Renal medulla in hypertension

Abstract: Studies have found that blood flow to the renal medulla is an important determinant of pressure-natriuresis and the long-term regulation of arterial pressure. First, a brief review of methods developed enabling the study of the medullary circulation is presented. Second, studies performed in rats are presented showing medullary blood flow plays a vital role in the pressure-natriuresis relationship and thereby in hypertension. Third, it is shown that chronic reduction of medullary blood flow results in hypertension and that enhancement of medullary blood flow reduces hypertension hereditary models of both salt-sensitive rats and salt-resistant forms of hypertension. The key role that medullary nitric oxide production plays in protecting this region from ischemic injury associated with circulating vasoconstrictor agents and reactive oxygen species is presented. The studies cited are largely the work of my students, research fellows, and colleagues with whom I have performed these studies dating from the late 1980s to more recent years.

Association of Body Mass Index, Blood Pressure with Fasting Serum Glucose in Female with Type-2 Diabetes Mellitus.

Type-2 diabetes mellitus is a global pandemic with immense social, health and financial consequences. The pathophysiology of type-2 diabetes is significantly influenced by overweight and obesity. Type-2 diabetes often goes hand-in-hand with high blood pressure. One way to check type-2 diabetes is by measuring fasting blood glucose. This cross-sectional analytical study looked at how blood pressure, body mass index (BMI) and fasting serum glucose relate to each other in women with type-2 diabetes in the Mymensingh locality. The research took place at the Physiology Department of Mymensingh Medical College, Bangladesh from Octy 2023 to June 2024. We included 200 participants: 100 apparently healthy women of 30-65 years without diabetes as the control group and 100 women with diabetes of same age group as the study group. The data was analyzed using SPSS software. Weight and height were measured anthropometrically in kilograms and meters, respectively. Blood pressure was checked with an aneroid sphygmomanometer for both systolic and diastolic values. To see if there were significant differences between groups, we used the unpaired Students 't' test and shared results as mean±SD. For relationships among fasting serum glucose, blood pressure and BMI, we used Pearson's correlation coefficient test. The average BMI for those in the control group was 24.19±1.22 kg/m². In contrast, the study group's average BMI was higher at 28.04±1.66 kg/m². The study group also had a greater average systolic blood pressure of 130.65±6.06 mm Hg compared to 115.30±5.07 mm Hg for controls. For diastolic blood pressure, values were also higher in the study group: 85.65±5.71 mm Hg compared to the control's 75.65±5.25 mm Hg. Fasting serum glucose levels showed a positive correlation with both BMI and blood pressure. We recommended from this study that routine evaluation of these parameters is important for preventing complications associated with type-2 diabetes mellitus.

Montelukast deprescribing in outpatient specialty clinics: A single center cross-sectional study.

Objective: To identify and evaluate montelukast deprescribing in outpatient specialty clinics. Methods: This was a single-center, retrospective, cross-sectional study conducted at an academic health system in the southern US including 21 specialty clinics. Subjects included adults ≥18 years with an active prescription for montelukast who attended at least one appointment in pulmonology, otolaryngology, or neurology outpatient specialty clinics between January 1, 2021 to December 31, 2022. Patients <18 years and those with diagnoses of uncontrolled asthma or allergic rhinitis were excluded. Outcomes assessed included the frequency and period prevalence of montelukast deprescribing, defined by a documented montelukast discontinuation within the medical record, and evaluation of reasoning for discontinuation mentioned in visit notes. Results: There were 1152 patients who met inclusion criteria. Of these, 43 (3.7 %) experienced a montelukast deprescribing event: 18 (41.9 %) in neurology, 13 (30.2 %) in otolaryngology, and 12 (27.9 %) in pulmonology. Documented reasons for deprescribing were only available for 11 patients (25.6 %); reasons for deprescribing included patient-provider shared decision-making regarding the Black Box Warning [n = 5 (11.6 %)], inadequate treatment response [n = 3 (7.0 %)], suicidal thought development [n = 1 (2.3 %)], adverse drug event [n = 1 (2.3 %)], and pregnancy planning [n = 1 (2.3 %)]. Conclusion: Montelukast deprescribing rates were less than 5 % in outpatient specialty clinics. Factors associated with montelukast deprescribing beget further investigation.

