Recruiting a prospective community cohort to study Alzheimer's disease and structural and social determinants of health among adults racialized as Black: The ARCHES cohort.

INTRODUCTION: This ongoing, prospective study examines the effectiveness of methods used to successfully recruit and retain 238 Black older adults in a longitudinal, observational Alzheimer's disease (AD) study. METHODS: Recruitment strategies included traditional media, established research registries, speaking engagements, community events, and snowball sampling. Participants were asked to complete an annual office testing session, blood-based biomarker collection, optional one-time magnetic resonance imaging (MRI) scan, and community workshop. RESULTS: Within the first 22 months of active recruitment, 629 individuals expressed interest in participating, and 238 enrolled in the ongoing study. Of the recruitment methods used, snowball sampling, community events, and speaking engagements were the most effective. DISCUSSION: The systemic underrepresentation of Black participants in AD research impacts the ability to generalize research findings and determine the effectiveness and safety of disease-modifying treatments. Research to slow, stop, or prevent AD remains a top priority but requires diversity in sample representation. Highlights: Provide flexible appointments in the evening or weekends, offering transportation assistance, and allowing participants to complete study visits at alternative locations, such as senior centers or community centers.Continuously monitor and analyze recruitment data to identify trends, challenges, and opportunities for improvement.Implement targeted strategies to recruit participants who are underrepresented based on sex, gender, or education to increase representation.Diversify the research team to include members who reflect the racial and cultural backgrounds of the target population, to enhance trust and rapport with prospective participants.

Membrane Tilt Drives Phase Separation of Adhesion Receptors.

Cell adhesion receptors are transmembrane proteins that bind cells to their environment. These proteins typically cluster into disk-shaped or linear structures. Here, we show that such clustering patterns spontaneously emerge when the receptor senses the membrane deformation gradient, for example, by reaching a lower-energy conformation when the membrane is tilted relative to the underlying binding substrate. Increasing the strength of the membrane gradient-sensing mechanism first yields isolated disk-shaped clusters and then long linear structures. Our theory is coherent with experimental estimates of the parameters, suggesting that a tilt-induced clustering mechanism is relevant in the context of cell adhesion.

Clinical characteristics and outcomes of Respiratory Syncytial Virus-associated ARF in immunocompetent patients: a seven-year experience at a tertiary hospital in France.

BACKGROUND: Respiratory syncytial virus (RSV) is widely recognized as a cause of acute respiratory failure in infants and immunocompromised patients. However, RSV can also contribute to acute respiratory failure in adults, particularly among the elderly population. The objective of this study was to analyze the clinical characteristics and outcomes of immunocompetent adults hospitalized for RSV infection. METHODS: This retrospective study included all immunocompetent adult patients consecutively admitted to a tertiary care hospital with RSV-related acute respiratory failure over a seven-year period (2016 - 2023). Diagnosis of RSV infection was made through nasal swabs or pulmonary samples, with multiplex reverse transcription polymerase chain reaction (RT-PCR). Patients were eligible for inclusion if they required supplemental oxygen therapy for at least 48hours. RESULTS: One hundred and four patients met the inclusion criteria. Median age [IQR] was 77 years [67 - 85]. Ninety-seven patients had at least one comorbidity (97/104, 93%). At the time of RSV diagnosis, 67 patients (67/104, 64%) experienced acute decompensation of a pre-existing chronic comorbidity. Antibiotics were started in 80% (77/104) of patients; however, only 16 patients had a confirmed diagnosis of bacterial superinfection. Twenty-six patients needed ventilatory support (26/104, 25%) and 21 were admitted to the intensive care unit (21/104, 20%). The median duration of oxygen therapy [IQR] was 6 days [3 - 9], while the median hospital length of stay [IQR] was 11 days [6 - 15]. The overall mortality rate within one month of hospital admission was 13% (14/104). The sole variables associated with one-month mortality were age and maximum oxygen flow during hospitalisation. CONCLUSION: RSV-associated acute respiratory failure affected elderly individuals with multiple comorbidities and was associated with prolonged hospitalization and a high mortality rate.

