Physician Empathy and Chronic Pain Outcomes.

Importance: Empathy is an aspect of the patient-physician relationship that may be particularly important in patients with chronic pain. Objective: To measure the association of physician empathy with pain, function, and health-related quality of life (HRQOL) among patients with chronic low back pain. Design, Setting, and Participants: This cohort study included adult enrollees from the Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation national pain research registry. Study dates were from April 1, 2016, to July 25, 2023, with up to 12 months of follow-up. Exposure: Physician empathy was assessed with the Consultation and Relational Empathy measure and dichotomized to yield very empathic physician and slightly empathic physician groups. Main Outcomes and Measures: Main outcomes were patient-reported pain, function, and HRQOL measured with a numerical rating scale for low back pain intensity, the Roland-Morris Disability Questionnaire for back-related disability, and the Patient-Reported Outcomes Measurement Information System for HRQOL deficits pertaining to anxiety, depression, fatigue, sleep disturbance, and pain interference. Data were collected at 5 quarterly encounters from registry enrollment through 12 months and analyzed with generalized estimating equations, including multivariable models to measure temporal trends and to adjust for baseline and longitudinal covariates. Results: Among the 1470 patients, the mean (SD) age was 53.1 (13.2) years, and 1093 (74.4%) were female. Patients completed 5943 encounters in which multivariable analyses demonstrated that greater physician empathy was inversely associated with pain intensity (ß = -0.014; 95% CI, -0.022 to -0.006; P < .001), back-related disability (ß = -0.062; 95% CI, -0.085 to -0.040; P < .001), and HRQOL deficits on each measure (eg, pain interference: ß = -0.080; 95% CI, -0.111 to -0.049; P < .001). Correspondingly, compared with the slightly empathic physician group, the very empathic physician group reported lower mean pain intensity (6.3; 95% CI, 6.1-6.5 vs 6.7; 95% CI, 6.5-6.9; P < .001), less mean back-related disability (14.9; 95% CI, 14.2-15.6 vs 16.8; 95% CI, 16.0-17.6; P < .001), and fewer HRQOL deficits on each measure (eg, fatigue: 57.3; 95% CI, 56.1-58.5 vs 60.4; 95% CI, 59.0-61.7; P < .001). All physician empathy group differences were clinically relevant, with Cohen d statistics ranging from 0.21 for pain intensity to 0.30 for back-related disability, fatigue, and pain interference. Physician empathy was associated with more favorable outcomes than non-pharmacological treatments, opioid therapy, and lumbar spine surgery. Conclusions and Relevance: In this cohort study of adult patients with chronic pain, physician empathy was associated with better outcomes over 12 months. Greater efforts to cultivate and improve physician empathy appear warranted.

Aberrant PRDM2 methylation as an early event in serrated lesions destined to evolve into microsatellite-instable colorectal cancers.

Up to 30% of colorectal cancers (CRCs) develop from sessile serrated lesions (SSLs). Within the serrated neoplasia pathway, at least two principally distinct oncogenetic routes exist generating microsatellite-stable and microsatellite-instable CRCs, respectively. Aberrant DNA methylation (DNAm) is found early in the serrated pathway and might play a role in both oncogenetic routes. We studied a cohort of 23 SSLs with a small focus (<10 mm) of dysplasia or cancer, 10 of which were MLH1 deficient and 13 MLH1 proficient. By comparing, for each SSL, the methylation status of (1) the region of dysplasia or cancer (SSL-D), (2) the nondysplastic SSL (SSL), and (3) adjacent normal mucosa, differentially methylated probes (DMPs) and regions (DMRs) were assessed both genome-wide as well as in a tumor-suppressor gene-focused approach. By comparing DNAm of MLH1-deficient SSL-Ds with their corresponding SSLs, we identified five DMRs, including those annotating for PRDM2 and, not unexpectedly, MLH1. PRDM2 gene promotor methylation was associated with MLH1 expression status, as it was largely hypermethylated in MLH1-deficient SSL-Ds and hypomethylated in MLH1-proficient SSL-Ds. Significantly increased DNAm levels of PRDM2 and MLH1, in particular at 'critical' MLH1 probe sites, were to some extent already visible in SSLs as compared to normal mucosa (p = 0.02, p = 0.01, p < 0.0001, respectively). No DMRs, nor DMPs, were identified for SSLs destined to evolve into MLH1-proficient SSL-Ds. Our data indicate that, within both arms of the serrated CRC pathway, the majority of the epigenetic alterations are introduced early during SSL formation. Promoter hypermethylation of PRDM2 and MLH1 on the other hand specifically initiates in SSLs destined to transform into MLH1-deficient CRCs suggesting that the fate of SSLs may not necessarily result from a stochastic process but possibly is already imprinted and predisposed.

