Odds of developing cancer among male and female volunteer firefighters in Florida: A case-control study design.

OBJECTIVE: Determine whether volunteer firefighters in Florida are at increased odds of developing cancer compared to non-firefighters. METHODS: A case-control study design was implemented to assess the odds of developing cancer among male and female volunteer firefighters in Florida. Gender-specific age and calendar year-adjusted odds ratios (aOR) and 95% confidence intervals (95%CI) were estimated. RESULTS: Male volunteer firefighters were at increased odds for developing prostate (aOR = 1.26; 95%CI;[1.10- 1.44]) and male genital cancers combined (1.22;[1.07-1.39]), while reduced odds for endocrine cancer (0.41;[0.17-1.00]), and all leukemias (0.55;[0.35-0.86]), including lymphocytic (0.48;[0.24-0.97]); and chronic lymphocytic (0.40;[0.17-0.97]) leukemias. Female volunteer firefighters were at increased odds of developing of kidney cancer (2.51;[1.29-4.91]). CONCLUSIONS: Male volunteer firefighters are at increased odds for prostate and overall male genital cancers, while female volunteers are increased odds of kidney cancer.

Multi-Surface Adhesion Luminescent Solar Concentrators for Supply-Less IoT.

The growing prevalence of Internet of Things (IoT) devices hinges on resolving the challenge of powering sensors and transmitters. Addressing this, supply-less IoT devices are gaining traction by integrating energy harvesters. This study introduces a temperature sensor devoid of external power sources, achieved through a novel luminescent solar concentrator (LSC) device based on a stretchable, adhesive elastomer. Leveraging a lanthanide-doped styrene-ethylene-butylene-styrene matrix, the LSC yielded 0.09% device efficiency. The resultant temperature sensor exhibits a thermal sensitivity of 2.1%°C-1 and a 0.06 °C temperature uncertainty, autonomously transmitting real-time data to a server for user visualization via smartphones. Additionally, the integration of LED-based lighting enables functionality in low-light conditions, ensuring 24 h cycle operation and the possibility of having four distinct thermometric parameters without changing the device configuration, stating remarkable robustness and reliability of the system.

Retrospective analysis of pediatric patients with Burkitt lymphoma treated in Tanzania following the implementation of the 2016 National Treatment Guidelines: Poor outcomes to current standard-of-care therapy.

BACKGROUND: Despite the excellent outcomes achieved in the treatment of pediatric Burkitt lymphoma (BL) in high-income countries (HICs), outcomes remain poor in low- and middle-income countries (LMICs). Efforts to improve BL outcomes in Tanzania included the creation of National Treatment Guidelines in 2016. However, disease outcomes in Tanzania following the creation of these guidelines have not been reported to date. PROCEDURE: Historical records from 2016 to 2021 for patients 0-18 years of age with a diagnosis of BL and seen at Bugando Medical Centre (BMC), in Mwanza, Tanzania, were curated into an electronic database and analyzed descriptively. Patients in this cohort were treated per the Tanzanian National Treatment Guidelines, which include six cycles of cyclophosphamide, vincristine, and methotrexate (COM) chemotherapy with intrathecal methotrexate and cytarabine. RESULTS: In total, 92 BL patients' records were eligible for analysis. Patients in this cohort were most commonly Murphy stage II (28%) or stage III (34%). Nearly all, 91%, met International Network for Cancer Treatment and Research (INCTR) high-risk criteria at presentation. Forty-two percent of patients did not receive a biopsy and were treated with a presumed diagnosis of BL alone. A 1-year event-free survival of 29.6% (95% confidence interval [CI]: 20.3%-39.5%) and a 1-year overall survival of 38.5% (95% CI: 28%-48.9%) were observed. A high rate of treatment abandonment (34%) was also observed. CONCLUSION: In a historical cohort of pediatric patients with BL treated per the 2016 Tanzanian National Treatment Guidelines, we observed poor outcomes and a high rate of abandonment. These outcomes appear inferior to those achieved in the INCTR clinical trial that informed the guidelines' creation, and highlights the importance of "real-world" outcomes data in LMICs. These data reinforce the idea that continued clinical research and capacity building efforts are necessary to improve BL outcomes in LMICs.

Methodological and Practical Challenges in Synthesizing Occupational Cancer Studies.