Inland navigation and land use interact to impact European freshwater biodiversity.

Inland navigation in Europe is proposed to increase in the coming years, being promoted as a low-carbon form of transport. However, we currently lack knowledge on how this would impact biodiversity at large scales and interact with existing stressors. Here we addressed this knowledge gap by analysing fish and macroinvertebrate community time series across large European rivers comprising 19,592 observations from 4,049 sampling sites spanning the past 32 years. We found ship traffic to be associated with biodiversity declines, that is, loss of fish and macroinvertebrate taxonomic richness, diversity and trait richness. Ship traffic was also associated with increases in taxonomic evenness, which, in concert with richness decreases, was attributed to losses in rare taxa. Ship traffic was especially harmful for benthic taxa and those preferring slow flows. These effects often depended on local land use and riparian degradation. In fish, negative impacts of shipping were highest in urban and agricultural landscapes. Regarding navigation infrastructure, the negative impact of channelization on macroinvertebrates was evident only when riparian degradation was also high. Our results demonstrate the risk of increasing inland navigation on freshwater biodiversity. Integrative waterway management accounting for riparian habitats and landscape characteristics could help to mitigate these impacts.

Bioreactance assessment of cardiac output lacks reliability for the follow-up of patients with pulmonary hypertension.

Cardiac output (CO) is one of the primary prognostic factors evaluated during the follow-up of patients treated for pulmonary hypertension (PH). It is recommended that it be measured using the thermodilution technique during right heart catheterization. The difficulty to perform iterative invasive measurements on the same individual led us to consider a non-invasive option. The aims of the present study were to assess the agreement between CO values obtained using bioreactance (Starling™ SV) and thermodilution, and to evaluate the ability of the bioreactance monitor to detect patients whose CO decreased by more than 15% during follow-up and, accordingly, its usefulness for patient monitoring. A prospective cohort study evaluating the performance of the Starling™ SV monitor was conducted in patients with clinically stable PH. Sixty patients referred for hemodynamic assessment were included. CO was measured using both the thermodilution technique and bioreactance during two follow-up visits. A total of 60 PH patients were included. All datasets were available at the baseline visit (V0) and 50 of them were usable during the follow-up visit (V1). Median [IQR] CO was 4.20 l/min [3.60-4.70] when assessed by bioreactance, and 5.30 l/min [4.57-6.20] by thermodilution (p<0.001). The Spearman correlation coefficient was 0.51 [0.36-0.64], and the average deviation on Bland-Altman plot was -1.25 l/min (95% CI [-1.48-1.01], p<0.001). The ability of the monitor to detect a variation in CO of more than 15% between two follow-up measurements, when such variation existed using thermodilution, was insufficient for clinical practice (AUC = 0.54, 95% CI [0.33-0.75]).

ProAKAP4 as Indicator of Long-Lasting Motility Marker in Post-Thaw Conditions in Stallions.

ProAKAP4, a precursor of AKAP4 (A-kinase anchor protein) found in the flagellum of mammalian and non-mammalian spermatozoa, serves as a structural protein with established correlations to motility parameters across diverse species. This study aimed to determine the proAKAP4 level evolution in thawed stallion semen over a 3 h period, examining its correlation with motility descriptors and mitochondrial membrane potential. Utilizing sixteen ejaculates from four French warmblood stallions, this study involved maintaining thawed samples at 37 °C for 3 h, conducting proAKAP4 enzyme-linked immunosorbent assays (ELISA), computer-assisted sperm analysis (CASA), and mitochondrial membrane potential by JC-1 probe and flow cytometry at 0, 1, and 3 h post-thawing. The findings indicate significant positive correlations (p ≤ 0.05) between proAKAP4 levels and sperm total or progressive motility at all time points analyzed. Spermatozoa velocity descriptors (VAP, VCL, VSL) and spermatozoa lateral head displacement (ALH) display positive correlations (p ≤ 0.05) with ProAKAP4 at the 0 h post-thawing. ProAKAP4 concentration exhibits no discernible difference between batches with or without a cryoprotectant. Notably, proAKAP4 consumption remains insignificant within the initial hour after thawing but becomes significant (p ≤ 0.05) between 1 and 3 h post-thawing. In summary, proAKAP4 demonstrates positive correlations with total and progressive motility in stallion semen for up to 3 h after thawing, albeit showing a noticeable decrease starting from the first hour post-thawing, indicating a progressive consumption as a result of spermatozoa motile activity.

