Pharmaceutical targeting of the cannabinoid type 1 receptor impacts the crosstalk between immune cells and islets to reduce insulitis in humans.

AIMS/HYPOTHESIS: Insulitis, a hallmark of inflammation preceding autoimmune type 1 diabetes, leads to the eventual loss of functional beta cells. However, functional beta cells can persist even in the face of continuous insulitis. Despite advances in immunosuppressive treatments, maintaining functional beta cells to prevent insulitis progression and hyperglycaemia remains a challenge. The cannabinoid type 1 receptor (CB1R), present in immune cells and beta cells, regulates inflammation and beta cell function. Here, we pioneer an ex vivo model mirroring human insulitis to investigate the role of CB1R in this process. METHODS: CD4+ T lymphocytes were isolated from peripheral blood mononuclear cells (PBMCs) from male and female individuals at the onset of type 1 diabetes and from non-diabetic individuals, RNA was extracted and mRNA expression was analysed by real-time PCR. Single beta cell expression from donors with type 1 diabetes was obtained from data mining. Patient-derived human islets from male and female cadaveric donors were 3D-cultured in solubilised extracellular matrix gel in co-culture with the same donor PBMCs, and incubated with cytokines (IL-1ß, TNF-α, IFN-γ) for 24-48 h in the presence of vehicle or increasing concentrations of the CB1R blocker JD-5037. Expression of CNR1 (encoding for CB1R) was ablated using CRISPR/Cas9 technology. Viability, intracellular stress and signalling were assayed by live-cell probing and real-time PCR. The islet function measured as glucose-stimulated insulin secretion was determined in a perifusion system. Infiltration of immune cells into the islets was monitored by microscopy. Non-obese diabetic mice aged 7 weeks were treated for 1 week with JD-5037, then euthanised. Profiling of immune cells infiltrated in the islets was performed by flow cytometry. RESULTS: CNR1 expression was upregulated in circulating CD4+ T cells from individuals at type 1 diabetes onset (6.9-fold higher vs healthy individuals) and in sorted islet beta cells from donors with type 1 diabetes (3.6-fold higher vs healthy counterparts). The peripherally restricted CB1R inverse agonist JD-5037 arrested the initiation of insulitis in humans and mice. Mechanistically, CB1R blockade prevented islet NO production and ameliorated the ATF6 arm of the unfolded protein response. Consequently, cyto/chemokine expression decreased in human islets, leading to sustained islet cell viability and function. CONCLUSIONS/INTERPRETATION: These results suggest that CB1R could be an interesting target for type 1 diabetes while highlighting the regulatory mechanisms of insulitis. Moreover, these findings may apply to type 2 diabetes where islet inflammation is also a pathophysiological factor. DATA AVAILABILITY: Transcriptomic analysis of sorted human beta cells are from Gene Expression Omnibus database, accession no. GSE121863, available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM3448161 .

Severe Neurologic Disorders in 2 Fetuses with Zika Virus Infection, Colombia.

We report the results of pathologic examinations of 2 fetuses from women in Colombia with Zika virus infection during pregnancy that revealed severe central nervous system defects and potential associated abnormalities of the eye, spleen, and placenta. Amniotic fluid and tissues from multiple fetal organs tested positive for Zika virus.

Dietary practices in ancient populations from northern Chile during the transition to agriculture (Tarapacá region, 1000 BC-AD 900).

OBJECTIVE: The goal of this research is to understand the relevance of diet diversity during the transition to agriculture, in ancient populations from northern Chile, especially considering the significance of marine resources and crops in a lesser degree. METHODS: A total of 14 human individuals were sampled from the Tarapacá 40 cemetery. Both bone and tooth samples were collected. Samples were studied from bone/dentine collagen for carbon and nitrogen isotopic analysis; and bone/enamel apatite for carbon isotope analysis. Inferential statistical analyses were performed in order to compare Tarapacá 40 stable carbon and nitrogen isotope values with other Formative and Late Intermediate Period groups. A nonparametrical hypothesis Kruskal-Wallis test was used. RESULTS: The results show that the individuals from Tarapacá 40 are intermediate to the values observed for terrestrial and marine fauna as well as C3 and C4 plants. CONCLUSIONS: A gradual transition to crop consumption, especially maize, is suggested. This complemented the earlier hunter-gatherer tradition of marine resources and wild fruit consumption. Contrarily to the predictions made by some archaeologists, the results obtained for northern Chile contrast with the classical perspective of a "Neolithic Revolution" in which transition to agriculture occurred more abruptly and linearly.