Where You Protonate Matters: Deciphering the Unimolecular Chemistry of Protonated Myrcene and Linalool.

The unimolecular reactions of protonated myrcene and linalool were investigated by collision-induced dissociation and density functional theory calculations. Experiments on a triple quadrupole mass spectrometer showed that protonated myrcene undergoes two major unimolecular reactions losing propene and isobutene, and two minor reactions of ethene and propane loss. In each case, the product ion consists of a substituted five-member ring. Protonation of myrcene was found to form four distinct protomers, three of which can be significantly populated in the ion source. The observed fragmentation reactions were calculated and found to depend on the starting protomer. Each pathway consisted of several hydrogen-migration and ring-forming/opening steps on the way to the observed products. Likewise, protonation of linalool also produces three distinct protomers, with the global minimum being formed by protonation of a central double bond. The major reaction is water loss to form protonated myrcene, but two minor channels were also observed resulting in loss of acetone and isobutene. The calculated minimum energy reaction pathways were found to be consistent with the relative abundances of the ions in the experimental breakdown diagrams.

Past Trends and Future Directions of Cardiac Regenerative Medicine - A Systematic Analysis of Clinical Trial Registries.

Cell therapy, gene therapy, and tissue engineering have been explored as potential strategies to repair or regenerate damaged cardiac tissue. Despite the presence of encouraging preclinical data, clinical trials of regenerative cardiac therapies have yielded mixed results. Our study aimed to investigate the fate of all registered clinical trials within regenerative cardiac medicine, with the purpose of exploring the potential role of publication bias (or trial-completion bias), how published and unpublished research affects the field, and to draw lessons and recommendations for future clinical trials. In this analysis, we show that only a third of all registered trials has yielded results and that a significant number of trials are not completed. Furthermore, we identified significant heterogeneity in study design, study phase, funding, specific therapies used, primary outcome measures and methods of outcome assessment. These observations might hinder the successful translation of cardiac regenerative therapies into clinical practice.

Prognostic Value of Echocardiographic Coupling Metrics in Systemic Sclerosis-Associated Pulmonary Vascular Disease.

BACKGROUND: Ineffective right ventricular (RV) adaptation to increasing pulmonary arterial (PA) afterload in pulmonary vascular disease (PVD) significantly contributes to morbidity and mortality. PVD in systemic sclerosis (SSc) arises through various mechanisms, yet detecting abnormal contractile response remains challenging. Here, we examine whether echocardiographic RV-PA coupling metrics correlate with invasive pressure-volume (PV) loops, enhancing the prediction of adverse clinical outcomes in SSc-PVD patients. METHODS: Prospectively enrolled patients with SSc-PVD with paired echocardiogram and PV loops were included. Linear regression and receiver-operating curve (ROC) analysis were used to assess the relationship between tricuspid annular plane systolic excursion (TAPSE)/PA systolic pressure (PASP), fractional area change (FAC)/PASP, tissue Doppler velocity (TDI S')/PASP, RV free wall strain (RVFWS)/PASP and coupling thresholds defined by end-systolic to end-arterial elastance (Ees/Ea), obtained by the multi-beat method. The contribution of right atrial strain (RAS) to RV-PA coupling parameters was also investigated. Kaplan-Meier analysis was used to identify the relationship between coupling ratios and composite outcomes including clinical worsening, lung transplant, and death. RESULTS: 42 patients with SSc were studied with mean age 59 ± 12 years, 91% female and varying degrees of PVD: mPAP 29.5 ± 12.8 mmHg, PVR 4.7 ± 4.2 WU, PCWP 10.3 ± 4.1 mmHg. Echocardiographic coupling metrics including TAPSE/PASP, FAC/PASP, TDI S'/PASP, RVFWSglobal and RVFWSbasal/PASP, and RASreservoir/PASP were linearly associated with Ees/Ea. At cut-points obtained through ROC analysis, all ratios were predictive of RV-PA uncoupling, defined by Ees/Ea, and composite outcomes. Additionally, RASreservoir/RVFWS correlated with Ees/Ea even after adjustment for PASP, suggesting that diminished RAS further impacts RV performance and coupling. CONCLUSION: Echocardiographic RV-PA coupling ratios strongly correlate with invasive Ees/Ea and predict adverse clinical outcomes in SSc patients across the spectrum of PVD. Further, we demonstrate how RAS impacts RV performance. These findings may refine risk stratification and prognostication in this at-risk cohort.