Late-onset refractory hemolytic anemia in siblings treated for methionine synthase reductase deficiency: A rare complication possibly prevented by hydroxocobalamin dose escalation?

Methionine synthase reductase deficiency (cblE) is a rare autosomal recessive inborn error of cobalamin metabolism caused by pathogenic variants in the methionine synthase reductase gene (MTRR). Patients usually exhibit early-onset bone marrow failure with pancytopenia including megaloblastic anemia. The latter can remain isolated or patients may present developmental delay and rarely macular dysfunction. Treatment mostly includes parenteral hydroxocobalamin to maximize the residual enzyme function and betaine to increase methionine concentrations and decrease homocysteine accumulation. We report herein 2 cblE siblings diagnosed in the neonatal period with isolated pancytopenia who, despite treatment, exhibited in adulthood hemolytic anemia (LDH >11 000 U/L, undetectable haptoglobin, elevated unconjugated bilirubin) which could finally be successfully treated by hydroxocobalamin dose escalation. There was no obvious trigger apart from a parvovirus B19 infection in one of the patients. This is the first report of such complications in adulthood. The use of LDH for disease monitoring could possibly be an additional useful biomarker to adjust hydroxocobalamin dosage. Bone marrow infection with parvovirus B19 can complicate this genetic disease with erythroblastopenia even in the absence of an immunocompromised status, as in other congenital hemolytic anemias. The observation of novel hemolytic features in this rare disease should raise awareness about specific complications in remethylation disorders and plea for hydroxocobalamin dose escalation.

Short fiber bundle filtering and test-retest reproducibility of the Superficial White Matter.

In recent years, there has been a growing interest in studying the Superficial White Matter (SWM). The SWM consists of short association fibers connecting near giry of the cortex, with a complex organization due to their close relationship with the cortical folding patterns. Therefore, their segmentation from dMRI tractography datasets requires dedicated methodologies to identify the main fiber bundle shape and deal with spurious fibers. This paper presents an enhanced short fiber bundle segmentation based on a SWM bundle atlas and the filtering of noisy fibers. The method was tuned and evaluated over HCP test-retest probabilistic tractography datasets (44 subjects). We propose four fiber bundle filters to remove spurious fibers. Furthermore, we include the identification of the main fiber fascicle to obtain well-defined fiber bundles. First, we identified four main bundle shapes in the SWM atlas, and performed a filter tuning in a subset of 28 subjects. The filter based on the Convex Hull provided the highest similarity between corresponding test-retest fiber bundles. Subsequently, we applied the best filter in the 16 remaining subjects for all atlas bundles, showing that filtered fiber bundles significantly improve test-retest reproducibility indices when removing between ten and twenty percent of the fibers. Additionally, we applied the bundle segmentation with and without filtering to the ABIDE-II database. The fiber bundle filtering allowed us to obtain a higher number of bundles with significant differences in fractional anisotropy, mean diffusivity, and radial diffusivity of Autism Spectrum Disorder patients relative to controls.

Does transport stress have any effect on carcass quality of Nellore cattle (Bos taurus indicus) in Brazil? - A case study.