Studies examining occupational exposures and cancer risk frequently report mixed findings; it is thus imperative for researchers to synthesize study results and identify any potential sources that explain such variabilities in study findings. However, when synthesizing study results using meta-analytic techniques, researchers often encounter a number of practical and methodological challenges. These challenges include (1) an incomparability of effect size measures due to large variations in research methodology; (2) a violation of the independence assumption for meta-analysis; (3) a violation of the normality assumption of effect size measures; and (4) a variation in cancer definitions across studies and changes in coding standards over time. In this paper, we first demonstrate these challenges by providing examples from a real dataset collected for a large meta-analysis project that synthesizes cancer mortality and incidence rates among firefighters. We summarize how each of these challenges has been handled in our meta-analysis. We conclude this paper by providing practical guidelines for handling challenges when synthesizing study findings from occupational cancer literature.

Highly Soluble Dacarbazine Multicomponent Crystals Less Prone to Photodegradation.

Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent solubility, in addition to being photosensitive. These features imply the formation of the inactive photodegradation product 2-azahypoxanthine (2-AZA) during pharmaceutical manufacturing and even drug administration. We have focused on developing novel DTIC salt/cocrystal forms with enhanced solubility and dissolution behaviors to overcome or minimize this undesirable biopharmaceutical profile. By cocrystallization techniques, two salts, two cocrystals, and one salt-cocrystal have been successfully prepared through reactions with aliphatic carboxylic acids. A detailed structural study of these new multicomponent crystals was conducted using X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR and 1H NMR), and thermal (TG and DSC) analyses. Most DTIC crystal forms reported display substantial enhancements in solubility (up to 19-fold), with faster intrinsic dissolution rates (from 1.3 to 22-fold), contributing positively to reducing the photodegradation of DTIC in solution. These findings reinforce the potential of these new solid forms to enhance the limited DTIC biopharmaceutical profile.

Necropsy findings in heart transplant recipients with or without primary graft dysfunction.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of death in the first year after heart transplant (HT), but pathophysiology and histology are not completely understood. This study describes and compares morphological findings of hearts of patients with and without PGD. METHODS: We included adult patients submitted to HT in a single center who died within the first 14 days after HT and were submitted to necropsy. Clinical and histological data were recorded retrospectively. All heart slides were reviewed by a blinded pathologist. We categorized patients in two groups (PGD and non-PGD) and compared findings between them. RESULTS: Among 322 HTs, 26 patients were included. Median age was 51.5 years, 57.7% were male, 46.1% had non-ischemic cardiomyopathy, 30.8% Chagas cardiomyopathy and 23% ischemic cardiomyopathy. Eleven patients presented PGD, while 15 patients did not. PGD was severe in 72.7% of cases and moderate in 27.3%. PGD group had longer ischemic time (p=0.08), higher incidence of mechanical circulatory support (p=0.004), lower post-transplant biventricular ejection fraction (p=0.005). However, necropsy findings were similar between groups. Necrosis was detected in 80.7% of all cases (p=0.907 comparing groups), taking ≥ 10% of myocardial area in 46.1% of them, and 4 types of necrosis were found either in patients with and without PGD. CONCLUSION: Cardiac pathological findings were similar in HT patients with or without PGD who died within 14 days after the transplant and necrosis was frequent in both groups, raising the hypothesis necrosis is not the cause of cardiac dysfunction in PGD.

A Mechanistic Analysis of the Neural Modulation of the Inflammatory System Through Vagus Nerve Stimulation: A Systematic Review and Meta-analysis.

OBJECTIVE: We aimed to conduct a systematic review and meta-analysis assessing the antiinflammatory effects of various VNS methods while exploring multiple antiinflammatory pathways. MATERIALS AND METHODS: We included clinical trials that used electrical stimulation of the vagus nerve and assessed inflammatory markers up to October 2022. We excluded studies lacking control groups, those with combined interventions, or abstracts without full text. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews. For each inflammatory marker, a random-effects meta-analysis using the inverse variance method was performed. Methods used include transcutaneous auricular VNS (taVNS), transcutaneous cervical VNS (tcVNS), invasive cervical VNS (iVNS), and electroacupuncture VNS (eaVNS). Main reported outcomes included tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, C-reactive protein (CRP), and IL-10. Risk of bias was evaluated using the Cochrane Collaboration Tool (RoB 2.0). RESULTS: This review included 15 studies, involving 597 patients. No statistically significant general VNS effect was observed on TNF-α, IL-6, and IL-1ß. However, CRP, IL-10, and interferon (IFN)-γ were significantly modulated by VNS across all methods. Subgroup analysis revealed specific stimulation techniques producing significant results, such as taVNS effects in IL-1ß and IL-10, and iVNS in IL-6, whereas tcVNS and eaVNS did not convey significant pooled results individually. Cumulative exposure to VNS, higher risk of bias, study design, and pulse width were identified as effect size predictors in our meta-regression models. CONCLUSIONS: Pooling all VNS techniques indicated the ability of VNS to modulate inflammatory markers such as CRP, IL-10, and IFN-γ. Individually, methods such as taVNS were effective in modulating IL-1ß and IL-10, whereas iVNS modulated IL-6. However, different VNS techniques should be separately analyzed in larger, homogeneous, and powerful studies to achieve a clearer and more consistent understanding of the effect of each VNS method on the inflammatory system.