The utility of disc space and vertebral body specimens cell count differential for the diagnosis of native vertebral osteomyelitis: a prospective cohort study.

BACKGROUND: Diagnostic methods for native vertebral osteomyelitis (NVO) often yield inconclusive results. Image-guided spine biopsies for culture are specific but diagnose NVO in only 50% of cases. Pre-exposure to antimicrobials further reduces diagnostic yield. Our study assesses the value of neutrophil percentage in disc space fluid and vertebral body (DS/VB) samples for diagnosing NVO. METHODS: Adults referred for spine biopsy at Mayo Clinic from August 2022 to September 2023 were consented and enrolled at the time of biopsy. Following routine specimen collection, the biopsy needle was rinsed in saline into an EDTA tube for cell analysis. NVO diagnosis required organism identification in spine tissue or blood and/or positive histopathology, and consistent symptoms and imaging. RESULTS: Sixty-eight patients were prospectively enrolled, comprising 14 with NVO and 54 with alternative diagnoses. The median biopsy sample polymorphonuclear (PMN) percentage for NVO patients was 80.5% (IQR 72.5-85.2), compared to 64.5% (IQR 54.0-69.0) for those without NVO (p < 0.001). Nine (64.3%) NVO patients received antibiotics within 10 days prior to spine biopsy. As a continuous measure, PMN differential showed a moderately strong ability in classifying NVO status with an area under ROC curve of 0.795; an optimal point on the curve of 71.5% corresponded to a sensitivity of 78.6%, specificity of 79.6%, negative predictive value of 93.5% and positive predictive value of 50.0%. CONCLUSION: PMN differential in DS/VB biopsies may serve as an effective diagnostic tool in the evaluation of patients with NVO particularly in ambiguous cases with an initially negative spine biopsy. Future efforts will aim to implement these findings within routine clinical practice.

Comprehensive Proteomic Profiling of Human Myocardium Reveals Signaling Pathways Dysregulated in Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Signaling pathways that link genetic sequence variants to clinically overt HCM and progression to severe forms of HCM remain unknown. OBJECTIVES: The purpose of this study was to identify signaling pathways that are differentially regulated in HCM, using proteomic profiling of human myocardium, confirmed with transcriptomic profiling. METHODS: In this multicenter case-control study, myocardial samples were obtained from cases with HCM and control subjects with nonfailing hearts. Proteomic profiling of 7,289 proteins from myocardial samples was performed using the SomaScan assay (SomaLogic). Pathway analysis of differentially expressed proteins was performed, using a false discovery rate <0.05. Pathway analysis of proteins whose concentrations correlated with clinical indicators of severe HCM (eg, reduced left ventricular ejection fraction, atrial fibrillation, and ventricular tachyarrhythmias) was also executed. Confirmatory analysis of differentially expressed genes was performed using myocardial transcriptomic profiling. RESULTS: The study included 99 HCM cases and 15 control subjects. Pathway analysis of differentially expressed proteins revealed dysregulation of the Ras-mitogen-activated protein kinase, ubiquitin-mediated proteolysis, angiogenesis-related (eg, hypoxia-inducible factor-1, vascular endothelial growth factor), and Hippo pathways. Pathways known to be dysregulated in HCM, including metabolic, inflammatory, and extracellular matrix pathways, were also dysregulated. Pathway analysis of proteins associated with clinical indicators of severe HCM and of differentially expressed genes supported these findings. CONCLUSIONS: The present study represents the most comprehensive (>7,000 proteins) and largest-scale (n = 99 HCM cases) proteomic profiling of human HCM myocardium to date. Proteomic profiling and confirmatory transcriptomic profiling elucidate dysregulation of both newly recognized (eg, Ras-mitogen-activated protein kinase) and known pathways associated with pathogenesis and progression to severe forms of HCM.