Effect of an E-learning resource on endoscopists' proximal serrated polyp detection rate: a randomized controlled trial.

BACKGROUND: Recent studies demonstrated that a higher proximal serrated polyp detection rate (PSPDR) among endoscopists is associated with a lower risk of post-colonoscopy colorectal cancer (PCCRC) incidence and death for their patients. Our objective was to evaluate the effect of an e-learning resource on PSPDR. METHODS: We performed a multicenter randomized controlled trial within the Dutch fecal immunochemical test-based colorectal cancer screening program. Endoscopists were randomized using block randomization per center to either receive a 60-minute e-learning resource on serrated polyp detection or not. PSPDR was calculated based on all colonoscopies performed during a 27-month pre-intervention and a 17-month post-intervention period. The primary end point was difference in PSPDR between intervention and control arms (intention to treat) using mixed effect logistic regression modeling, with time (pre-intervention/post-intervention) and interaction between time and arm (intervention/control) as fixed effects, and endoscopists as random effects. RESULTS: 116 endoscopists (57 intervention, 59 controls) were included, and performed 27494 and 33888 colonoscopies, respectively. Median PSPDR pre-intervention was 13.6% (95%CI 13.0-14.1) in the intervention arm and 13.8% (95%CI 13.3-14.3) in controls. Post-intervention PSPDR was significantly higher over time in the intervention arm than in controls (17.1% vs. 15.4%, P=0.01). CONCLUSION: In an era of increased awareness and increasing PSPDRs, endoscopists who undertook a one-time e-learning course significantly accelerated the increase in PSPDR compared with endoscopists who did not undertake the e-learning. Widespread implementation might reduce PCCRC incidence.

Polyps and Colorectal Cancer in Serrated Polyposis Syndrome: Contribution of the Classical Adenoma-Carcinoma and Serrated Neoplasia Pathways.

INTRODUCTION: Patients with serrated polyposis syndrome (SPS) have an increased risk to develop colorectal cancer (CRC). Due to an abundance of serrated polyps, these CRCs are assumed to arise mainly through the serrated neoplasia pathway rather than through the classical adenoma-carcinoma pathway. We aimed to evaluate the pathogenetic routes of CRCs in patients with SPS. METHODS: We collected endoscopy and pathology data on CRCs and polyps of patients with SPS under treatment in our center. Our primary end point was the proportion of BRAFV600E mutated CRCs, indicating serrated pathway CRCs (sCRCs). CRCs lacking BRAFV600E most likely inferred a classical adenoma-carcinoma origin (aCRCs). We assessed patient, polyp, and CRC characteristics and stratified for BRAFV600E mutation status. RESULTS: Thirty-five patients with SPS harbored a total of 43 CRCs. Twenty-one CRCs (48.8%) carried a BRAFV600E mutation, 10 of which lacked MLH1 staining and 17 (81%) were located in the proximal colon. Twenty-two CRCs (51.1%) did not carry a BRAFV600E mutation and were MLH1 proficient. Of these 22 putatively aCRCs, 17 (77.3%) were located distally and one-third (36.4%) harbored a pathogenic KRAS or NRAS mutation. In patients with BRAFwt -CRCs, a higher ratio of the median number of conventional adenomas versus serrated polyps was found (4 vs 13) than patients with BRAFV600E -CRCs (1 vs 14). DISCUSSION: Our study indicates that in patients with SPS, the ratio of sCRCs:aCRCs on average is 50:50. This elevated sCRC:aCRC ratio in patients with SPS, when compared with non-SPS patients, correlates well with the differences in the ratios of the numbers of sessile serrated lesions and conventional adenomas in patients with SPS and non-SPS patients, respectively.