Endometrial Cancer Survival in Populations of African Descent.

To examine whether the endometrial cancer (EC) survival disadvantage among Black populations is US-specific, a comparison between African descent populations from different countries with a high development index is warranted. We analyzed 28,213 EC cases from cancer registries in Florida (2005-2018) and Martinique (2005-2018)/Guadeloupe (2008-2018), French Caribbean islands. Kaplan-Meier and all-cause Cox proportional hazards models were used to compare survival. Models were stratified by EC histology type and the main predictor examined was race/ethnicity [non-Hispanic White (NHW) and Black (NHB) women in the US versus Black women residing in the Caribbean]. For endometrioid and non-endometrioid EC, after adjusting for age, histology, stage at diagnosis, receipt of surgery, period of diagnosis, and poverty level, US NHB women and Caribbean Blacks had a higher risk of death relative to US NHWs. There was no difference between US NHBs and Caribbean Blacks (HR 1.07, 95% CI: 0.88-1.30) with endometrioid EC. However, Caribbean Black women with non-endometrioid carcinomas had a 40% (HR 1.40, 95% CI: 1.13-1.74) higher risk of death than US NHBs. The low EC survival among US Black women extends to foreign populations of African descent. For the aggressive non-endometrioid ECs, survival in Caribbean Blacks outside of the US is considerably worse.

Exploring the Potential of Structure-Based Deep Learning Approaches for T cell Receptor Design.

Deep learning methods, trained on the increasing set of available protein 3D structures and sequences, have substantially impacted the protein modeling and design field. These advancements have facilitated the creation of novel proteins, or the optimization of existing ones designed for specific functions, such as binding a target protein. Despite the demonstrated potential of such approaches in designing general protein binders, their application in designing immunotherapeutics remains relatively unexplored. A relevant application is the design of T cell receptors (TCRs). Given the crucial role of T cells in mediating immune responses, redirecting these cells to tumor or infected target cells through the engineering of TCRs has shown promising results in treating diseases, especially cancer. However, the computational design of TCR interactions presents challenges for current physics-based methods, particularly due to the unique natural characteristics of these interfaces, such as low affinity and cross-reactivity. For this reason, in this study, we explored the potential of two structure-based deep learning protein design methods, ProteinMPNN and ESM-IF, in designing fixed-backbone TCRs for binding target antigenic peptides presented by the MHC through different design scenarios. To evaluate TCR designs, we employed a comprehensive set of sequence- and structure-based metrics, highlighting the benefits of these methods in comparison to classical physics-based design methods and identifying deficiencies for improvement.

Colloid Transport in Bicontinuous Nanoporous Media.

Colloid transport and retention in porous media are critical processes influencing various Earth science applications, from groundwater remediation to enhanced oil recovery. These phenomena become particularly complex in the confined spaces of nanoporous media, where strong boundary layer effects and nanoconfinement significantly alter colloid behavior. In this work, we use particle dynamics models to simulate colloid transport and retention processes in bicontinuous nanoporous (BNP) media under pressure gradients. By utilizing particle-based models, we track the movement of each colloid and elucidate the underlying colloid retention mechanisms. Under unfavorable attachment conditions, the results reveal two colloid retention mechanisms: physical straining and trapping in low-flow zone. Furthermore, we investigate the effects of critical factors including colloid volume fraction, d, pressure difference, ΔP, interaction between colloids and BNP media, Ec-p, and among colloids, Ec-c, on colloid transport. Analysis of breakthrough curves and colloid displacements demonstrates that higher values of d, lower values of ΔP, and strong Ec-p attractions significantly increase colloid retention, which further lead to colloid clogging and jamming. In contrast, Ec-c has minimal impact on colloid transport due to the limited colloid-colloid interaction in nanoporous channels. This work provides critical insights into the fundamental factors governing colloid transport and retention within stochastic nanoporous materials.

