenile rainbow trout to water accommodated fraction (WAF) of crude oil (62 µg L-1 TPH) for 48 h and subsequently exposed the livers ex vivo to the insecticide Chlorpyrifos (CPF) (20 µg L-1) for 1 h. We analyzed the mRNA expression of nuclear receptors and proteins involved in detoxifying, antioxidant, immune and apoptosis responses by qRT-PCR. We also performed histopathological analysis. WAF induced the expression of the androgen (AR) and the Liver X receptor (LXR) by 8- and 3-fold, respectively. AR induction was reversed by subsequent exposure to CPF. The progesterone receptor (PR) and glucocorticoid receptor (GR) were increased 2-fold and 3-fold by WAF respectively, while estrogen and mineralocorticoid receptors were not affected. GR was also induced by CPF with an additive effect in the WAF-CPF treatment. The antioxidant genes, gamma glutamyl transferase (GGT), superoxide dismutase (SOD1) were induced by WAF (2-3-fold). WAF upregulated the ATP Binding Cassette Subfamily C Member 2 (ABCC2, MRP2) (4-fold) and downregulated alkaline phosphatase. WAF also induced the inflammatory interleukins (IL) IL-8, and IL-6 and the anti-inflammatory IL-10, while CPF induced the inflammatory tumor necrosis factor (-α) and IL-6, and activated the intrinsic apoptotic pathway through the induction of caspases 3 and 9. Both, WAF and CPF downregulated the expression of the extrinsic apoptosis initiator caspase 8 and the inflammatory caspase 1. In conclusion, WAF hydrocarbons alter O. mykiss endocrine regulation by inducing AR, PR and GR. The subsequent exposure to CPF reverses AR, suggesting a complex interaction of different pollutants in contaminated environments, WAF hydrocarbons alter liver metabolism by inducing the expression of LXR, GR, antioxidant and detoxifying enzymes, and both inflammatory and anti-inflammatory cytokines, and causing mild hepatic steatosis. CPF activates inflammatory and stress responses associated with the induction of inflammatory cytokines together with apoptosis initiator and executioner caspases.

Alterations in the intestine of Patagonian silverside (Odontesthes hatcheri) exposed to microcystin-LR: Changes in the glycosylation pattern of the intestinal wall and inhibition of multidrug resistance proteins efflux activity.

Accumulation and toxicity of cyanobacterial toxins, particularly microcystin-LR (MCLR) have been extensively studied in fish and aquatic invertebrates. However, MCLR excretion mechanisms, which could reduce this toxin's effects, have received little attention. The Patagonian silverside, Odontesthes hatcheri, is an omnivorous-planktivorous edible fish, which has been shown to digest cyanobacterial cells absorbing MCLR and eliminating the toxin within 48h without suffering significant toxic effects. We studied the effects of MCLR on glycoconjugate composition and the possible role of multidrug resistance associated proteins (Abcc) in MCLR export from the cells in O. hatcheri intestine. We treated O. hatcheri with 5µg MCLRg(-1) body mass administered with the food. Twenty four hours later, the intestines of treated and control fish were processed for lectin-histochemistry using concanavalin A (ConA), Triticum vulgaris agglutinin (WGA), and Dolichos biflorus agglutinin (DBA). MCLR affected the distribution of glycoconjugates by augmenting the proportion of ConA-positive at the expense of WGA-positive cells. We studied MCLR effects on the transport of the Abcc-like substrates 2,4-dinitrophenyl-S-glutathione (DNP-SG) and calcein in ex vivo intestine preparations (everted and no-everted sacs and strips). In treated preparations, CDNB together with MCLR (113µg MCLRg(-1) intestine, equivalent to 1.14µmolL(-1) when applied in the bath) or the Abcc inhibitor, MK571 was applied for one hour, during which DNP-SG was measured in the bath every 10min in order to calculate mass-specific DNP-SG transport rate. MCLR significantly inhibited DNP-SG transport (p<0.05), especially in middle intestine (47 and 24%, for luminal and serosal transport, respectively). In middle intestine strips, MCLR and MK571inhibited DNP-SG transport in a concentration dependent fashion (IC50 3.3 and 0.6µmolL(-1), respectively). In middle intestine strips incubated with calcein-AM (0.25µmolL(-1)), calcein efflux was inhibited by MCLR (2.3µmolL(-1)) and MK571 (3µmolL(-1)) by 38 and 27%, respectively (p<0.05). Finally, middle intestine segments were incubated with different concentrations of MCLR applied alone or together with 3µM MK571. After one hour, protein phosphatase 1 (PP1) activity, the main target of MCLR, was measured. 2.5µM MCLR did not produce any significant effect, while the same amount plus MK571 inhibited PP1 activity (p<0.05). This effect was similar to that of 5µM MCLR. Our results suggest that in O. hatcheri enterocytes MCLR is conjugated with GSH via GST and then exported to the intestinal lumen through Abcc-like transporters. This mechanism would protect the cell from MCLR toxicity, limiting toxin transport into the blood, which is probably mediated by basolateral Abccs. From an ecotoxicological point of view, elimination of MCLR through this mechanism would reduce the amount of toxin available for trophic transference.

Morbidity and mortality of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: national cancer institute, Mexico city, Mexico.

Peritoneal carcinomatosis (PC) is generally considered a lethal disease, with a poor prognosis. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a new approach for peritoneal surface disease. This study investigated the early experience with this combined modality treatment at a single institute. From January 2007 to March 2010, 24 patients were treated After aggressive CS, with HIPEC (cisplatin 25 mg/m(2)/L and mitomycin C 3.3 mg/m(2)/L was administered for 90-minutes at 40.5° C). These data suggest that aggressive CRS with HIPEC for the treatment of PC may result in low mortality and acceptable morbidity. Rigorous patient selection, appropriate and prudent operative procedures were associated with encouraging results in our experience.