Search

Current irritable bowel syndrome (IBS) treatments have limited efficacy and probiotics like Bacillus clausii (B. clausii) were found to be effective in the management of several gastrointestinal disorders. This phase III trial assessed the efficacy and safety of adding B. clausii (four strains: O/C, N/R, SIN, T), versus placebo, to conventional treatment of pediatric IBS in Mexico.Patients aged 6-17 years 11 months with IBS (Rome IV) for at least 2 months were randomized to receive either B. clausii (oral suspension, total dose 4 billion spores/day) or placebo once daily for 8 weeks. All patients also received conventional treatment. The primary endpoint was the difference in the proportion of patients with clinical improvements at Week 8 (Global Assessment Questions [GAQ]). Secondary endpoints included responders by Subject's Global Assessment of Relief for Children with IBS (SGARC); number/consistency of stools; abdominal distention/bloating; abdominal pain/intensity; and IBS behavior.73.6% (95% confidence interval [CI] 67.3-80.0; B. clausii n = 129) and 78.5% (95% CI 72.5-84.4; placebo n = 130) of patients had symptom improvement (p = 0.8182). For Week 8 SGARC, 19.2% (B. clausii) and 20.9% (placebo) reported complete symptom relief. Stool evaluations, bloating, abdominal pain/intensity, and IBS behavior were similar between groups. Both treatments were well tolerated.No significant differences in efficacy between B. clausii and placebo were demonstrated in addition to conventional treatment. The sample size calculation was based on an expected placebo/conventional treatment response of 30-40%. However, the actual treatment response observed was 80% and, thus, a study with larger population would be warranted. In addition, this study was conducted during the COVID-19 pandemic, when such controlled social conditions may have resulted in better diet, greater family stability, less psychological stress, and lower risk of infections exacerbating IBS, thereby improving symptoms in both groups.2018-004519-31.

A central goal of neuroscience is to advance knowledge of the molecular basis of human brain function. Most molecular studies of the human brain have been performed using tissue from postmortem brain donors rather than living people. The assumption underlying this practice – which had never been rigorously tested prior to this report – is that the postmortem human brain is an appropriate proxy for the living human brain at the molecular level. Here, this assumption is thoroughly challenged for the first time by comparing human prefrontal cortex gene expression between 275 living samples and 243 postmortem samples. Vast differences in gene expression were found between the living and postmortem human brain. Expression levels differed significantly for nearly 80% of genes, and this finding was not a consequence of any potential technical or biological confounders of the gene expression data. Postmortem brain gene expression signatures of Alzheimer’s disease, schizophrenia, Parkinson’s disease, bipolar disorder, and autism spectrum disorder were shown to be inaccurate representations of disease processes occurring in the living brain. In light of these findings, the use of postmortem tissue as a proxy for living tissue in human brain research should be reconsidered. To advance knowledge of the molecular basis of human brain function, the study of tissue from living people should be prioritized.

Introduction and Objectives: Allergic rhinitis is a condition with high global prevalence most effectively treated with antihistamines and antileukotrienes. This study aimed to evaluate the bioequivalence of fexofenadine and montelukast in a fixed-dose combination tablet versus the components administered simultaneously.Materials and Methods: An open, randomized, 2×2 crossover study was performed in 78 healthy volunteers. Fexofenadine–montelukast tablets containing 120 mg and 10 mg, respectively, were used as the test treatment, and 120 mg fexofenadine tablets and 10 mg montelukast tablets were used as the reference treatment. Concentrations of fexofenadine and montelukast in plasma were determined by protein precipitation and analysis by liquid chromatography/mass spectrometry or liquid chromatography tandem mass spectrometry.Results: The 90% confidence intervals (CIs) obtained for fexofenadine were 87.612–102.144 for area under the curve of the plasma concentration after administration to the last concentration (AUC0-t), 88.471–102.282 for the AUC of the plasma concentration extrapolated to infinity (AUC0–∞), and 91.413–108.544 for the maximum plasma concentration (Cmax). For montelukast, they were 96.418–108.416 for AUC0-t, 93.273–106.642 for AUC0-∞ and 94.749–110.178 for Cmax. The ratio and CIs of the values subjected to logarithmic transformation for each parameter were within the range of acceptability of 80%–125%, demonstrating the bioequivalence of the combined fixed-dose tablet to the components administered separately at the same doses. No adverse events were recorded during the study.Conclusions: This study has shown the bioequivalence of the combined fixed-dose tablet, which may be considered a new alternative for the treatment of allergic rhinitis.

