Leveraging pooled medical examiner records to surveil complex and emerging patterns of polysubstance use in the United States.

BACKGROUND: The United States (US) is an extreme global outlier for drug-related death rates. However, data describing drug-related deaths are generally available only on an 8-13-month lag. Furthermore, granular details about substance-involvement are often not available, which particularly stymies efforts to track fatal polysubstance and novel psychoactive substance use. Detailed medical examiner records provide a powerful source of information for drug-related death surveillance, but have been underutilized. METHODS: We pooled medical examiner data from five US states and 14 counties that together comprise 18% of the US population to examine demographic, geographic, and drug-specific trends in polysubstance drug-related deaths. We employed mixed effects logistic regression to identify demographic factors associated with polysubstance rather than single substance drug-related deaths. We assessed the correlations between drug classes and described geographic variation in the prevalence of specific drugs and the presence of novel and emerging psychoactive substances. RESULTS: Our sample included 73,077 drug-related deaths from 2012 through early 2022. Nearly two-thirds of drug-related deaths were polysubstance-involved, with the number and percentage growing annually. High percentages of polysubstance drug-related deaths were observed in both urban and rural jurisdictions. After adjusting for year and jurisdiction, female, American Indian and Alaska Native, and White individuals had the most elevated odds of polysubstance drug-related deaths. Drug-related deaths involving benzodiazepines or opioids, whether pharmaceutical or illicit, and other pharmaceutical drugs were most likely to have polysubstance involvement, while methamphetamine-involved deaths were least likely to involve multiple substances. Strong correlations were observed between prescription opioids and prescription benzodiazepines, fentanyl and xylazine, and designer benzodiazepines and novel synthetic opioids. CONCLUSIONS: Analysis of detailed medical examiner records reveals the breadth and complexity of polysubstance drug-related deaths in the US. Future efforts to use this unique resource can improve population-based surveillance of drug-related deaths to better tailor interventions and solutions to this critical health crisis.

Beyond the anti-PD-1/PD-L1 era: promising role of the BTLA/HVEM axis as a future target for cancer immunotherapy.

Recent introduction of monoclonal antibodies targeting immune checkpoints to harness antitumor immunity has revolutionized the cancer treatment landscape. The therapeutic success of immune checkpoint blockade (ICB)-based therapies mainly relies on PD-1/PD-L1 and CTLA-4 blockade. However, the limited overall responses and lack of reliable predictive biomarkers of patient´s response are major pitfalls limiting immunotherapy success. Hence, this reflects the compelling need of unveiling novel targets for immunotherapy that allow to expand the spectrum of ICB-based strategies to achieve optimal therapeutic efficacy and benefit for cancer patients. This review thoroughly dissects current molecular and functional knowledge of BTLA/HVEM axis and the future perspectives to become a target for cancer immunotherapy. BTLA/HVEM dysregulation is commonly found and linked to poor prognosis in solid and hematological malignancies. Moreover, circulating BTLA has been revealed as a blood-based predictive biomarker of immunotherapy response in various cancers. On this basis, BTLA/HVEM axis emerges as a novel promising target for cancer immunotherapy. This prompted rapid development and clinical testing of the anti-BTLA blocking antibody Tifcemalimab/icatolimab as the first BTLA-targeted therapy in various ongoing phase I clinical trials with encouraging results on preliminary efficacy and safety profile as monotherapy and combined with other anti-PD-1/PD-L1 therapies. Nevertheless, it is anticipated that the intricate signaling network constituted by BTLA/HVEM/CD160/LIGHT involved in immune response regulation, tumor development and tumor microenvironment could limit therapeutic success. Therefore, in-depth functional characterization in different cancer settings is highly recommended for adequate design and implementation of BTLA-targeted therapies to guarantee the best clinical outcomes to benefit cancer patients.

BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) progressively develop marked immunosuppression, dampening innate and adaptive-driven antitumor responses. However, the underlying mechanisms promoting immune exhaustion are largely unknown. Herein, we provide new insights into the role of BTLA/HVEM axis promoting defects in T cell-mediated responses against leukemic cells. Increased expression of BTLA, an inhibitory immune checkpoint, was detected on the surface of CD4 + and CD8 + T lymphocytes in patients with CLL. Moreover, high levels of BTLA on CD4 + T cells correlated with diminished time to treatment. Signaling through BTLA activation led to decreased IL-2 and IFN-γ production ex vivo, whereas BTLA/HVEM binding disruption enhanced IFN-γ + CD8 + T lymphocytes. Accordingly, BTLA blockade in combination with bispecific anti-CD3/anti-CD19 antibody promoted CD8 + T cell-mediated anti-leukemic responses. Finally, treatment with an anti-BLTA blocking monoclonal antibody alone or in combination with ibrutinib-induced leukemic cell depletion in vitro. Altogether, our data reveal that BTLA dysregulation has a prognostic role and is limiting T cell-driven antitumor responses, thus providing new insights about immune exhaustion in patients with CLL.

The Emerging Role of NK Cells in Immune Checkpoint Blockade.

Natural killer (NK) cells are innate cytotoxic immune cells that play a fundamental role in anti-tumor immunity, particularly in hematological cancers, disseminated cancers, and metastasis [...].

Engaging Same-Day Peer Ambassadors to Increase Coronavirus Disease 2019 Vaccination Among People Experiencing Unsheltered Homelessness in Los Angeles County: A Hybrid Feasibility-Evaluation Study.

BACKGROUND: This study aimed to evaluate the feasibility and acceptability of engaging unhoused peer ambassadors (PAs) in coronavirus disease 2019 (COVID-19) vaccination efforts to reach people experiencing unsheltered homelessness in Los Angeles County. METHODS: From August to December 2021, vaccinated PAs aged ≥18 years who could provide informed consent were recruited during vaccination events for same-day participation. Events were held at encampments, service providers (eg, housing agencies, food lines, and mobile showers), and roving locations around Los Angeles. PAs were asked to join outreach alongside community health workers and shared their experience getting vaccinated, receiving a $25 gift card for each hour they participated. Postevent surveys evaluated how many PAs enrolled and how long they participated. In October 2021, we added a preliminary effectiveness evaluation of how many additional vaccinations were attributable to PAs. Staff who enrolled the PAs estimated the number of additional people vaccinated because of talking with the PA. RESULTS: A total of 117 PAs were enrolled at 103 events, participating for an average of 2 hours. At events with the effectiveness evaluation, 197 additional people were vaccinated over 167 PA hours ($21.19 gift card cost per additional person vaccinated), accounting for >25% of all vaccines given at these events. DISCUSSION: Recruiting same-day unhoused PAs is a feasible, acceptable, and preliminarily effective technique to increase COVID-19 vaccination in unsheltered settings. The findings can inform delivery of other health services for people experiencing homelessness.

Exploring Reddit conversations about mental health difficulties among college students during the COVID-19 pandemic.

Objective: We aimed to explore conversations about mental health difficulties by Reddit users who posted within college subreddits during the COVID-19 pandemic. Participants: Data were collected from the subreddits of 22 California campuses, representing 113,579 anonymous members. Using the following search terms, we retrieved 577 posts (ie, 268 original posts and 309 replies): COVID, Coronavirus, Quarantine, Pandemic, Anxiety, Anxious, Depressed, Depression, Overwhelmed, Stress, and Stressed. Methods: We used inductive, thematic data analysis to explore themes within posts and replies dated from 3/16/2020 to 3/16/2021. Results: We identified the following themes: 1) the COVID-19 pandemic has negatively impacted engagement with learning; 2) remote learning has exacerbated students' mental health difficulties; and 3) students provide and receive social support online. Conclusions: These findings have implications that are particularly relevant as campuses are faced with continuous decisions related to repopulation.

Prescription Stimulant Misuse and Diversion Events Among College Students: A Qualitative Study.