Risk factors and outcomes of conversions in robotic and laparoscopic liver resections: A nationwide analysis.

BACKGROUND: Unfavorable intraoperative findings or incidents during minimally invasive liver surgery may necessitate conversion to open surgery. This study aimed to identify predictors for conversion in minimally invasive liver surgery and gain insight into outcomes following conversions. METHODS: This nationwide, retrospective cohort study compared converted and non-converted minimally invasive liver surgery procedures using data from 20 centers in the Dutch Hepatobiliary Audit (2014-2022). Propensity score matching was applied. Subgroup analyses of converted robotic liver resection versus laparoscopic liver resection and emergency versus non-emergency conversions were performed. Predictors for conversions were identified using backward stepwise multivariable logistic regression. RESULTS: Of 3,530 patients undergoing minimally invasive liver surgery (792 robotic liver resection, 2,738 laparoscopic liver resection), 408 (11.6%) were converted (4.9% robotic liver resection, 13.5% laparoscopic liver resection). Conversion was associated with increased blood loss (580 mL [interquartile range 250-1,200] vs 200 mL [interquartile range 50-500], P < .001), major blood loss (≥500 mL, 58.8% vs 26.7%, P < .001), intensive care admission (19.0% vs 8.4%, P = .005), overall morbidity (38.9% vs 21.0%, P < .001), severe morbidity (17.9% vs 9.6%, P = .002), and a longer hospital stay (6 days [interquartile range 5-8] vs 4 days [interquartile range 2-5], P < .001) but not mortality (2.2% vs 1.2%, P = .387). Emergency conversions had increased intraoperative blood loss (1,500 mL [interquartile range 700-2,800] vs 525 mL [interquartile range 208-1,000], P < .001), major blood loss (87.5% vs 59.3%, P = .005), and intensive care admission (27.9% vs 10.6%, P = .029), compared with non-emergency conversions. Robotic liver resection was linked to lower conversion risk, whereas American Society of Anesthesiologists grade ≥3, larger lesion size, concurrent ablation, technically major, and anatomically major resections were risk factors. CONCLUSION: Both emergency and non-emergency conversions negatively impact perioperative outcomes in minimally invasive liver surgery. Robotic liver resection reduces conversion risk compared to laparoscopic liver resection.

Nanoscale View of Alignment and Domain Growth in a Hexagonal Columnar Liquid Crystal.

Highly ordered liquid crystalline (LC) phases have important potential for organic electronics. We studied the molecular alignment and domain structure in a columnar LC thin film with nanometer resolution during in situ heating using four-dimensional scanning transmission electron microscopy (4D STEM). The initial disordered vapor-deposited LC glass thin film rapidly ordered at its glass transition temperature into a hexagonal columnar phase with small (<10 nm), well-aligned, planar domains (columns oriented parallel to the surface). Upon further heating, the domains coarsen via bulk diffusion, then the film crystallizes, then finally transforms back to an LC phase at an even higher temperature. The LC phase at high temperature shows straight columns of molecules, which we attribute to structure inherited from the intermediate crystalline phase. Nanoscale 4D STEM offers direct insight into the mechanisms of domain reorganization, and intermediate crystallization is a potential approach to manipulate orientational order and texture at the nano- to mesoscale in LC thin films.

Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum.

Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .

Choice architecture promotes sustainable choices in online food-delivery apps.

Greenhouse gas emissions from the food system constitute about one-third of the global total, hence mitigation in this sphere of human activity is a vital goal for research and policy. This study empirically tests the effectiveness of different interventions to reduce the carbon footprint of food choices made on food-delivery apps, using an incentive-compatible online randomized controlled trial with 4,008 participants. The experiment utilized an interactive web platform that mimics popular online food-delivery platforms (such as Just Eat) and included three treatment conditions: a sign-posted meat tax, a carbon-footprint label, and a choice-architecture intervention that changed the order of the menu so that the lowest carbon-impact restaurants and dishes were presented first. Results show that only the choice-architecture nudge significantly reduced the average meal carbon footprint-by 0.3 kg/CO2e per order (12%), driven by a 5.6 percentage point (13%) reduction in high-carbon meal choices. Moreover, we find evidence of significant health and well-being co-benefits. Menu repositioning resulted in the average meal order having greater nutritional value and fewer calories, whilst significantly increasing self-reported satisfaction with the meal choice. Simple back-of-the-envelope calculations suggest that menu repositioning would be a highly cost-effective policy instrument if implemented at scale, with the return on investment expected to be in the range of £1.28 to £3.85 per metric ton of avoided CO2 emissions, depending on implementation costs.

Effect of Elevated Body Mass Index on Outcomes of Transcatheter Aortic Valve Replacement for Severe Aortic Stenosis.

BACKGROUND: The association of body mass index (BMI) and an "obesity paradox" with cardiovascular risk prediction is controversial. This study aimed to evaluate the impact of elevated BMI on the outcome of transcatheter aortic valve replacement (TAVR) for aortic stenosis. METHODS: This retrospective study included 1019 patients with a BMI of ≥18.5 kg/m2 divided into 3 groups: 1) normal BMI (18.5-24.9 kg/m2), 2) overweight (25-29.9 kg/m2), and 3) obese (≥30 kg/m2). Propensity score matching was used to compare normal BMI with overweight and normal BMI with obese. RESULTS: The median age of the cohort was 82 years, and 348 patients had a normal BMI, while 319 and 352 patients were overweight and obese, respectively. After 1 : 1 propensity score matching, 258 and 192 pairs between normal BMI and overweight, and normal BMI and obese patients, respectively, were analyzed. Both overweight and obese patients had higher post-transaortic mean gradients and lower indexed effective orifice areas compared to normal BMI patients. During a median follow-up of 25 (range: 0.1-72) months, all-cause mortality was similar between overweight or obese patients and patients with a normal BMI. However, in a subgroup analysis of patients with moderate/severe chronic lung disease, all-cause mortality was significantly higher in obese patients compared with normal BMI patients (hazard ratio = 3.49, 95% confidence interval, 1.21-10.0, P = .021). CONCLUSIONS: In this study, the "obesity paradox" was not observed in patients undergoing TAVR; rather, in patients with significant lung disease, obesity may be associated with worse midterm outcomes after TAVR.

Exploring the role of diffusive coupling in spatiotemporal chaos.

We explore the chaotic dynamics of a large one-dimensional lattice of coupled maps with diffusive coupling of varying strength using the covariant Lyapunov vectors (CLVs). Using a lattice of diffusively coupled quadratic maps, we quantify the growth of spatial structures in the chaotic dynamics as the strength of diffusion is increased. When the diffusion strength is increased from zero, we find that the leading Lyapunov exponent decreases rapidly from a positive value to zero to yield a small window of periodic dynamics which is then followed by chaotic dynamics. For values of the diffusion strength beyond the window of periodic dynamics, the leading Lyapunov exponent does not vary significantly with the strength of diffusion with the exception of a small variation for the largest diffusion strengths we explore. The Lyapunov spectrum and fractal dimension are described analytically as a function of the diffusion strength using the eigenvalues of the coupling operator. The spatial features of the CLVs are quantified and compared with the eigenvectors of the coupling operator. The chaotic dynamics are composed entirely of physical modes for all of the conditions we explore. The leading CLV is highly localized and localization decreases with increasing strength of the spatial coupling. The violation of the dominance of Oseledets splitting indicates that the entanglement of pairs of CLVs becomes more significant between neighboring CLVs as the strength of diffusion is increased.