Cushing’s disease (CD) is characterized by chronic exposure to excess glucocorticoids due to an ACTH-producing tumor. Obesity is a prominent feature of CD, although the mechanisms of weight gain have not been completely elucidated. In some patients, obesity persists despite appropriate medical or surgical treatment of CD and normalization of cortisol levels (1). Few studies have followed patients prospectively to understand the effect of CD remission and cortisol normalization on appetite and body weight. Previous studies have not shown a correlation between appetite or food cravings and circulating total peptide YY (PYY), ghrelin, or leptin concentrations, leading to interest in other hormones which may regulate appetite in CD (2). One of these is the neuropeptide Agouti-related protein (AgRP). AgRP is known to promote appetite and decrease energy expenditure by acting as a melanocortin antagonist at the level of the hypothalamus. Plasma AgRP may be elevated in patients with active CD and decreases with normalization of cortisol levels (3). We sought to determine if AgRP may play a role in regulating appetite or food cravings in CD. Plasma AgRP was measured before and prospectively after treatment in 19 patients with CD. Patients completed surveys on appetite and food cravings at these same time points. As expected, AgRP significantly decreased following treatment for CD, with mean AgRP before treatment 128.72 pg/mL (SD 55.41) and mean AgRP after treatment 75.23 pg/mL (SD 23.46). Using a paired t-test, the mean difference of 53.5 pg/mL was significant (p=0.0006). In addition, there were significant decreases in BMI, weight, and waist circumference with CD treatment. We found that plasma AgRP concentrations did not correlate with an 8-question visual analogue scale (VAS) used to assess hunger and satiety. However, treatment of CD significantly reduced Trait Food Craving Questionnaire scores in parallel with circulating AgRP levels using a one-way analysis of variance (p=0.004). Our data suggest that AgRP may play a role in food craving, rather than appetite, in patients with CD. Further research may clarify the relationship between AgRP and food cravings in CD patients before and after treatment. References: 1. Geer et al. Endocrinol Metab Clin North Am. 2014; 43: 75-102. Geer et al. Pituitary. 2016; 19: 117-126.Page-Wilson et al, J Clin Endocrinol Metab. 2019; 104 (3): 961-969.

3059 Background: Immune checkpoint inhibitors (ICI) have recently been shown to be effective for brain metastases (BM) in melanoma and lung cancer. Several studies demonstrate that 20-50% of BM patients respond to ICI. The reasons behind this wide variability in treatment response is not clear. Therefore, using physiologic imaging, we seek to identify the longitudinal biological changes exerted on BM as a result of ICI administration. Methods: Given the importance of aberrant tumor vasculature in cancer proliferation, we have focused on assessing changes in vascular physiology. We analyzed standard post-contrast and dynamic susceptibility contrast (DSC) MRI to identify characteristic vascular signatures as part of an ongoing Phase 2 study of pembrolizumab for patients with untreated or progressive, previously treated BM from any histology. Tumor volume measurements were calculated by summating all enhancing voxels. As per modified RECIST and RANO criteria for immunotherapy, volumetric increase of > 40% was defined as progressive disease (PD), a decrease of > 60% as partial response (PR), and stable disease (SD) as between -60% and +40%. Results: 35 patients, out of the total cohort of 60, have undergone DSC-MRI analysis. Histologies include 15 with breast cancer, 6 with non-small cell lung cancer, 4 with melanoma, and 10 with other cancers. At baseline, the total number of BM was 1-50+ per patient. Based on summing the entire enhancing intracranial disease burden, best volumetric responses for the 35 evaluable patients include 4 PR, 12 SD, and 19 PD. Thus far, we found that ICI-resistant BM had a 50% increase in cerebral blood flow (CBF), 105% increase in cerebral blood volume (CBV), a 15% increase in mean transit time (MTT), and an 80% increase in vessel caliber at 6 weeks post-treatment. On the other hand, ICI-responsive BM had no change in CBF, a 33% increase in CBV, a 10% decrease in MTT, and no change in vessel caliber. Ongoing analysis to uncover additional vascular changes (e.g. tumor oxygenation, vessel size index) within BM to ICI are pending. Conclusions: Our data provides evidence that effective ICI for BM is associated with unique intra-tumoral vascular physiology. With final analysis, we will uncover other facets of vascular physiology that correlate with ICI response, and may reveal mechanisms of response/resistance within tumors to ICI.