Prescription stimulant misuse and diversion are interrelated behaviors: diversion increases the availability of stimulants for misuse, and persons who misuse are also more likely to divert. To date, research has examined these behaviors using a primarily quantitative lens. We led a qualitative investigation to better understand misuse and diversion events. Data are from a diverse southern California campus where we interviewed students who misuse and/or divert prescription stimulants (32 total interviews: 16 interviews with students who had a history of misuse, and 16 different interviews with students who had a history of diversion). We analyzed interview data inductively. We identified the following themes about misuse and diversion events, several of which intersected during interviews: medication surplus, diversion and misuse hubs, ease of behavior performance, academic stress, and other drugs commonly involved. For diversion, altruism and monetary gain were juxtaposed themes. Across themes, friends and family were influential figures. Implications for prevention, intervention, and future research directions are discussed.

Subcutaneous panniculitis-like T-cell lymphoma, lupus erythematosus profundus, and overlapping cases: molecular characterization through the study of 208 genes.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare cytotoxic cutaneous lymphoma. Differential diagnosis with lupus erythematosus panniculitis (LEP) can be challenging and overlapping cases have been described. In this study, we investigate whether gene expression profiling may or not identify markers that can be used to improve our understanding of the disease and to make a precise differential diagnosis. SPTCL, LEP, and overlapping cases were analyzed using a customized NanoString platform including 208 genes related to T-cell differentiation, stromal signatures, oncogenes, and tumor suppressor genes. Gene expression unsupervised analysis of the samples differentiated SPTCL from LEP samples. Most overlapping cases were clustered with LEP cases. Differentially expressed genes were observed when comparing SPTCL with LEP cases; and overlapping with LEP cases. Gene set enrichment analysis recognized gene sets defining each group. In conclusion, SPTCL and LEP have distinctive molecular profiles and the molecular background of overlapping cases more closely resembles LEP.

Comparative analysis of the ERα/ERß ratio and neurotensin and its high-affinity receptor in myometrium, uterine leiomyoma, atypical leiomyoma, and leiomyosarcoma.

Deregulated steroids are involved in different hormone-dependent tumors, including benign and malignant uterine neoplasms. Leiomyomas (LM) are estrogen and progesterone-dependent benign tumors, whereas "bizarre or atypical LMs" (AL) are considered a subgroup of LM and clinically benign, although their malignant potential is suspect. Uterine leiomyosarcomas (LMS) are malignant smooth muscle tumors, and ovarian steroids may control their growth. Estrogen effects are mediated by 2 receptors, estrogen receptors (ER) α and ß, and the ratio of both receptors seems to be a critical parameter in the estrogen-mediated carcinogenic process. Estradiol induces the expression of neurotensin (NTS), and the coupling of this peptide with its high-affinity receptor, NTS1, has been involved in the regulation of tumoral cell growth. Given the importance of these markers in tumor development, we aim to determine the status of ERα and ERß in the myometrium and LM, AL, and LMS, concomitantly with the expression of NTS/NTS receptor 1 in these tumors. For that purpose, we use immunohistochemistry for all markers analyzed and in-situ hybridization to detect NTS mRNA. These data suggest that LMS are estrogen-dependent tumors, which may use NTS as an autocrine growth factor. In addition, the phenotype of AL with regard to ERα and ERß status and NTS expression is closer to LMS than LM; thus, a potential malignization of this tumor is feasible.

Neurotensin and neurotensin receptor 1 expression in human myometrium and uterine leiomyomas.