Mood and cue reactivity among smokers with a history of major depression: the role of rumination and impulsivity.

The present study tested the influence of rumination and impulsivity on experimentally induced negative mood among a sample of smokers with a lifetime history of major depression (MDD Hx+). Participants (N = 40) were categorized into four vulnerability groups: nonvulnerable (low rumination, low impulsivity), ruminative (elevated rumination, low impulsivity), impulsive (low rumination, elevated impulsivity), and vulnerable (elevated rumination, elevated impulsivity). Participants were counterbalanced to four experimental conditions, using a combination of a mood induction (negative mood induction vs. control) and smoking cue (in vivo cigarette vs. control cue). Although all participants reported greater anger responses when exposed to the negative mood induction versus control, vulnerable and ruminative smokers reported significantly greater anger responses than impulsive and nonvulnerable smokers [F(9,87) = 2.93, p = .038, Mse = 79.38]. Implications are discussed.

Microglia HMC3 cells are highly susceptible to Rhinovirus infection.

Human rhinovirus (HRV) affects the lower and upper respiratory tract, however, some studies suggest that HRV infection can lead to extrapulmonary complications in critical illness. Moreover, some reports have shown the presence of HRV in patients with Central Nervous System (CNS) disease. During a CNS infection, the microglia cells are the first line of defense against pathogens. In this study, the susceptibility of the human microglial clone 3 cell line (HMC3) to HRV infection was analyzed. Our findings demonstrate for the first time that HRV is capable of completing the entire viral cycle in microglial cells.

Reliability of age estimation from iliac auricular surface in a subactual Chilean sample.

The aim of this study was to test the reliability of Osborne et al. (2004) [8] age estimation based on the iliac auricular surface of the ilium. We selected 172 skeletons with documented sex and age-at-death and established six uniformly distributed age intervals for analysis. ANOVA was employed to assess the association of the documented age with sex and the auricular surface classification. We employed Bonferroni post-hoc tests to find any statistical differences across documented ages within each phase of Osborne's criteria. While the ANOVA showed a significant association between the documented age and the auricular surface classification, post-hoc tests found that phases 2 and 3 were the only consecutive phases with significant differences. We argue that a lack of statistical significance between consecutive phases undermines the reliability of this method for forensic purposes especially in middle adults. It may be possible that the collapse of intermediate phases would increase the accuracy of this method.

Ocular Histopathologic Features of Congenital Zika Syndrome.

Importance: Congenital Zika syndrome (CZS) is known to be associated with severe malformations in newborns. Although microcephaly is the hallmark of this disease, the ocular findings are important given the severe visual impairment that has been observed in these patients. Regardless of the increased number of CZS cases reported, to date, no studies have described the ocular histopathologic findings of this entity. Objectives: To evaluate the presence of Zika virus (ZIKV) antigens and describe the associated ocular histopathologic features of 4 cases of CZS. Design, Setting, and Participants: In this observational case series performed from June 19, 2015, through April 30, 2017, ocular tissue samples from 4 deceased fetuses with a diagnosis of CZS from the National Institute of Health in Colombia were sent to the Florida Lions Ocular Pathology Laboratory for evaluation. Main Outcomes and Measures: The microscopic features of each specimen were described, and immunostaining was performed using a ZIKV NS2B protein antibody. Results: Ocular tissue samples from the 4 deceased fetuses (2 female, 2 male) ranging from 21.5 to 29 weeks' gestation with a diagnosis of CZS were studied. The 4 eyes manifested with pupillary membranes, immature anterior chamber angles, loss of pigment and thinning of the retinal pigment epithelium, choroidal thinning, undifferentiated nuclear layers of the retina, and a perivascular inflammatory infiltrate within the choroid. The optic nerve, present in 2 of the eyes, demonstrated atrophy. Expression of ZIKV antigen was present in the iris in cases 1, 3, and 4; the neural retina and choroid in case 1; and in the optic nerve in case 4. Conclusions and Relevance: Loss of retinal pigment epithelium, the presence of a thin choroid, a perivascular choroidal inflammatory infiltrate, and atrophic changes within the optic nerve were consistently present. These findings may be attributed to ZIKV infection and warrant further study.