Appendiceal lesions in serrated polyposis patients are easily overlooked but only seldomly lead to colorectal cancer.

BACKGROUND: Serrated polyposis syndrome (SPS) is the most prevalent colonic polyposis syndrome and is associated with an increased colorectal cancer risk. A recent study in resected appendices of SPS patients reported that 6/23 (26.1 %) of identified serrated polyps had histological dysplasia. We evaluated the prevalence and clinical relevance of appendiceal lesions in a large SPS cohort. METHODS: Prospective data from 2007 to 2020 for a cohort of 199 SPS patients were analyzed. Data were retrieved from endoscopy and pathology reports. Patients who underwent (pre)clearance colonoscopies, surveillance colonoscopies, or colorectal surgery including the appendix were separately evaluated for the presence of appendiceal lesions. The primary outcome was the prevalence of adenocarcinomas and serrated polyps/adenomas with advanced histology in the surgery group. RESULTS: 171 patients were included, of whom 110 received endoscopic surveillance and 34 underwent surgery. Appendiceal lesion prevalence in the surgery group was 14 /34 (41.2 %, 95 %CI 24.7 %-59.3 %); none were advanced on histology. Detection rates in the (pre)clearance group were 1 /171 (0.6 %, 95 %CI 0.01 %-3.2 %) for advanced and 3 /171 (1.8 %, 95 %CI 0.04 %-5.0 %) for nonadvanced appendiceal lesions, all of which were sessile serrated lesions. During 522 patient-years of surveillance, no advanced appendiceal lesions were detected at endoscopy, and in 1 /110 patients (0.9 %, 95 %CI 0.02 %-5.0 %) was a nonadvanced lesion detected. CONCLUSION: Appendiceal lesions are common in SPS patients. The discrepancy between the endoscopic detection rate of appendiceal lesions and the reported prevalence in surgically resected appendices suggests a substantial miss-rate of appendiceal lesions during colonoscopy. Advanced appendiceal lesions are however rare and no appendiceal adenocarcinomas occurred, implying limited clinical relevance of these lesions.

Advanced serrated polyps as a target of screening: detection rate and positive predictive value within a fecal immunochemical test-based colorectal cancer screening population.

BACKGROUND : Advanced serrated polyps (ASPs) have a comparable risk to advanced adenomas for progression to colorectal cancer (CRC). The yield of most CRC screening programs, however, is based on advanced adenomas and CRC only. We assessed the ASP detection rate, and positive predictive value (PPV) including ASPs in a fecal immunochemical test (FIT)-based screening program. METHODS : We analyzed the findings of follow-up colonoscopies of FIT-positive screenees in the Dutch CRC screening program from 2014 until 2020. Data were retrieved from the national screening and pathology database. An ASP was defined as any serrated polyp of ≥ 10 mm, sessile serrated lesion with dysplasia, or traditional serrated adenoma. The ASP detection rate was defined as the proportion of colonoscopies with ≥ 1 ASP. PPV was originally defined as the proportion of individuals with a CRC or advanced adenoma. The updated PPV definition included CRCs, advanced adenomas, and/or ASPs. RESULTS : 322 882 colonoscopies were included in the analyses. The overall detection rate of ASPs was 5.9 %. ASPs were detected more often in women than men (6.3 % vs. 5.6 %; P < 0.001). ASP detection rates in individuals aged 55-59, 60-64, 65-69, and 70 + were 5.2 %, 6.1 %, 6.1 %, and 5.9 %, respectively (P < 0.001). The PPV for CRCs and advanced adenomas was 41.1 % and increased to 43.8 % when including ASPs. The PPV increase was larger in women than in men (3.2 vs. 2.4 percentage points). CONCLUSIONS : 5.9 % of FIT-positive screenees had ASPs, but half of these were detected in combination with a CRC or advanced adenoma. Therefore, including ASPs results in a small increase in the yield of FIT-based screening.