Six years of Project ECHO: Implementation and evaluation of a hospice-led multiprofessional education programme.

Objectives: This article reports on the implementation and evaluation of an established technology-enabled collaborative learning programme (Project ECHO) at an independent UK hospice in the North of England over a 6-year period. Methods: An independent audit of collated, anonymised data from the programme is used to report attendance patterns and session evaluations. Results: The results show a gradual increase in attendances, programmes, sessions and hours of education, coupled with consistently positive evaluation reports. Conclusion: This supports existing evidence that Project ECHO is an effective method of delivering remote healthcare education, demonstrating impact on the first three levels of Moore's education framework; participation, satisfaction and learning. Future expansion in terms of geography and topics covered is proposed, alongside enhanced evaluation methods to demonstrate impact at the higher levels of Moore's framework.

Investigating oral microbiome dynamics in chronic kidney disease and post-transplantation in continuous culture.

The oral microbiome is influenced by environmental factors in chronic kidney disease and following kidney transplantation affecting microbial composition, which may have implications for health and recovery. A major driver of oral microbiome perturbation is the accumulation of urea in saliva. We have modelled increased salivary urea concentrations associated with CKD and subsequent reductions that may occur post-transplantation. Oral microbiota were established in constant-depth film fermenters by inoculation with saliva. Duplicate validation runs were maintained with artificial saliva with baseline urea concentrations (0.205 mg/mL) for 21 days. Triplicate treatment runs were then done with baseline urea for 10 days (healthy phase) before urea was increased for 10 days to reflect CKD concentrations (0.92 mg/mL) (CKD phase). This was followed by reversion to baseline urea concentrations (post-transplant phase). Biofilms in primary validation runs reached dynamic stability within 5 days according to viable counting. DNA sequence data indicated minimal taxonomic variation over time and between low and high urea treatments despite background noise indicating changes in bacteria belonging to the family Gemellaceae and the genera TG5 and Leptotrichia. Significant differences in alpha and beta diversity occurred between low and high urea states but not following reversion to a low urea environment. Increased abundance of the TG5 was detected in late model phases, despite apparent count stability, and independent of changes in urea concentrations. IMPORTANCE: This study investigates dynamic changes in the oral microbiome associated with changes in salivary urea concentration, an important factor in chronic kidney disease (CKD). The in vitro system modeled increased urea concentrations and subsequent reductions post-transplantation. The study provides insight into the oral microbial shifts during different simulated clinical phases. Understanding these dynamics is crucial for advancing our comprehension of CKD-associated oral microbiome variations and their potential impact on patient well-being and recovery.

Association between coagulation indicators and menorrhagia among women in Kenya.

Background: Despite the significant burden of menorrhagia (bleeding > 80 mL every menstrual cycle) among women in Western Kenya, it remains unknown whether coagulation disorders are an important underlying cause of this condition in the region. Objective: This study assessed differences in coagulation profiles, associations between menorrhagia and coagulation profiles and compared morphological features of platelets among women attending Bungoma County Referral Hospital in Kenya. Methods: A comparative cross-sectional study of women with and without menorrhagia, aged 18-45 years, was performed between December 2022 and September 2023. Sociodemographic factors, prothrombin time (PT), activated partial thromboplastin time, thrombin time, fibrinogen, international normalised ratio (INR), and platelet count were compared between groups, and associations with menorrhagia were assessed. Prothrombin time and INR levels above normal references were deemed increased. Results: A total of 428 (214 per group) women were included. Family history of bleeding disorders (p < 0.0001) was more frequent in menorrhagic than in non-menorrhagic women. Additionally, menorrhagic women had high PT (p < 0.0001) and high INR (p < 0.0001) levels. Menorrhagia was significantly associated with an increased PT (odds ratio = 2.129, 95% confidence interval = 1.658-2.734; p < 0.0001) and increased INR (odds ratio = 7.479, 95% confidence interval = 3.094-18.080; p < 0.0001). Conclusion: In this population in Western Kenya, menorrhagia was associated with a family history of bleeding disorders, increased PT, and increased INR. Routine assessment of the coagulation profile and family history of bleeding disorders is crucial for diagnosing and managing menorrhagia. What this study adds: Our findings suggest that menorrhagic and non-menorrhagic women differ in terms of PT and INR, which may be predictive of menorrhagia.