Mapping Conformational Changes in the Saliva Proteome Potentially Associated with Oral Cancer Aggressiveness.

Diverse proteomics-based strategies have been applied to saliva to quantitatively identify diagnostic and prognostic targets for oral cancer. Considering that these targets may be regulated by events that do not imply variation in protein abundance levels, we hypothesized that changes in protein conformation can be associated with diagnosis and prognosis, revealing biological processes and novel targets of clinical relevance. For this, we employed limited proteolysis-mass spectrometry in saliva samples to explore structural alterations, comparing the proteome of healthy control and oral squamous cell carcinoma (OSCC) patients with and without lymph node metastasis. Thirty-six proteins with potential structural rearrangements were associated with clinical patient features including transketolase and its interacting partners. Moreover, N-glycosylated peptides contribute to structural rearrangements of potential diagnostic and prognostic markers. Altogether, this approach utilizes saliva proteins to search for targets for diagnosing and prognosing oral cancer and can guide the discovery of potential regulated sites beyond protein-level abundance.

Distinct Prostate Cancer Survival Outcomes in Firefighters: A Population-Based Study.

Introduction: Survival outcomes for prostate cancer among specific occupational groups prone to regular medical check-ups vis-à-vis the general population have been understudied. For firefighters, a demographic subject to rigorous medical evaluations, possessing above-average medical expertise, and exposed to specific carcinogens of interest, prostate cancer survival in the US has never been studied. Methods: We conducted a retrospective study, utilizing data from the Florida Cancer Data System spanning 2004 to 2014, coupled with firefighter certification records from the Florida State Fire Marshal's Office. Our study cohort consisted of 1058 prostate cancer cases among firefighters as well as prostate cases for the Florida general population (n = 150,623). We compared cause-specific survival between the two using Cox regression models adjusted for demographics and clinical characteristics, including PSA levels, Gleason scores, and treatment modalities. Results: Firefighters demonstrated a higher five-year cause-specific survival rate (96.1%, 95% CI: 94.7-97.1%) than the general population (94.2%, 95%CI: 94.1-94.3%). Overall, firefighters' diagnoses were established at younger ages (median age 63 vs. 67 in the general population), exhibited a higher proportion of localized stage cancers (84.7% vs. 81.1%), and had a greater utilization of surgery (46.4% vs. 37.6%), a treatment modality with a high success rate but potential side effects. In multivariable analysis, firefighters displayed a survival advantage for localized stage (adjusted hazard ratio [aHR] = 0.53; 95%CI: 0.34-0.82). However, for regional or distant stages, firefighters aged 65 and above exhibited a higher risk of death (aHR = 1.84; 95% CI: 1.18-2.86) than the general population. Conclusion: Firefighters experience enhanced prostate cancer survival, primarily in cases diagnosed at localized stages, likely due to increased PSA testing. Nonetheless, for regional or distant stage, survival among older firefighters' lags behind that of the general population. Further investigations are warranted to unravel factors influencing the development of aggressive disease beyond PSA and Gleason scores in this population, as well as to assess the impact of a higher rate of surgical treatment on firefighters' quality of life.

Disparities in incidence and survival for patients with Ewing sarcoma in Florida.

BACKGROUND: Ewing sarcoma (ES) is a malignant bone tumor most commonly affecting non-Hispanic White (NHW) adolescent males, though recognition among Hispanic individuals is rising. Prior population-based studies in the United States (US), utilizing Surveillance, Epidemiology, and End Results (SEER) have shown higher all-cause mortality among White Hispanics, Blacks, and those of low socioeconomic status (SES). Florida is not part of SEER but is home to unique Hispanic populations including Cubans, Puerto Ricans, South Americans that contrasts with the Mexican Hispanic majority in other US states. This study aimed to assess racial/ethnic disparities on incidence and survival outcomes among this diverse Florida patient population. METHODOLOGY: Our study examined all patients diagnosed with osseous ES (2005-2018) in Florida (n = 411) based on the state's population-based cancer registry dataset. Florida Age-adjusted Incidence Rates (AAIRs) were computed by sex and race-ethnicity and compared to the equivalent populations in SEER. Cause-specific survival disparities among Florida patients were examined using Kaplan-Meier analysis. Univariable and multivariable analyses using Cox regression were performed for race/ethnicity, with adjustment for age, sex, year of diagnosis, site of disease, staging, SES, and insurance type. RESULTS: There was a significantly higher incidence of osseous ES in Florida Hispanic males (AAIR 2.6/1,000,000); (95% CI: 2.0-3.2 per 1,000,000; n = 84) compared to the SEER Hispanic males (AAIR 1.2/1,000,000;1.1-1.4 per 1,000,000; n = 382). Older age, distant metastasis, lack of chemotherapy or surgical resection were statistically significant determinants of poor survival while SES, insurance status and race-ethnicity were not. However, among nonmetastatic ES, Florida Hispanics had an increased risk of death compared to Florida NHW (adjusted Hazard Ratio 2.32; 95%CI: 1.20-4.46; p = 0.012). CONCLUSIONS: Florida Hispanic males have a higher-than-expected incidence of osseous ES compared to the US. Hispanics of both sexes show remarkably worse survival for nonmetastatic disease compared to NHW. This disparity is likely multifactorial and requires further in-depth studies.