Self-Reported Sleeping Time Effects on Physical Performance and Body Composition Among Spanish Older Adults: EXERNET-Elder 3.0 study.

Objective: To determine the link between physical fitness and body composition with nocturnal and nap time in Spanish older adults. Methods: Eight hundred thirty older adults underwent several tests. Sleep was measured using Jenkins Sleep Scale. Nocturnal sleep was categorized (<7, 7-9, and >9 hours), and nap time (no nap, 1-30 minutes, and >30 minutes).Physical fitness was evaluated using validated tests, and body composition by electric bioimpedance. Results: 75.1% of participants were female, mean age 77.7 ± 5.1 years. Mean nocturnal sleep and nap time was 6.7 hours and 23.3 minutes, respectively. Models showed nocturnal sleep >9 hours was significant and positively associated with body shape index (Odds ratio[OR] = 4.07 (p = .011)) and waist circumference OR = 1.04 (p = .024) in females. Males' waist and hip circumference were positively significantly related to nap time between 1 and 30 minutes, OR = 1.08, p = .009 and OR = 1.08, p = .048, respectively. In females, nap time >30 minutes was associated with greater fat mass and body shape index OR = 1.22, p = .032 and OR = 3.95, p = .027, respectively. Physical fitness showed no associations with sleep outcomes. Conclusions: Sleep patterns do not influence physical fitness but body composition, being more related to female body composition as nocturnal and nap sleep were associated with higher fat mass, waist circumference and body shape index, while only short nap times were related to higher waist and hip circumference in males.

Serrated polyp detection and risk of interval post-colonoscopy colorectal cancer: a population-based study.

BACKGROUND: Adenoma detection rate (ADR) is a well-established quality indicator for colonoscopy and is inversely associated with the incidence of interval post-colonoscopy colorectal cancer. However, interval post-colonoscopy colorectal cancers frequently develop from serrated polyps, which are not included in the ADR. Therefore, the proximal serrated polyp detection rate (PSPDR) has been proposed as a quality indicator, but its association with interval post-colonoscopy colorectal cancer has not been studied. We aimed to evaluate this potential association based on data collected in the Dutch colorectal cancer screening programme. METHODS: In this population-based study, using colonoscopy data from the Dutch faecal immunochemical test-based colorectal cancer screening programme and cancer data from the Netherlands Cancer Registry, we evaluated the association between endoscopists' individual PSPDR and their patients' risk of interval post-colonoscopy colorectal cancer with a shared frailty Cox proportional-hazard regression analysis. Participants in the screening programme who were eligible for inclusion were aged 55-76 years, had a positive faecal immunochemical test (cutoff 15 µg Hb/g faeces at start and changed mid-2014 to 47 µg Hb/g faeces), were asymptomatic, and underwent a colonoscopy between Jan 1, 2014, and Dec 31, 2020. The PSPDR was defined as the proportion of colonoscopies in which at least one serrated polyp proximal to the descending colon was detected, confirmed by histopathology. The ADR was defined as the proportion of all colonoscopies in which at least one conventional adenoma was detected, confirmed by histopathology. Detection rates were determined for each endoscopist individually. We additionally evaluated the risk of interval post-colonoscopy colorectal cancer for endoscopists with a PSPDR and ADR above the median versus endoscopists with either one or both parameters below the median. This study is registered with the Netherlands Trial Registry, NL8350. FINDINGS: During the study period, 329 104 colonoscopies were done, of which 277 555, done by 441 endoscopists, were included in the PSPDR calculations. The median PSPDR was 11·9% (IQR 8·3-15·8) and median ADR was 66·3% (61·4-69·9). The correlation between the PSDPR and ADR was moderate (r=0·59; p<0·0001). During a median follow-up of 33 months (IQR 21-42), 305 interval post-colonoscopy colorectal cancers were detected. For each percentage point increase in PSPDR, the adjusted interval post-colonoscopy colorectal cancer hazard was 7% lower (hazard ratio [HR] 0·93, 95% CI 0·90-0·95; p<0·0001). Compared with endoscopists with a PSPDR greater than 11·9% and ADR greater than 66·3%, the HR of interval post-colonoscopy colorectal cancer for endoscopists with a low PSPDR and high ADR was 1·79 (95% CI 1·22-2·63), for endoscopists with a high PSPDR and low ADR was 1·97 (1·19-3·24), and for endoscopists with a low PSPDR and low ADR was 2·55 (1·89-3·45). INTERPRETATION: The PSPDR of an endoscopist is inversely associated with the incidence of interval post-colonoscopy colorectal cancer. Implementation of PSPDR monitoring, in addition to ADR monitoring, could optimise colorectal cancer prevention. FUNDING: None.