Functionalization of silk with actinomycins from Streptomyces anulatus BV365 for biomedical applications.

Silk, traditionally acclaimed as the "queen of fiber," has been widely used thanks to its brilliant performance such as gentleness, smoothness and comfortableness. Owing to its mechanical characteristics and biocompatibility silk has a definitive role in biomedical applications, both as fibroin and fabric. In this work, the simultaneous dyeing and functionalization of silk fabric with pigments from Streptomyces anulatus BV365 were investigated. This strain produced high amounts of orange extracellular pigments on mannitol-soy flour agar, identified as actinomycin D, C2 and C3. The application of purified actinomycins in the dyeing of multifiber fabric was assessed. Actinomycins exhibited a high affinity towards protein fibers (silk and wool), but washing durability was maintained only with silk. Acidic condition (pH5) and high temperature (65°C) facilitated the silk dyeing. The morphologies and chemical components of the treated silk fabrics were analyzed using scanning electron microscopy and Fourier transform infrared spectroscopy. The results showed the pigments bind to the silk through interaction with the carbonyl group in silk fibroin rendering the functionalized, yet surface that does not cause skin irritation. The treated silk exhibited a remarkable antibacterial effect, while the biocompatibility test performed with 3D-reconstructed human epidermis model indicated safe biological properties, paving the way for future application of this material in medicine.

The Protective Role of Transcription Factor Nrf2 in Murine Macrophage Activation Syndrome.

OBJECTIVE: Macrophage activation syndrome (MAS) is characterized by multi-lineage cytopenias, hypercytokinemia, and tissue hemophagocytosis. Transcription factor Nrf2 is a master regulator of redox homeostasis. In this work we aim to investigate the role of Nrf2 in murine hyperinflammation and the mechanisms by which Nrf2 activation by red blood cell products regulates pro-inflammatory cytokine production. METHODS: We induce murine MAS in wildtype and Nrf2 knockout (Nrf2 -/-) mice by repeat administration of TLR9-agonist CpG. Clinical and biochemical markers of disease were measured including complete blood counts, liver and spleen pathology, serum free heme, ferritin, and cytokine profiles. In vitro bone marrow derived macrophages and dendritic cells were used to investigate regulation of CpG-induced cytokine expression by oxidized red blood cells and hemin. RESULTS: Patients with hyperinflammatory disease have higher levels of Nrf2 gene expression. Mice with CpG-induced hyperinflammation have elevated systemic lipid peroxidation which is exacerbated in Nrf2 -/- mice. Compared to wildtype controls, Nrf2 -/- mice develop significantly worse organomegaly, organ pathology, and reticulocytosis. Nrf2 -/- mice have exacerbated hypercytokinemia in cytokines central MAS physiology: IL-12, IFNg, and IL-10. In vitro we found that oxidized red blood cell lysates and hemin are able to suppress IL-12 transcription and protein production from bone marrow derived dendritic cells in a Nrf2-dependent manner. CONCLUSION: Together our findings show that transcription factor Nrf2 is highly expressed in patients with hyperinflammatory disease and demonstrate a protective role for Nrf2 in a murine model of MAS in part due to Nrf2-mediated suppression of proinflammatory cytokine production.