The histamine H4 receptor antagonist 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]-4-methyl-piperazine(LINS01007) prevents the development of DSS-induced colitis in mice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with growing incidence worldwide. Our group reported the compound 5-choro-1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01007) as H4R antagonist (pKi 6.2) and therefore the effects and pharmacological efficacy on a DSS-induced mice model of UC were assessed in this work. Experimental acute colitis was induced in male BALB/c mice (n = 5-10) by administering 3 % DSS in the drinking water for six days. The test compound LINS01007 was administered daily i.p. (5 mg/kg) and compared to control group without treatment. Body weight, water and food consumption, and the presence of fecal blood were monitored during 7-day treatment period. The levels of inflammatory markers (PGE2, COX-2, IL-6, NF-κB and STAT3) were also analyzed. Animals subjected to the acute colitis protocol showed a reduction in water and food intake from the fourth day (p < 0.05) and these events were prevented by LINS01007. Histological signs of edema, hyperplasia and disorganized intestinal crypts, as well as neutrophilic infiltrations, were found in control mice while these findings were significantly reduced in animals treated with LINS01007. Significant reductions in the levels of PGE2, COX-2, IL-6, NF-κB and STAT3 were observed in the serum and tissue of treated animals. The results demonstrated the significant effects of LINS01007 against DSS-induced colitis, highlighting the potential of H4R antagonism as promising treatment for this condition.

Avanzando Caminos (Leading Pathways): design and procedures of the Hispanic/Latino Cancer Survivorship Study.

Avanzando Caminos (Leading Pathways): The Hispanic/Latino Cancer Survivorship Cohort Study aims to examine the influence of sociocultural, medical, stress-related, psychosocial, lifestyle, behavioral, and biological factors on symptom burden, health-related quality of life, and clinical outcomes among Hispanics/Latinos who have been previously treated for cancer. Avanzando Caminos is a prospective, cohort-based study of 3000 Hispanics/Latinos who completed primary cancer treatment within the past 5 years that is representative of the general Hispanic/Latino population in the United States. Participants will complete self-report measures at baseline (time [T] 1), 6 months (T2), 1 year (T3), 2 years (T4), 3 years (T5), 4 years (T6), and 5 years (T7). Blood samples drawn for assessment of leukocyte gene expression, cardiometabolic markers, and genetic admixture will be collected at baseline (T1), 1 year (T3), 3 years (T5), and 5 years (T7). Medical and cancer characteristics and clinical outcomes will be extracted from the electronic medical record and/or state cancer registry at each time point. Data analysis will include general latent variable modeling and latent growth modeling. Avanzando Caminos will fill critical gaps in knowledge in order to guide future secondary and tertiary prevention efforts to mitigate cancer disparities and optimize health-related quality of life among Hispanic/Latino cancer survivors.

Anabolic steroids and the evaluation of patients with acute PM tendon rupture using microscopy and MRI.

This study presented a pioneering investigation of the changes in the magnetic resonance imaging images of pectoralis major muscle (PMM) tendon rupture. In all, 26 men were evaluated with acute total PMM rupture (<3 months since injury) with a mean age of 37.3 years (SD = 9.7 years) and 10 control patients with a mean age of 32.6 years (SD = 4.2 years). The evaluation of the tendon PMM injuries was based on the magnetic resonance imaging exam and the histological analysis. The magnetic resonance imaging of the surgically showed two (7.1%) contralateral sides were normal, 16 (57.1%) showed superior tendinopathy, and 10 (35.7%) had total tendinopathy. Inferior tendinopathy was not observed. The tendon histology revealed degenerative changes in 16 (66.7%) fragments, with 12 (50.0%) considered as mild (<25%), and four considered as (16.7%) high (>50.0%) tendinopathy. Total acute rupture of the PMM tendon among weightlifters might be associated with tendinous degeneration prior to injury.