Current Approaches in Managing Colonic Serrated Polyps and Serrated Polyposis.

For decades, conventional adenomas were the only known precursor lesions of colorectal cancer (CRC). Accordingly, education and research regarding CRC prevention were mainly focused on adenomas. The groundbreaking discovery that serrated polyps (SPs) also have the potential to develop into CRCs, and seem to account for a considerable proportion of sporadic CRCs, has led to a paradigm shift in the prevention, diagnosis, and treatment of CRC. Studies in recent years have led to our current understanding of SPs and associated CRC, but a lot of work is still to be done to further improve knowledge about this serrated neoplasia pathway and the clinical management of SPs and serrated polyposis syndrome (SPS). In this review, we reflect on the current understanding of SPs with respect to terminology, detection, resection, and surveillance and reflect on the management of SPS.

Analysis of Effectiveness of a Supplement Combining Harpagophytum procumbens, Zingiber officinale and Bixa orellana in Healthy Recreational Runners with Self-Reported Knee Pain: A Pilot, Randomized, Triple-Blind, Placebo-Controlled Trial.

Recreational running (RR) is becoming a popular way to increase physical activity for improving health, together with a higher incidence of knee injuries. The aim was to analyze the effect of a four-week supplementation with a mixture of Harpagophytum procumbens, Zingiber officinale and Bixa orellana on males, middle-aged, RR with an undiagnosed knee discomfort. A randomized triple-blind placebo-control trial was conducted among male RR aged 40-60 years suffering from self-declared knee discomfort after training. Participants were assigned to supplementation (2 g/day in 6 doses; n = 13; intervention group (IG)) or matched placebo (n = 15; control group (CG)) for 4 weeks. At pre- and post-intervention, assessment of routine blood biomarkers, body composition, running biomechanics and body temperature was performed using standardized procedures. Machine learning (ML) techniques were used to classify whether subjects belonged to IG or CG. ML model was able to correctly classify individuals as IG or CG with a median accuracy of 0.857. Leg fat mass decreased significantly (p = 0.037) and a deeper reduction in knee thermograms was observed in IG (p < 0.05). Safety evaluation revealed no significant differences in the rest of parameters studied. Subjects belonging to IG or CG are clearly differentiated, pointing into an effect of the supplement of ameliorating inflammation.