Lipid changes and their relationship with vitamin D levels in children under 18 years with type 1 diabetes.

OBJECTIVE: To analyze lipid changes and their relationship with 25-hydroxy vitamin D3 (25-OH-D) levels in patients under 18 years old with type 1 diabetes mellitus (T1DM). MATERIAL AND METHODS: A cross-sectional, descriptive study. Patients under 18 years with T1DM were enrolled by consecutive, nonrandomized sampling. Data collected included sex, age, pubertal stage, time since T1DM onset, weight, height, body mass index (BMI), waist circumference, glycosylated hemoglobin (HbA1c), 25-OH-D, total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglycerides (TG). Results were stratified by sex, age, and pubertal stage. Data were analyzed using SPSS(®). RESULTS: Ninety patients with a mean age of 11.7 ± 3.6 years (51.1% males) and mean HbA1c levels of 7.5 ± 1.3% were enrolled. Of these, 26.6% had 25-OH-D levels<20 ng/mL and 13.3% 25-OH-D levels ≤ 15 ng/mL. No differences were found in 25-OH-D between patients with overweight or obesity and the rest. HDL-C levels<40 ng/mL were found in 1.1%, 34.4% had LDL-C levels ≥ 100 mg/dL, and 2.2% had TG levels ≥ 150 mg/dL. Patients with 25-OH-D<20 ng/mL had higher TG levels than the rest (76.80 ± 45.62 vs 57.55 ± 26.08; P=.04) in the multivariate analysis controlled for BMI, waist circumference, and HbA1c. A correlation was found between 25-OH-D and TG levels (-0.230; P=.029). CONCLUSIONS: Patients in our population with vitamin D deficiency had higher TG levels. Long-term follow-up should be performed to understand the potential impact of such levels on diabetes-related complications.

Past major depression and smoking cessation outcome: a systematic review and meta-analysis update.

AIMS: To update our prior meta-analysis that showed past major depression (MD+) to be unrelated to smoking cessation outcome. METHODS: Eligible trials included 14 from our original review and 28 identified through an updated systematic review (2000-2009). We coded for assessment of past MD, exclusion for recent MD episode (MDE; ≤6 months versus no exclusion), duration/modality of cognitive behavioral treatment (CBT; face-to-face versus self-help) and other factors. To minimize influence of experimental treatments that may selectively benefit MD+ smokers we analyzed placebo/lowest intensity control arms only. Study-specific ORs for the effect of past MD on short-term (≤3 months) and long-term (≥6 months) abstinence were estimated and combined using random effects. Two-way interaction models of past MD with study methodology and treatment factors were used to evaluate hypothesized moderators of the past MD-abstinence association. RESULTS: MD+ smokers had 17% lower odds of short-term abstinence (n = 35, OR = 0.83, 95% CI = 0.72-0.95, P = 0.009) and 19% lower odds of long-term abstinence (n = 38, OR = 0.81, 95% CI = 0.67-0.97, P = 0.023) than MD- smokers after excluding the sole study of varenicline because of its antidepressant properties. The association between past MD and abstinence was affected by methodological (recent MDE exclusion, type of MD assessment) and treatment (CBT modality) factors. CONCLUSIONS: Past major depression has a modest adverse effect on abstinence during and after smoking cessation treatment. An increased focus on the identification of effective treatments or treatment adaptations that eliminate this disparity in smoking cessation for MD+ smokers is needed.

[Prevalence of known diabetes mellitus and unknown diabetes in adults from Castilla-La Mancha, Spain]. / Prevalencia de diabetes y diabetes oculta en adultos de Castilla-La Mancha.

BACKGROUND AND OBJECTIVE: To estimate the prevalence of known diabetes mellitus (KD), unknown diabetes (UD), and carbohydrate metabolism disturbances in a population of Castilla-La Mancha (CLM) older than 30 years old; To study the cardiovascular risk factors related with diabetes. PATIENTS AND METHODS: A transversal study was performed in order to determine these prevalence data. Reference date: 2007/06/01. 3,092 subjects were selected, and 1,181 of them (38.1%) participated in the study. A questionnaire, physical exploration and glucose tolerance test were performed. The diagnostic criteria of diabetes were those established by the American Association of Diabetes (ADA) and were compared with the World Health Organization criteria (WHO). RESULTS: Prevalence of diabetes in individuals younger than 30 years: 17.9% (DM 10.7%, DO 7.2%). Ratio UD/KD: 0.7. Prevalence of impaired glucose tolerance (IGT) 5.6% and impaired fasting glucose (IFG) 22.3% based on ADA criteria and 7.2% if WHO criteria applied. KD, IFT and IFG increased with age. Global prevalence was higher in males (20.9%) than females (14.5%), but the prevalence was higher in females older than 74 years. A positive relationship was found with obesity, male sex, age and familiar history of diabetes. CONCLUSIONS: Prevalence of diabetes in the adult population of CLM is very high, higher in males and increase with age. A great percentage of diabetic people or with carbohydrate metabolism alterations do not know that condition. This situation makes necessary to create early detection strategies.