With the increasing concomitant demands for Brazilian beef and in particular high-quality beef, there is a need for observational studies of the effects of pre- and post-slaughter practices on beef carcass traits. We hypothesized in our case study that pre-slaughter transport of bovines over significant distances would induce stress in animals, and that this would reduce carcass quality because of higher pH resulting from long-distance transportation. To test this hypothesis, 30,230 Nellore carcasses from a private slaughterhouse were evaluated 24 h postmortem. Analysis showed correlations between animal maturity, ultimate pH, distance, and carcass weight. More precisely, there was a slight positive correlation between ultimate pH and weight (but not with transportation distance) and a slight positive correlation between maturity and weight. A linear regression model (R2 = 0.016) failed to show distance having a significant effect on ultimate pH (P = 0.63), while carcass weight significantly affected ultimate pH (P < 0.001) with a low coefficient of 0.0003. Maturity negatively affected ultimate pH also (P < 0.001) but with also a small effect (-0.0008). Results (from 95% confidence intervals of variance of the random effects and of the random errors) showed that the variability within farms was higher than between farms. The linear mixed model showed that maturity had a significant effect on carcass weight value (P < 0.001) with a large coefficient of 2.90. The R2 of the linear mixed model was 46.03%. In conclusion, while weight and maturity both affect ultimate pH, long distances did not significantly impact ultimate pH and therefore the beef quality from Nellore cattle. This could be because of low stress during transport, as well as the physical characteristics of the Nellore breed that favor greater resistance to tropical climatic conditions.

Interactive effects of drought and deforestation on multitrophic communities and aquatic ecosystem functions in the Neotropics-a test using tank bromeliads.

Background: Together with the intensification of dry seasons in Neotropical regions, increasing deforestation is expected to exacerbate species extinctions, something that could lead to dramatic shifts in multitrophic communities and ecosystem functions. Recent studies suggest that the effects of habitat loss are greater where precipitation has decreased. Yet, experimental studies of the pure and interactive effects of drought and deforestation at ecosystem level remain scarce. Methods: Here, we used rainshelters and transplantation from rainforest to open areas of natural microcosms (the aquatic ecosystem and microbial-faunal food web found within the rainwater-filled leaves of tank bromeliads) to emulate drought and deforestation in a full factorial experimental design. We analysed the pure and interactive effects of our treatments on functional community structure (including microorganisms, detritivore and predatory invertebrates), and on leaf litter decomposition in tank bromeliad ecosystems. Results: Drought or deforestation alone had a moderate impact on biomass at the various trophic level, but did not eliminate species. However, their interaction synergistically reduced the biomass of all invertebrate functional groups and bacteria. Predators were the most impacted trophic group as they were totally eliminated, while detritivore biomass was reduced by about 95%. Fungal biomass was either unaffected or boosted by our treatments. Decomposition was essentially driven by microbial activity, and did not change across treatments involving deforestation and/or drought. Conclusions: Our results suggest that highly resistant microorganisms such as fungi (plus a few detritivores) maintain key ecosystem functions in the face of drought and habitat change. We conclude that habitat destruction compounds the problems of climate change, that the impacts of the two phenomena on food webs are mutually reinforcing, and that the stability of ecosystem functions depends on the resistance of a core group of organisms. Assuming that taking global action is more challenging than taking local-regional actions, policy-makers should be encouraged to implement environmental action plans that will halt habitat destruction, to dampen any detrimental interactive effect with the impacts of global climate change.

Return to Running after Knee Arthroplasty: A Case Report.

Individuals who have undergone knee arthroplasty may still want to run, but no study has reported a progression to guide patients and clinicians. The objective of this case report is to document the process of returning to running after total knee arthroplasty with a 1-year follow-up. The client was a 55-year-old woman, former triathlete, who underwent unilateral knee arthroplasty 1 year prior to consultation. She alternated slow running with walking and increased based on symptoms. She also performed a lower limb exercise programme. The client was a low-impact forefoot striker, ran with a high step rate and wore minimalist shoes. During the 1-year follow-up, she reported no knee pain but experienced minor episodes of calf strains. Towards the end, her comfort level was best when alternating running and walking for 3-4 km, three to four times per week. The client reached her objective of finishing an olympic distance triathlon. The exercise programme also helped to increase lower limb strength and improve physical performance. This case report suggests that it is possible to return to running up to 1 year after total knee arthroplasty. Future research should study bigger samples and monitor implant wear to provide better guidance to patients and physiotherapists.