L’impératif d’agir contre le racisme est constitutif de l’antiracisme. L’action suppose de nommer et représenter son objet. Le discours antiraciste majoritaire en France pose que « les races n’existent pas » et, sur cette négation, définit son objet par une condamnation morale du racisme et une promotion de son supposé contraire, l’antiracisme. Cela n’empêche pas la prolifération d’idées et de propos racisants, véhiculés par d’autres catégories, tant l’antiracisme entretient avec son adversaire une rivalité mimétique qui en prolonge les logiques. Dans une perspective sociologique. En référence à une approche du racisme comme rapports social, cet article interroge la représentation médiatico-politique du phénomène et les problèmes qui en résultent. Plus spécifiquement, cet article examine comment et en quel sens opère le discours médiatique, afin de construire les frontières du racisme (vs non-racisme ou antiracisme) et d’entretenir un discours hégémonique sur l’ordre du problème, ses formes et ses significations sociopolitiques. À travers une analyse de discours de presse quotidienne régionale et locale, nous voulons montrer comment la représentation du racisme tend à dissoudre le problème dans une certaine représentation consensuelle de la nation, officiellement plus légitime mais non moins problématique.

The mechanisms by which glucocorticoids regulate food intake and resulting body mass in humans are not well-understood. One potential mechanism could involve modulation of reward processing, but human stress models examining effects of glucocorticoids on behavior contain important confounds. Here, we studied individuals with Cushing's syndrome, a rare endocrine disorder characterized by chronic excess endogenous glucocorticoids. Twenty-three patients with Cushing's syndrome (13 with active disease; 10 with disease in remission) and 15 controls with a comparably high body mass index (BMI) completed two simulated food-choice tasks (one with “explicit” task contingencies and one with “probabilistic” task contingencies), during which they indicated their objective preference for viewing high calorie food images vs. standardized pleasant, unpleasant, and neutral images. All participants also completed measures of food craving, and approximately half of the participants provided 24-h urine samples for assessment of cortisol and cortisone concentrations. Results showed that on the explicit task (but not the probabilistic task), participants with active Cushing's syndrome made fewer food-related choices than participants with Cushing's syndrome in remission, who in turn made fewer food-related choices than overweight controls. Corroborating this group effect, higher urine cortisone was negatively correlated with food-related choice in the subsample of all participants for whom these data were available. On the probabilistic task, despite a lack of group differences, higher food-related choice correlated with higher state and trait food craving in active Cushing's patients. Taken together, relative to overweight controls, Cushing's patients, particularly those with active disease, displayed a reduced vigor of responding for food rewards that was presumably attributable to glucocorticoid abnormalities. Beyond Cushing's, these results may have relevance for elucidating glucocorticoid contributions to food-seeking behavior, enhancing mechanistic understanding of weight fluctuations associated with oral glucocorticoid therapy and/or chronic stress, and informing the neurobiology of neuropsychiatric conditions marked by abnormal cortisol dynamics (e.g., major depression, Alzheimer's disease).