Niveles de glicemia capilar en pacientes diabéticos sometidos a cirugía programada

RESUMEN Introducción: la diabetes mellitus es una de las enfermedades metabólicas más prevalentes a nivel mundial y es considerado un factor de riesgo para la realización de procedimientos quirúrgicos. Objetivo: determinar los valores de glicemia capilar en pacientes diabéticos sometidos a cirugía programada. Sujetos y métodos: diseño observacional, descriptivo, prospectivo con componentes analíticos. Se incluyó a pacientes con diabetes mellitus sometidos a cirugía electiva en el Hospital de Clínicas (San Lorenzo, Paraguay). Se determinaron las variables demográficas, requerimiento de infusión de insulina, clasificación de ASA, glicemia capilar, nivel de hemoglobina glicada y tipo de anestesia. Resultados: se incluyeron 114 pacientes diabéticos, edad promedio 55 ±12 años. La hemoglobina glicada media fue 7,3 ±1,2 %, el valor promedio de la glicemia al inicio del acto quirúrgico fue 109 ± 12 mg/dL y a los 60 min 124 ± 17 mg/dL. Se encontró asociación significativa (p 0,001) entre los valores de hemoglobina glicada mayor a 7,5 % y la glicemia elevada durante la cirugía (≥ 180). Conclusión: los niveles de glicemia al inicio de la cirugía fue 109 ±12 mg/dL y a los 60 min 124 ±17 mg/dL. Se encontró asociación significativa entre valores elevados de hemoglobina glicada e hiperglicemia intraoperatoria.

ABSTRACT Introduction: Diabetes mellitus is one of the most prevalent metabolic diseases worldwide and is considered a risk factor for performing surgical procedures. Objective: To determine capillary glycemia values ​​in diabetic patients undergoing elective surgery. Subjects and methods: Observational, descriptive, prospective design with analytical components. Patients with diabetes mellitus undergoing elective surgery at the Hospital de Clínicas (San Lorenzo, Paraguay) were included. Demographic variables, insulin infusion requirement, ASA classification, capillary glycemia, glycated hemoglobin level, and type of anesthesia were determined. Results: One hundred fourteen diabetic patients were included, mean age 55±12 years. The mean glycated hemoglobin was 7.3±1.2%, the mean value of glycemia at the beginning of the surgery was 109±12 mg/dL and at 60 min 124±17 mg/ dL. A significant association (p = 0.001) was found between glycated hemoglobin values ​​greater than 7.5% and elevated glycemia during surgery (≥ 180). Conclusion: Glycemic levels at the beginning of surgery were 109±12 mg/dL and at 60 min 124±17 mg/dL. A significant association was found between elevated glycated hemoglobin values ​​and intraoperative hyperglycemia.

Paracoccidioidomicosis crónica diseminada de presentación con derrame pleural

Se presenta el caso de un hombre de 30 años de edad con cuadro de 3 meses de evolución de adenomegalias, lesiones en piel y mucosas, síndrome de derrame pleural. La biopsia de piel y ganglio confirman infección por Paracoccidioides braziliensis. Presentó buena evolución al tratamiento con itraconazol.

This is the case of a 30-year old man with 3-month evolution of adenomegalies, skin and mucous lesions, syndrome of pleural effusion. Skin and lymph node biopsy confirm infection by Paracoccidioides braziliensis. The patient presented good evolution after treatment with itraconazole.

The role of prescribed burn associations in the application of prescribed fires in rangeland ecosystems.