Leiomyomas or fibroids are the most frequently diagnosed tumors of the female genital tract, and their growth seems to be steroid-hormone dependent by a yet undetermined cellular and molecular mechanism. Sexual hormones induce the secretion of growth factor peptides and the expression of their receptors, stimulating cell proliferation. One of these factors is neurotensin, and increasing evidence suggests that it can promote growth of different cancer cells. Since there are no data on neurotensin expression in normal and tumoral uterine tissue, we have analyzed the expression of NTS and NTSR1 receptor using immunohistochemistry for protein detection, in situ hybridization to detect cells expressing NTS mRNA, and RT-PCR to detect NTSR1 transcript as well as any of the alternative splice variants recently described for this receptor. We found that NTS and NTSR1 are expressed in connective cells of normal myometrium. In leiomyomas, immunoreactivity for NTS and NTSR1 receptor is colocalized in the smooth muscle cells that are also transcribing NTS. Women receiving high doses of steroids for in vitro fertilization showed tumor growth and increased immunoreactivity for neurotensin and NTSR1 receptor. Interestingly, alternative splice variants of NTSR1 receptor were detected only in tumoral tissue. These findings suggest a role of steroid hormones inducing neurotensin expression in leiomyoma smooth muscle cells. In these cells, NTS could act autocrinally through NTSR1 receptor, promoting their proliferation.

Riesgo de displasia de alto grado o carcinoma invasivo en los adenomas colorrectales planos en población española / Risk for high-grade dysplasia or invasive carcinoma in colorectal flat adenomas in a Spanish population

Objetivo: Determinar la frecuencia y el riesgo de malignidad de los adenomas colorrectales de tipo plano en pacientes españoles. Métodos: Se revisaron 1.300 colonoscopias; se detectaron 640 pólipos en 298 pacientes, que fueron extirpados endoscópicamente. Se aplicó indigocarmín al 0,2% para clarificar el aspecto macroscópico de las lesiones planas. Se registraron las siguientes variables en las lesiones planas y en los pólipos protruidos: tamaño, localización (proximal o distal al ángulo esplénico), histología (neoplásico o no), presencia de displasia de alto grado, y existencia de carcinoma invasivo a submucosa o mayor. Resultados: Un total de 490 pólipos (76,6%) fueron neoplásicos y 150 (23,4%) no neoplásicos; 114 (23,3%) adenomas fueron planos (3 planos-deprimidos) frente a 376 (76,7%) protruidos. El diámetro medio de los adenomas planos y protruidos fue de 9,2 ± 7,9 y 7,0 ± 5,9 mm, respectivamente (p < 0,001). La localización proximal fue más frecuente en los adenomas planos (63,1%) que en los protruidos (48,7%) (p = 0,003). La frecuencia de displasia de alto grado o carcinoma invasivo fue significativamente mayor en los adenomas planos que en los protruidos (el 7,0 frente al 2,6%; p < 0,04). Dos de las 3 lesiones planas-deprimidas) (ambas de ¾ 10 mm de diámetro) fueron carcinomas (T1 y T2, respectivamente). Los adenomas planos presentaron un riesgo superior de histología avanzada (displasia de alto grado o carcinoma invasivo) (odds ratio = 2,7; intervalo de confianza, 1,04-7,04; p < 0,05). Conclusiones: En la población española los adenomas planos representan casi la cuarta parte de todos los pólipos neoplásicos, su localización más frecuente es el colon proximal, y presentan mayor riesgo de malignidad que los adenomas protruidos (en especial el tipo plano-deprimido)

Aim: to determine the frequency and malignancy risk of colonic flat adenomas among patients with colorectal polyps in a Spanish population. Methods: 1300 consecutive colonoscopic examinations were reviewed; 640 polyps were detected and removed endoscopically in 298 patients. Chromoendoscopy with 0.2% indigo carmine was applied to clarify the macroscopical appearance of flat lesions. The following data was collected for flat and protruding polyps: size, location (proximal or distal to splenic flexure), histology (neoplastic or non neoplastic), high grade dysplasia (HGD) and submucosal invasive carcinoma (SIC) or beyond. Results: 490 polyps (76.6%) were adenomas and 150 (23.4%) hyperplastic; 114 (23.3%) adenomas were flat (3 flat-depressed) whereas 376 (76.7%) were protruding. The diameter of flat and protruding adenomas was 9.2 ± 7.9. mm and 7.0 ± 5.9 mm, respectively (p < 0.001). A proximal location was more frequent for flat (63.1%) than for protruding adenomas (48.7%) (p = 0.003). The rate of HGD or SIC was significantly higher in flat than in protruding adenomas (7.0 vs 2.6%; p < 0.04). Two of the 3 flat-depressed lesions (both ¾ 10 mm in diameter) were carcinomas (T1 and T2, respectively). Flat adenomas had an increased risk for HGD or SIC (OR = 2,7; CI, 1,04-7,04; p < 0.05). Conclusions: In a Spanish population, flat adenomas represent nearly one quarter of all colorectal neoplastic polyps, their most frequent location being the right colon and they bear a higher risk of malignancy than protruding adenomas, especially for the flat depressed type

Characterization of estrogen receptors alpha and beta in uterine leiomyoma cells.