Pharmaceutical Medicine is a scientific medical discipline concerned with the discovery, development, evaluation, registration, monitoring and medical aspects of the marketing of medicines for the benefit of patients and the public health. This discipline has gone through an important evolution on a worldwide scale in the last 50 years. However, in Mexico and Latin America, its development has been recent and very satisfactory, both on an organizational level, as well as academically. Pharmaceutical Medicine in Mexico has reached a level of development that must be reinforced and perfected for maintaining regional and global leadership. Mexico’s current level of development can be measured by the new empowerment of undergraduate and specialist educational programmes for those interested in Pharmaceutical Medicine at both public and private universities. Mexico is the first country in Latin America to obtain official recognition and support by one of two most renowned upper education and postgraduate institutions in the country. In addition, local associations, such as the Association of Medical Specialists in the Pharmaceutical Industry (Asociacion de Me dicos Especialistas en la Industria Farmaceutica, A.C. [AMEIFAC]), have become major drivers for the development and growth of Pharmaceutical Medicine in Mexico by performing multiple activities of relevance to the discipline. Important examples include the publishing of books and articles, organizing presentations, workshops, symposia and forums, and participating in both national and international conferences, such as the 6th Latin American Congress on Clinical Research held in Mexico City in 2009, and the 7th Latin American Congress on Clinical Research, which will be held in Sao Paolo, Brazil in late 2010. AMEIFAC also organizes important social and educational events such as bi-monthly seminars, annual meetings and a biennial congress for the entire pharmaceutical and academic arena in Mexico. Topics such as pharmacoeconomics, sustainable development and fast-tracking oncology clinical trials are only some of the many topics covered during these gatherings. A new age of maturity and solidification of Pharmaceutical Medicine as a specialty and medical development realm in both Mexico and throughout the world is underway. Our growth and development will continue to flourish as Pharmaceutical Medicine gains increasing global recognition as a vital part of future drug, biotechnological and device development.

Glucocorticoid (GC) exposure increases food intake, but the mechanisms in humans are not known. Investigation of appetite and food craving has not been done in patients with chronic GC exposure due to Cushing's disease (CD), either before or after treatment, and could provide insight into mechanisms of food intake and obesity in these patients.To examine whether surgical remission of CD changes appetite (prospective consumption, hunger, satisfaction, and fullness) and food cravings (sweet, salty, fatty, and savory); and to identify predictors of appetite and craving in CD remission.30 CD patients, mean age 40.0 years (range 17-70), mean BMI 32.3 ± 6.4, were prospectively studied before and at a mean of 17.4 mo. after remission. At each visit fasting and post-test meal (50% carbohydrate, 35% protein, 15% fat) appetite and craving scores were assessed.Remission decreased prospective consumption, sweet and savory craving (p0.05), but did not change hunger, satisfaction, fullness, or fat craving, despite decreases in BMI and fat mass. In CD remission, serum cortisol predicted lower satisfaction and fullness, and masses of abdominal fat depots predicted higher hunger and consumption (p0.05).Chronic GC exposure in CD patients may stimulate the drive to eat by enhancing craving, rather than regulating the sensation of hunger. Continued alterations in appetite regulation due to abdominal fat mass and circulating cortisol could play a role in the cardiovascular and metabolic risk that has been reported in CD patients despite remission.

Background: Auricular pseudocyst is a rare, asymptomatic, cystic-like swelling of the auricle that may pose a diagnostic challenge to the clinician. If inadequately treated, recurrences and ear deformities may ensue. Objective: The authors present a case of auricular pseudocyst in a previously healthy 43-year-old man. Aetiologies, histology, differential diagnosis, and treatment modalities are discussed.