[An update on the pathogenesis of celiac disease]. / Enfermedad celíaca y su patogenia.

Celiac disease (CD), with a 1% worldwide prevalence, is an enteropathy caused by an autoimmune reaction to gluten in genetically susceptible individuals, which codify for histocompatibility molecules HLA DQ-2/DQ-8. From the anatomical point of view, CD is characterized by intestinal villous atrophy, crypt hyperplasia, intraepithelial lymphocytosis (IELs) and leukocyte infiltration of the lamina propriety. Patients achieve a complete clinical and endoscopic remission with a gluten free diet. However, symptoms and anatomical alterations recur when this protein is reintroduced in the diet. The pathogenic mechanisms in this disease are not yet well understood, but it is clear that genetic, environmental and immunological factors play a role. The latter are the focus of this review, since this is the only autoimmune disease whose precipitating factor for immunological tissue damage is known.

Pancreatitis aguda severa y precoz por liraglutide / Liraglutide-induced severe early acute pancreatitis

Los agonistas GLP-1 presentan como efectos secundarios más frecuentes las náuseas y vómitos que son de carácter leves y moderados, siendo transitorios y dosis dependiente sin necesidad de suspender el fármaco en la mayoría de casos. Estos efectos ocurren más frecuentemente con exenatide y raramente con liraglutide, sin conocer un caso clínico de tal severidad y sobre todo precocidad. Se describe una mujer de 55 años caucasiana con diabetes mellitus tipo 2 de larga evolución asociadas que presentó cuadro de dolor abdominal, náuseas, vómitos incoercibles e hiperlipasemia de aparición súbita tras la primera dosis de titulación de liraglutide, completando solo 2 dosis en 48 horas, consultando en urgencias donde se apreció fracaso renal agudo y descompensación hiperosmolar que requirió su ingreso en unidad de cuidados intensivos. Al emplear la escala de probabilidad de reacción a fármaco de Naranjo obtenemos dicha reacción como probable, sin encontrar otras alternativas justificables clinicamente.

The most frequent side effects seen with GLP-1 agonists are mild and moderate nausea and vomiting, which are typically transient and dose-dependent, in most cases not requiring discontinuation of the drug. These effects occur most frequently with exenatide, and rarely with liraglutide; no clinical cases with such a severity -and especially with such an early occurrence- had been previously reported. The case herein described is that of a 55-year-old Caucasian female with a long-standing Type 2 diabetes mellitus, who presented with sudden abdominal pain, nausea, relentless vomiting an increased lipase serum levels after the first dosage of liraglutide, after completing only 2 dosages in 48 hours. The patient was seen at the emergency room, where she was diagnosed acute renal failure and hyperosmolar decompensation that required admission at the intensive care unit. According to Naranjo’s odds scale, the reaction was considered to be likely related to the drug; no other alternatives were considered to be clinically justified.

Enfermedad celíaca y su patogenia / An update on the pathogenesis of celiac disease

Celiac disease (CD), with a 1 percent worldwide prevalence, is an enteropathy caused by an autoimmune reaction to gluten in genetically susceptible individuals, which codify for histocompatibility molecules HLA DQ-2/DQ-8. From the anatomical point of view, CD is characterized by intestinal villous atrophy, crypt hyperplasia, intraepithelial lymphocytosis (IELs) and leukocyte infiltration of the lamina propriety. Patients achieve a complete clinical and endoscopic remission with a gluten free diet. However, symptoms and anatomical alterations recur when this protein is reintroduced in the diet. The pathogenic mechanisms in this disease are not yet well understood, but it is clear that genetic, environmental and immunological factors play a role. The latter are the focus of this review, since this is the only autoimmune disease whose precipitating factor for immunological tissue damage is known.