OBJECTIVE: Cellular and subcellular localization of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) in uterine leiomyomas. DESIGN: Retrospective study. SETTING: University of La Laguna (ULL) and Canary University Hospital (HUC). PATIENT(S): Premenopausal and postmenopausal women with uterine leiomyomas. INTERVENTION(S): Hysterectomy and myomectomy. RESULT(S): Estrogen receptor alpha was only present in smooth muscle cells with variation in the subcellular location in different leiomyomas. Estrogen receptor beta was widely distributed in smooth muscle, endothelial, and connective tissue cells with nuclear location in all cases studied; variations were only found in the muscle cells for this receptor. CONCLUSION(S): Estrogens operate in leiomyoma smooth muscle cells through different receptors, alpha and beta. However they only act through the ERbeta in endothelial and connective cells.

[Effect of intravenous magnesium sulfate on chronic obstructive pulmonary disease exacerbations requiring hospitalization: a randomized placebo-controlled trial]. / Efecto del sulfato de magnesio intravenoso en la exacerbación de la EPOC que precisa hospitalización: estudio aleatorizado controlado con placebo.

OBJECTIVE: Magnesium sulfate has been shown to have a bronchodilating effect in asthma, but this effect has not been clearly established in the context of chronic obstructive pulmonary disease (COPD). For this reason we investigated the possible bronchodilating effect of magnesium sulfate in COPD exacerbations. PATIENTS AND METHODS: We studied 24 patients with exacerbated COPD who required admission to our hospital's pneumology department. All patients underwent baseline spirometry and were subsequently randomized to groups in a double-blind crossover design. Patients received 1.5 g of magnesium sulfate or placebo in an intravenous solution for 20 minutes. Those who received magnesium sulfate the first day were given placebo the second day, and vice versa. Spirometry was performed 15, 30, and 45 minutes after administration of magnesium sulfate or placebo. Finally, 400 microg of salbutamol were administered using a spacer and a final spirometry was performed 15 minutes later. All patients also received treatment with corticosteroids, intravenous antibiotics, oxygen, and regularly-scheduled bronchodilator therapy (salbutamol and ipratropium bromide every 6 hours). RESULTS: When we compared absolute increase in milliliters and percentage increase in forced expiratory volume in 1 second (FEV1) obtained with magnesium sulfate application to the increases obtained with placebo after 15, 30, and 45 minutes, no significant differences were found. When we compared absolute and percentage increases in FEV1 after administering salbutamol, we found significantly greater increases after magnesium sulfate administration. The mean (SD) absolute increase in FEV1 was 0.18 [corrected] (0.42) L after magnesium sulfate administration and 0.081 [0.01] L after placebo (P=.004). The percentage increase in FEV1 was 17.11% (3.7%) after magnesium sulfate and 7.06% (1.8%) after placebo (P=.008). CONCLUSIONS: Intravenous administration of magnesium sulfate has no bronchodilating effect in patients with COPD exacerbations. It does, however, enhance the bronchodilating effect of inhaled ss2-agonists.