Risk and liability concerns regarding fire affect people's attitudes toward fire and have led to human-induced alterations of fire regimes. This has, in turn, contributed to brush encroachment and degradation of many grasslands and savannas. Efforts to successfully restore such degraded ecosystems at the landscape scale in regions of the United States with high proportions of private lands require the reintroduction of fire. Prescribed Burn Associations (PBA) provide training, equipment, and labor to apply fire safely, facilitating the application of this rangeland management tool and thereby reducing the associated risk. PBAs help build networks and social capital among landowners who are interested in using fire. They can also change attitudes toward fire and enhance the social acceptability of using prescribed fire as a management practice. PBAs are an effective mechanism for promoting the widespread use of prescribed fire to restore and maintain the biophysical integrity of grasslands and savannas at the landscape scale. We report findings of a project aimed at determining the human dimensions of using prescribed fire to control woody plant encroachment in three different eco-regions of Texas. Specifically, we examine membership in PBAs as it relates to land manager decisions regarding the use of prescribed fire. Perceived risk has previously been identified as a key factor inhibiting the use of prescribed fire by landowners. Our results show that perceived constraints, due to lack of skill, knowledge, and access to equipment and membership in a PBAs are more important factors than risk perceptions in affecting landowner decisions about the use of fire. This emphasizes the potential for PBAs to reduce risk perceptions regarding the application of prescribed fire and, therefore, their importance for restoring brush-encroached grasslands and savannas.

Rapid response of a grassland ecosystem to an experimental manipulation of a keystone rodent and domestic livestock.

Megaherbivores and small burrowing mammals commonly coexist and play important functional roles in grassland ecosystems worldwide. The interactive effects of these two functional groups of herbivores in shaping the structure and function of grassland ecosystems are poorly understood. In North America's central grasslands, domestic cattle (Bos taurus) have supplanted bison (Bison bison), and now coexist with prairie dogs (Cynomys spp.), a keystone burrowing rodent. Understanding the ecological relationships between cattle and prairie dogs and their independent and interactive effects is essential to understanding the ecology and important conservation issues affecting North American grassland ecosystems. To address these needs, we established a long-term manipulative experiment that separates the independent and interactive effects of prairie dogs and cattle using a 2 x 2 factorial design. Our study is located in the Janos-Casas Grandes region of northwestern Chihuahua, Mexico, which supports one of the largest remaining complexes of black-tailed prairie dogs (C. ludovicianus). Two years of posttreatment data show nearly twofold increases in prairie dog abundance on plots grazed by cattle compared to plots without cattle. This positive effect of cattle on prairie dogs resulted in synergistic impacts when they occurred together. Vegetation height was significantly lower on the plots where both species co-occurred compared to where either or both species was absent. The treatments also significantly affected abundance and composition of other grassland animal species, including grasshoppers and banner-tailed kangaroo rats (Dipodomys spectabilis). Our results demonstrate that two different functional groups of herbivorous mammals, burrowing mammals and domestic cattle, have distinctive and synergistic impacts in shaping the structure and function of grassland ecosystems.

Peroxide is a key mediator of Bcl-2 down-regulation and apoptosis induction by cisplatin in human lung cancer cells.

Susceptibility to apoptosis is an essential prerequisite for successful eradication of tumor cells by chemotherapy. Consequently, resistance to apoptosis has been established as one of the mechanisms responsible for the failure of therapeutic approaches in many types of cancers. In the present study, we investigated the susceptibility of human lung cancer H460 cells to apoptotic cell death induced by cisplatin and determined its regulatory mechanisms. Treatment of the cells with cisplatin induced rapid generation of multiple oxidative species and a concomitant increase in apoptotic cell death. Apoptosis induced by cisplatin was mediated through the mitochondrial death pathway, which requires caspase-9 activation and is regulated by Bcl-2. Cisplatin induced down-regulation of Bcl-2 through a process that involves dephosphorylation and ubiquitination of the protein, which facilitates its degradation by proteasome. This down-regulation was inhibited by antioxidant enzymes catalase and glutathione peroxidase (H(2)O(2) scavenger), but not by superoxide dismutase (O(2)(.) scavenger) or deferoxamine (OH. inhibitor). Electron spin resonance and flow cytometric analyses showed the formation of H(2)O(2) along with O(2)(.) and OH. radicals after cisplatin treatment. H(2)O(2) was generated in part by dismutation of O(2)(.) and served as a precursor for OH.. Together, our results indicate an essential role of H(2)O(2) in the regulation of Bcl-2 and apoptotic cell death induced by cisplatin. Because aberrant expression of Bcl-2 has been associated with death resistance of cancer cells to chemotherapy, the results of this study could be used to aid the design of more effective strategies for cancer treatment.