Certains individus désirent reprendre la course à pied après une arthroplastie du genou. Cependant, aucune étude n'a exploré une progression sécuritaire. L'objectif de cette étude de cas est de documenter un retour à la course avec un suivi d'un an. La cliente était une femme triathlète de 55 ans, ayant subi une arthroplastie unilatérale du genou. Un an après sa chirurgie, elle a alterné la course à vitesse lente avec la marche et a progressé en fonction des symptômes, en plus d'effectuer un programme d'exercices. La cliente courait avec une attaque avant-pied, à faible impact, avec une cadence de pas élevée et portait des chaussures minimalistes. Pendant le suivi d'un an, elle n'a ressenti aucune douleur au genou mais a subi des blessures musculaires mineures aux mollets. Vers la fin du suivi, un régime hebdomadaire de 3-4 entraînements alternant course-marche pour 3­4 km était confortable. La cliente a atteint son objectif de compléter un triathlon de distance Olympique. Le programme de renforcement a permis d'augmenter la force du membre inférieur et d'améliorer les résultats aux tests fonctionnels. Cette étude de cas suggère qu'il est possible de retourner à la course après une arthroplastie du genou, jusqu'à un suivi d'un an.

Five Years After Cannabis Legalization, Is It Time to Ease Restrictions on Promotion?

In the spring of 2024, the federal government is expected to report on its legislative review of the Cannabis Act (2018). One of the most contentious issues is whether to relax restrictions on cannabis promotion. This commentary describes the tension between the public health aims of legalization and the secondary aim of displacing the illicit market. We maintain that among jurisdictions that have legalized cannabis, Canada stands out as having the stated primary objective of safeguarding public health, and its restrictions on promotion are evidence-based and innovative. These measures must be preserved, even in the face of growing industry pressure to loosen them.

Antimicrobial Therapeutic Drug Monitoring in critically ill adult patients -an international perspective on access, utilisation, and barriers.

BACKGROUND: Therapeutic drug monitoring (TDM) is an effective method for individualizing antimicrobial therapy in critically ill patients. The 2021 ADMIN-ICU survey studied a wide range of intensive care unit (ICU) clinicians worldwide to gain their perspectives on antimicrobial TDM. This paper reports the responses from this survey relating to TDM access, utilisation, barriers, and clinical value. METHODS: An online survey consisted of multiple-choice questions and 5-point Likert scales. The survey examined respondent's access to minimum inhibitory concentration (MIC) results, drug assays and dosing software, as well as barriers to TDM. RESULTS: The survey included 538 clinicians from 409 hospitals in 45 countries, with 71% physicians and 29% pharmacists. Despite most respondents having access to assays, 21% and 26% of respondents lacked access to vancomycin and aminoglycosides, respectively. In lower-income countries, almost 40% reported no access. Delayed drug assay turnaround time was the most significant barrier to TDM, particularly in lower-income countries. Routine access to MIC results was unavailable for 41% of respondents, with 25% of lower-income country respondents having no access to MIC or susceptibility reports. CONCLUSIONS: This global survey indicated that consistent TDM usage is hindered by assay access in some sites, and timeliness of assay results in others. Addressing barriers to TDM, particularly in low-income countries, should be a priority to ensure equitable access to affordable TDM.

Staphylococcus aureus-specific skin resident memory T cells protect against bacteria colonization but exacerbate atopic dermatitis-like flares in mice.

BACKGROUND: The contribution of Staphylococcus aureus (S. aureus) to the exacerbation of atopic dermatitis (AD) is widely documented, but its role as a primary trigger of AD skin symptoms remains poorly explored. OBJECTIVE: To reappraise the main bacterial factors and underlying immune mechanisms by which S. aureus triggers AD-like inflammation. METHODS: We capitalized on a pre-clinical model, in which different clinical isolates were applied in the absence of any prior experimental skin injury. RESULTS: We report that the development of S. aureus-induced dermatitis depended on the nature of the S. aureus strain, its viability, the concentration of the applied bacterial suspension, the production of secreted and non-secreted factors, as well as the activation of accessory gene regulatory quorum sensing system. In addition, the rising dermatitis, which exhibited the well-documented AD cytokine signature, was significantly inhibited in inflammasome adaptor protein ASC- and monocyte/macrophage-deficient animals, but not in T- and B-cell-deficient mice, suggesting a major role for the innate response in the induction of skin inflammation. However, bacterial exposure generated a robust adaptive immune response against S. aureus, and an accumulation of S. aureus-specific γδ and CD4+ tissue resident memory T (Trm) cells at the site of previous dermatitis. The latter both contributed to worsen the flares of AD-like dermatitis upon new bacteria exposures, but also, protected the mice from persistent bacterial colonization. CONCLUSION: These data highlight the induction of unique AD-like inflammation, with the generation of pro-inflammatory but protective Trm cells in a context of natural exposure to pathogenic S. aureus strains.