Efecto del sulfato de magnesio intravenoso en la exacerbación de la EPOC que precisa hospitalización: estudio aleatorizado controlado con placebo / Effect of intravenous magnesium sulfate on chronic obstructive pulmonary disease exacerbations requiring hospitalization: a randomized placebo-controlled trial

Objetivo: El sulfato de magnesio (SM) ha demostrado tener en el asma bronquial un efecto broncodilatador, que resulta dudoso en el caso de la enfermedad pulmonar obstructiva crónica (EPOC). Por ello hemos llevado a cabo un estudio con el objetivo de investigar el posible efecto broncodilatador del SM intravenoso en la EPOC agudizada. Pacientes y métodos: Se estudió a 24 pacientes diagnosticados de EPOC agudizada que requirieron ingreso en la Unidad de Hospitalización de Neumología. A cada uno se le realizó una espirometría basal. Posteriormente, se efectuó una aleatorización a doble ciego y cruzada de los pacientes para recibir 1,5 g de SM o placebo en solución intravenosa (20 min). A quienes el primer día recibieron SM se les administró placebo el segundo día, y al revés. Se realizaron espirometrías a los 15, 30 y 45 min de la administración de SM o placebo. Por último, se administraron 400 µg de salbutamol inhalados mediante cámara espaciadora y a los 15 min se realizó una última espirometría. Todos los enfermos recibieron además tratamiento con esteroides, antibióticos intravenosos, oxígeno y broncodilatadores pautados (salbutamol y bromuro de ipratropio cada 6 h). Resultados: Cuando se compararon los incrementos absolutos (en ml) y porcentuales del volumen espiratorio forzado en el primer segundo (FEV1) obtenidos con SM y placebo a los 15, 30 y 45 min, no se encontraron diferencias significativas. Al comparar los incrementos absolutos y porcentuales del FEV1 tras la administración de salbutamol se observaron incrementos significativos con el SM (incrementos absolutos FEV1 SM/placebo: 0,185 ± 0,42 frente a 0,081 ± 0,01 l; p = 0,004. Incrementos porcentuales FEV1 SM/placebo: 17,11 ± 3,7% frente al 7,06 ± 1,8%; p = 0,008). Conclusiones: La administración de SM intravenoso carece de efecto broncodilatador en pacientes con EPOC agudizada; sin embargo, sí potencia dicho efecto de los betamiméticos inhalados

Objective: Magnesium sulfate has been shown to have a bronchodilating effect in asthma, but this effect has not been clearly established in the context of chronic obstructive pulmonary disease (COPD). For this reason we investigated the possible bronchodilating effect of magnesium sulfate in COPD exacerbations. Patients and methods: We studied 24 patients with exacerbated COPD who required admission to our hospital's pneumology department. All patients underwent baseline spirometry and were subsequently randomized to groups in a double-blind crossover design. Patients received 1.5 g of magnesium sulfate or placebo in an intravenous solution for 20 minutes. Those who received magnesium sulfate the first day were given placebo the second day, and vice versa. Spirometry was performed 15, 30, and 45 minutes after administration of magnesium sulfate or placebo. Finally, 400 µg of salbutamol were administered using a spacer and a final spirometry was performed 15 minutes later. All patients also received treatment with corticosteroids, intravenous antibiotics, oxygen, and regularly-scheduled bronchodilator therapy (salbutamol and ipratropium bromide every 6 hours). Results: When we compared absolute increase in milliliters and percentage increase in forced expiratory volume in 1 second (FEV1) obtained with magnesium sulfate application to the increases obtained with placebo after 15, 30, and 45 minutes, no significant differences were found. When we compared absolute and percentage increases in FEV1 after administering salbutamol, we found significantly greater increases after magnesium sulfate administration. The mean (SD) absolute increase in FEV1 was 0.185 (0.42) L after magnesium sulfate administration and 0.081 [0.01] L after placebo (P=.004). The percentage increase in FEV1 was 17.11% (3.7%) after magnesium sulfate and 7.06% (1.8%) after placebo (P=.008). Conclusions: Intravenous administration of magnesium sulfate has no bronchodilating effect in patients with COPD exacerbations. It does, however, enhance the bronchodilating effect of inhaled Beta2-agonists

Risk for high-grade dysplasia or invasive carcinoma in colorectal flat adenomas in a Spanish population.