Regulation of Fas (CD95)-induced apoptotic and necrotic cell death by reactive oxygen species in macrophages.

Although reactive oxygen species (ROS) have long been suspected to play a key role in Fas (CD95)-induced cell death, the identity of specific ROS involved in this process and the relationship between apoptotic and necrotic cell death induced by Fas are largely unknown. Using electron spin resonance (ESR) spectroscopy, we showed that activation of Fas receptor by its ligand (FasL) in macrophages resulted in a rapid and transient production of hydrogen peroxide (H2O2) and hydroxyl radicals (*OH). The response was visible as early as 5 min and peaked at approximately 45 min post-treatment. Morphological analysis of total death response (apoptosis vs. necrosis) showed dose and time dependency with apoptosis significantly increased at 6 h after the treatment, while necrosis remained at a baseline level. Only at a 35-fold increase in apoptosis did necrosis become significant. Inhibition of apoptosis by a pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone (zVAD-fmk), significantly inhibited cell necrosis, indicating the linkage between the two events. Catalase (H2O2 scavenger) and deferoxamine (*OH scavenger) effectively inhibited the total death response as well as the ESR signals, while superoxide dismutase (SOD) (O2*- scavenger) had minimal effects. These results established the role for H2O2 and *OH as key participants in Fas-induced cell death and indicated apoptosis as a primary mode of cell death preceding necrosis. Because the Fas death pathway is implicated in various inflammatory and immunologic disorders, utilization of antioxidants and apoptosis inhibitors as potential therapeutic agents may be advantageous.

Regulation of Fas (CD95)-induced apoptosis by nuclear factor-kappaB and tumor necrosis factor-alpha in macrophages.

The APO-1/Fas ligand (FasL) and tumor necrosis factor-alpha (TNF-alpha) are two functionally related molecules that induce apoptosis of susceptible cells. Although the two molecules have been reported to induce apoptosis via distinct signaling pathways, we have shown that FasL can also upregulate the expression of TNF-alpha, raising the possibility that TNF-alpha may be involved in FasL-induced apoptosis. Because TNF-alpha gene expression is under the control of nuclear factor-kappaB (NF-kappaB), we investigated whether FasL can induce NF-kappaB activation and whether such activation plays a role in FasL-mediated cell death in macrophages. Gene transfection studies using NF-kappaB-dependent reporter plasmid showed that FasL did activate NF-kappaB promoter activity. Gel shift studies also revealed that FasL mobilized the p50/p65 heterodimeric form of NF-kappaB. Inhibition of NF-kappaB by a specific NF-kappaB inhibitor, caffeic acid phenylethyl ester, or by dominant expression of the NF-kappaB inhibitory subunit IkappaB caused an increase in FasL-induced apoptosis and a reduction in TNF-alpha expression. However, neutralization of TNF-alpha by specific anti-TNF-alpha antibody had no effect on FasL-induced apoptosis. These results indicate that FasL-mediated cell death in macrophages is regulated through NF-kappaB and is independent of TNF-alpha activation, suggesting the antiapoptotic role of NF-kappaB and a separate death signaling pathway mediated by FasL.

Nitricum acidum, un caso clinico / Nitricum acidum, a clinical case

Se presenta un caso clinico de excrecencias en el prepucio resuelto con una sola dosis de Nitricum acidum 200c, en una semana, en un paciente refractario a la homeopatia. (AU)

Repertorios: comparacion y analisis / Repertories: comparation and analysis

El autor hace en este recorrido historico un breve estudio analitico de las obras de este tipo tan singularmente caracterizadas en la metodologia homeopatica, que seran de suma importancia para los practicantes de este recurso en su practica clinica.