Identifying Candidate Gene Drivers Associated with Relapse in Pediatric T-Cell Acute Lymphoblastic Leukemia Using a Gene Co-Expression Network Approach.

Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) relapses are still associated with a dismal outcome, justifying the search for new therapeutic targets and relapse biomarkers. Using single-cell RNA sequencing (scRNAseq) data from three paired samples of pediatric T-ALL at diagnosis and relapse, we first conducted a high-dimensional weighted gene co-expression network analysis (hdWGCNA). This analysis highlighted several gene co-expression networks (GCNs) and identified relapse-associated hub genes, which are considered potential driver genes. Shared relapse-expressed genes were found to be related to antigen presentation (HLA, B2M), cytoskeleton remodeling (TUBB, TUBA1B), translation (ribosomal proteins, EIF1, EEF1B2), immune responses (MIF, EMP3), stress responses (UBC, HSP90AB1/AA1), metabolism (FTH1, NME1/2, ARCL4C), and transcriptional remodeling (NF-κB family genes, FOS-JUN, KLF2, or KLF6). We then utilized sparse partial least squares discriminant analysis to select from a pool of 481 unique leukemic hub genes, which are the genes most discriminant between diagnosis and relapse states (comprising 44, 35, and 31 genes, respectively, for each patient). Applying a Cox regression method to these patient-specific genes, along with transcriptomic and clinical data from the TARGET-ALL AALL0434 cohort, we generated three model gene signatures that efficiently identified relapsed patients within the cohort. Overall, our approach identified new potential relapse-associated genes and proposed three model gene signatures associated with lower survival rates for high-score patients.

Impact of liquid sublingual immunotherapy on asthma onset and progression in patients with allergic rhinitis: a nationwide population-based study (EfficAPSI study).

Background: The only disease-modifying treatment currently available for allergic rhinitis (AR) is allergen immunotherapy (AIT). The main objective of the EfficAPSI real-world study (RWS) was to evaluate the impact of liquid sublingual immunotherapy (SLIT-liquid) on asthma onset and evolution in AR patients. Methods: An analysis with propensity score weighting was performed using the EfficAPSI cohort, comparing patients dispensed SLIT-liquid with patients dispensed AR symptomatic medication with no history of AIT (controls). Index date corresponded to the first dispensation of either treatment. The sensitive definition of asthma event considered the first asthma drug dispensation, hospitalisation or long-term disease (LTD) for asthma, the specific one omitted drug dispensation and the combined one considered omalizumab or three ICS ± LABA dispensation, hospitalisation or LTD. In patients with pre-existing asthma, the GINA treatment step-up evolution was analysed. Findings: In this cohort including 112,492 SLIT-liquid and 333,082 controls, SLIT-liquid exposure was associated with a significant lower risk of asthma onset vs. control, according to all definitions (combined: HR [95% CI] = 0.62 [0.60-0.63], sensitive: 0.77 [0.76-0.78], and specific: 0.67 [0.61-0.72]). Exposure to SLIT was associated with a one-third reduction in GINA step-up regardless baseline steps. Interpretation: In this national RWS with the largest number of person-years of follow-up to date in the field of AIT, SLIT-liquid was associated with a significant reduction in the risk of asthma onset or worsening. The use of three definitions (sensitive or specific) and GINA step-up reinforced the rigorous methodology, substantiating SLIT-liquid evidence as a causal treatment option for patients with respiratory allergies. Funding: Stallergenes Greer.