Surgical treatment of patients with chronic rupture of the pectoralis major muscle tendon. Prospective comparative study with 2 years of follow-up.

To compare outcomes between autologous fascia lata and autologous hamstring grafts for chronic pectoralis major muscle (PMM) rupture repair, and perform histological, and imaging analyses. Forty male patients with chronic PMM ruptures (time since injury ranging from >3 months to 5 years) and a mean age of 37.3 years (SD = 9.7 years) were evaluated. One group (20 patients) received an autologous semitendinosus graft, and another group (20 patients) received an autologous fascia lata graft for PMM reconstruction. These patients with fascia lata grafts by Bak 2criterium 60% of the patients presented excellent results, 20% presented good results, 15% presented fair results, and 5% presented poor results. In the hamstring group 65% of the patients presented excellent results, 30% presented good results, and 5% presented fair results. In this comparative study, no difference was observed regarding the functional result, image, and histology between groups.

Human proinsulin production in the milk of transgenic cattle.

BACKGROUND: The worldwide growing demand for human insulin for treating diabetes could be supplied by transgenic animals producing insulin in their milk. METHODS AND RESULTS: Pseudo-lentivirus containing the bovine ß-casein promoter and human insulin sequences was used to produce modified adult fibroblasts, and the cells were used for nuclear transfer. Transgenic embryos were transferred to recipient cows, and one pregnancy was produced. Recombinant protein in milk was evaluated using western blotting and mass spectrometry. One transgenic cow was generated, and in milk analysis, two bands were observed in western blotting with a molecular mass corresponding to the proinsulin and insulin. The mass spectrometry analysis showed the presence of human insulin more than proinsulin in the milk, and it identified proteases in the transgenic milk that could convert proinsulin into insulin and insulin-degrading enzyme that could degrade the recombinant protein. CONCLUSION: The methodologies used for generating the transgenic cow allowed the detection of the production of recombinant protein in the milk at low relative expression compared to milk proteins, using mass spectrometry, which was efficient for detecting recombinant protein with low expression in milk. Milk proteases could act on protein processing converting recombinant protein to functional protein. On the other hand, some milk proteases could act in degrading the recombinant protein.

Cannabinoid type 2 receptor inhibition enhances the antidepressant and proneurogenic effects of physical exercise after chronic stress.

Chronic stress is a major risk factor for neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects on cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophic factor levels, we hypothesised that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, overall reduction in neuroinflammation, and increased hippocampal levels of BDNF. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasises the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalise on lifestyle interventions complemented with endocannabinoid pharmacomodulation.

Sickle cell disease and increased adverse maternal and perinatal outcomes in different genotypes.

BACKGROUND: Sickle cell disease (SCD) comprises a heterogeneous group of inherited hemolytic disorders that increases the risk of maternal and perinatal complications due to chronic systemic inflammatory response, endothelial damage and vaso-occlusion. The contribution of genotypes to the severity of outcomes during pregnancy is not completely established. METHODS: A retrospective study of medical charts was performed to compare maternal and perinatal outcomes in Hb SS, Hb SC disease and sickle-beta thalassemia (Hb Sß) pregnancies followed at a high-risk antenatal care unit over a 6-year period. A descriptive analysis of morphological findings was performed of the placenta when pathology reports were available. RESULTS: Sixty-two SCD pregnant women [25 Hb SS (40 %), 29 Hb SC (47 %) and 8 Hb Sß (13 %)] were included. Overall, SCD was associated with maternal complications (77 %), preterm birth (30 %), cesarean section (80 %) and a need of blood transfusion. In general there were no statistically significant differences between genotypes. The only significant difference was the hemoglobin level at first antenatal care visit which was lower for the homozygous genotype (7.7 g/dL) compared to Hb SC and Hb Sß (9.7 g/dL and 8.4 g/dL, respectively; p-value = 0.01). Ten of 15 evaluated placentas showed abnormal morphological findings CONCLUSION: SCD, regardless of the underlying genotype, is associated with increased adverse maternal and perinatal outcomes and placental abnormalities associated with maternal vascular malperfusion.