Cushing's disease (CD) is a rare endocrine disorder (1.2-2.4/million/year) characterized by chronic excess endogenous glucocorticoids (GC) due to an adrenocorticotropic hormone-secreting pituitary adenoma. Untreated CD results in increased mortality and multiple morbidities (obesity, diabetes, hypertension, cardiovascular disease) and, in one case report, erythrocytosis (Gursoy et al, J End Invest. 2006;29:742). The effects of chronic GC exposure on erythropoiesis in a CD cohort have not yet been studied. We prospectively quantified hematocrit (Hct), hemoglobin (Hb) and platelets (ptl) values in CD patients before (v1) and after surgical remission (v2, mean time since surgery=14.5 months) and in matched healthy controls (HC). Frequency, antigenic profiling and erythroid (Ery) expansion potential of circulating hematopoietic progenitor cells (HPC) in the three cohorts were also evaluated. The subjects analyzed included 28 v1 [6 males, 22 females, mean age=41 years; body mass index (BMI)=33.3 kg/m2 ] and 13 HC [2 males, 11 females, mean age=41 years; BMI=30.7 kg/m2 (range 26.7-34.7, p=0.073). Eleven patients were analyzed over time in both v1 and v2. Mean cortisol in v1 (22.2±6.3 ug/dL) was higher than in HC (8.5±3.8 ug/dL, p=3.4E-07) and decreased in v2 (17.6±5.1% vs. 8.7±3.9%, N= 11, p=0.0006). Hct was higher in v1 than in HC (39.8±4.7%, vs. 38.8±2.7%, p = 0.045). In the 11 patients analyzed over time, hct decreased in v2 vs. v1 (39.2±4.7% vs. 42.3±4.4%, p=0.011). Hb in v1 was not different than in HC (13.10±1.6 vs. 13.12±3.8 g/dL, p =0.225) but decreased in patients studied both in v1 and V2 (14.1±1.5 g/dL vs. 13.2±1.8 g/dL, p=0.009). Similarly, plts were not different in v1 and HC (272.3±81.4 vs. 240.8±76.0 K/uL, p=0.274) but decreased in v2 (307.7±112.1 vs. 270.6±74.5 K/uL, p=0.021). In v1, Hct did not correlate with serum (R = 0.34, p = 0.33) or 24h urine (R = 0.072, p = 0.73) cortisol concentrations. There was no difference in frequency of HPC among v1, v2 and HC [2.6±3.0, 0.34±0.28 and 1.26±0.67% of CD34+ cells and 30.2±27.2, 23.7±13.2 and 16.5±11.5 CFC/105 mononuclear cells (MNC) in v1, v2 and HC]. CD34pos cells from all groups expressed similar levels of cKIT, IL-3Rβ and prominin1, but a greater proportion of those from v1 and v2 expressed thrombospondin and thrombopoietin (Mpl) receptors than those from HC (2 vs 0.4%), suggesting that CD HPC are biased toward erythro-megakaryocytopoiesis. Consistently, in cultures without the synthetic GC dexamethasone (Dex), MNC from v1 (12±6 %) and v2 (19%) generated in 10 days a greater proportion of Erys than MNC from HC (2±1% ). However, in cultures with Dex, MNC from v1 (48±25), but not those from v2 (70±23), generated less Erys than MNC from HC (83±26 , p=0.03), suggesting that Erys from v1 HPC respond poorly to Dex. This was tested by comparing the ability of Dex to induce biochemical (GRα phosphorylation at S211 and cell-surface expression of CXCR4/calreticulin) and biological (proliferation in synergy with growth factors, GFs) responses in Erys from CD and HC. Erys from v1, v2 and HC expressed equivalent levels of GRα but those from v1 Erys contained lower levels of pGRαS211/S203 than those from v2 or HC (Fig 1A). In contrast with HC Erys, Dex decreased GRα and did not induce pGRαS211 in v1 Erys (Fig 1B). Moreover, Dex increased cell-surface expression of CXCR4 (MFI from 580 to 700) and calreticulin (MFI from 300 to 700) and proliferation (by 30%) in HC Erys but not in those from v1 s (CXCR4 MFI from 278 to 154, calreticulin MFI from 136 to 152; proliferation increases by 6%). These results indicate that chronic GC excess increases Hct values but may also activate a post-transcriptional mechanism that reduces GRα expression inducing desensitization of erythroid cells to GC. Figure 1. A) Levels of total, pS211 and pS203 GRα in Erys from HC, v1 and v2. B) levels of GRα and GRα phosphorylated at pS203 in Erys from HC and v1 exposed from 15' to Dex alone or in combination with the GR inhibitor RU486. Figure 1. A) Levels of total, pS211 and pS203 GRα in Erys from HC, v1 and v2. B) levels of GRα and GRα phosphorylated at pS203 in Erys from HC and v1 exposed from 15' to Dex alone or in combination with the GR inhibitor RU486. Disclosures No relevant conflicts of interest to declare.