Fetal sex and the relative reactivity of human umbilical vein and arteries are key determinants in potential beneficial effects of phosphodiesterase inhibitors.

Intrauterine growth restriction (IUGR) is a common complication of pregnancy. We previously demonstrated that IUGR is associated with an impaired nitric oxide (NO)-induced relaxation in the human umbilical vein (HUV) of growth-restricted females compared to appropriate for gestational age (AGA) newborns. We found that phosphodiesterase (PDE) inhibition improved NO-induced relaxation in HUV, suggesting that PDEs could represent promising targets for therapeutic intervention. This study aimed to investigate the effects of PDE inhibition on human umbilical arteries (HUAs) compared to HUV. Umbilical vessels were collected in IUGR and AGA term newborns. NO-induced relaxation was studied using isolated vessel tension experiments, in the presence or absence of the non-specific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX). PDE1B, PDE1C, PDE3A, PDE4B and PDE5A were investigated by Western blot. NO-induced vasodilation was similar between IUGR and AGA HUAs. In HUAs precontracted with serotonin, IBMX enhanced NO-induced relaxation only in IUGR females, whereas in HUV IBMX increased NO-induced relaxation in all groups except IUGR males. In umbilical vessels pre-constricted with the thromboxane A2 analog U46619, IBMX improved NO-induced relaxation in all groups, in a greater extent in HUV than HUAs. However, the PDEs protein content was higher in HUAs than HUV, in all study groups. Therefore, the effects of PDE inhibition depend on the presence of IUGR, fetal sex, vessel type and vasoconstrictors implicated. Despite a higher PDEs protein content, HUAs are less sensitive to IBMX than HUV, which could lead to adverse effects of PDE inhibition in vivo, by impairment of the fetoplacental hemodynamics.

Entering deeper into the mysteries of the GroEL-GroES nanomachine.

In the densely populated intracellular milieu, polypeptides are at constant risk of nonspecific interactions and aggregation, posing a threat to essential cellular functions. Cells rely on a network of protein folding factors to deal with this challenge. The Hsp60 family of molecular chaperones, which depend on ATP for function, stands out in the proteostasis network by a characteristic structure comprising two multimeric rings arranged back to back. This review provides an updated overview of GroEL, the bacterial Hsp60, and its GroES (Hsp10) cofactor. Specifically, we highlight recent breakthroughs in understanding the intricate folding mechanisms of the GroEL-GroES nanomachine and explore the newly discovered interaction between GroEL and the chaperedoxin CnoX. Despite considerable research on the GroEL-GroES system, numerous questions remain to be explored.

Aseptic meningitis and Fabry disease.

OBJECTIVE: Fabry disease is caused by enzymatic defects in alpha-galactosidase A that leads to the accumulation of glycosphingolipids throughout the body, resulting in a multisystemic disorder. The most common neurological manifestations are neuropathic pain, autonomic nervous system dysfunction and strokes, but some rarer neurological manifestations exist. Among these, aseptic meningitis is a possible complication. Our objectives were to measure the prevalence of this complication in a cohort of patients with Fabry disease, and to describe its clinical features. METHODS: We conducted a retrospective review of Fabry disease patients followed at our tertiary referral center between 1995 and September 2023 with at least one episode of meningitis, and performed a systematic review to identify similar published cases. RESULTS: Four patients out of 107 (3.7%) had at least one episode of aseptic meningitis. Our systematic review identified 25 other observations. The median age of these 29 patients was 29.0 years, the median cerebrospinal fluid leukocyte count was 24 cells/mm3 with a predominance of lymphocytes in 64.7% of cases. In 82.8% of the patients, the diagnosis of Fabry disease was unknown before the meningitis. Large artery stenosis was present in 17.2% of patients and 57.1% of patients had a recent stroke concomitant with the meningitis. Several differential diagnoses were evoked, such as multiple sclerosis or central nervous system vasculitis. INTERPRETATION: Our study suggests that Fabry disease should be considered as a cause of aseptic meningitis. The pathophysiological mechanisms underlying meningeal inflammation remain largely unknown but may reflect the dysregulation of pro-inflammatory signaling pathways.