AIM: to determine the frequency and malignancy risk of colonic flat adenomas among patients with colorectal polyps in a Spanish population. METHODS: 1300 consecutive colonoscopic examinations were reviewed; 640 polyps were detected and removed endoscopically in 298 patients. Chromoendoscopy with 0.2% indigo carmine was applied to clarify the macroscopical appearance of flat lesions. The following data was collected for flat and protruding polyps: size, location (proximal or distal to splenic flexure), histology (neoplastic or non neoplastic), high grade dysplasia (HGD) and submucosal invasive carcinoma (SIC) or beyond. RESULTS: 490 polyps (76.6%) were adenomas and 150 (23.4%) hyperplastic; 114 (23.3%) adenomas were flat (3 flat-depressed) whereas 376 (76.7%) were protruding. The diameter of flat and protruding adenomas was 9.2 +/- 7.9. mm and 7.0 +/- 5.9 mm, respectively (p < 0.001). A proximal location was more frequent for flat (63.1%) than for protruding adenomas (48.7%) (p = 0.003). The rate of HGD or SIC was significantly higher in flat than in protruding adenomas (7.0 vs 2.6%; p < 0.04). Two of the 3 flat-depressed lesions (both

Enantioselective synthesis and biological activity of (3S,4R)- and (3S,4S)-3-hydroxy-4-hydroxymethyl- 4-butanolides in relation to PGE2.

Compounds 9 and 13 were synthesized, and their structures and stereochemistry were elucidated by spectroscopic methods. In competition binding experiments, specific [(3)H]-PGE(2) binding was significantly displaced by compound 9 and, to a lesser extent, by 13, in a dose-dependent manner. The biological properties of compound 9 were studied on HL-60 cells, and several effects were found related to those of PGE(2). Compound 9 increases c-fos mRNA level as does PGE(2) and antagonizes TPA-induced terminal differentiation.

Dietary fish oil does not influence acute rejection rate and graft survival after renal transplantation: a randomized placebo-controlled study.

BACKGROUND: Dietary fish oil, rich in omega-3 polyunsaturated fatty acids, decreases TNF-alpha, IL-1beta and IL-2 levels, which may benefit renal transplant recipients. To explore this possibility, we studied the effect of fish oil on the incidence of acute rejection, in situ expression of interleukins (TNF-alpha, IL-1beta and IL-2) and renal function after renal transplantation. METHODS: In a double-blind clinical trial, 86 subjects with no immunological risk randomly received either 6 g/day of fish oil (fish oil group; n=46) or soy oil (control group; n=40) during the first 3 months after transplantation. The mRNA expression of interleukins (TNF-alpha, IL-1beta and IL-2) was determined by RT-PCR using fine-needle aspiration during follow-up (at baseline and the 1st, 2nd and 3rd month after renal transplantation), as well as during acute rejection episodes and after anti-rejection therapy. The glomerular filtration rate was determined at baseline, and at 1 and 3 months post-graft by [(51)Cr]EDTA clearances. RESULTS: The incidence of acute rejection during the first post-transplant year was similar in both groups (44 vs. 47%), as was 1-year graft survival (86 vs. 89%). There were no differences between groups in overall renal expression of interleukins in patients who did not suffer rejections during the study. At rejection episodes, the fish oil group showed a trend toward a lower renal expression of TNF-alpha (3.7+/-6.8 vs. 15+/-18.6 TNF-alpha/actin, ratio of arbitrary optical units; P=0.05). In addition, a trend toward a lower IL-1beta expression after therapy was observed in the fish oil group (49.3+/-54 vs. 84.4+/-59 IL-1beta/actin, ratio of arbitrary optical units; P=0.05). However, the severity of acute rejections (Banff criteria) as well as renal function after anti-rejection treatment were similar in both groups. Finally, a greater reduction in triglyceride levels was observed in the fish oil group compared with the control group (-6.6+/-52.7 vs. 12.7+/-40.2%; P<0.05). CONCLUSIONS: Treatment with fish oil during the first 3 months post-transplantation does not influence acute rejection rate and has no beneficial effect on renal function or graft survival.