Factors Affecting Biochemical and Echocardiographic Indices in Type 2 Diabetes Mellitus Patients Without Overt Symptoms of Heart Failure: A Cross-Sectional Study.

Introduction Diabetes is a known risk factor for heart failure (HF), and HF often manifests as a common cardiovascular event in people with type-2 diabetes mellitus (T2DM). Once HF is present, diabetes presents an especially adverse prognosis for subsequent morbidity and mortality. Brain natriuretic peptide (BNP) and n-terminal ProBNP (NT-proBNP) are used as diagnostic biomarkers for HF that are secreted by the ventricles in response to increased myocardial wall stress. If we could unmask some clinical and routine laboratory parameters affecting BNP and ejection fraction (EF), we can predict impending HF and take measures to prevent it. The current study was conducted to investigate the factors affecting BNP and EF for detecting potential HF in T2DM patients who do not exhibit overt HF symptoms. Materials and methods The present cross-sectional study was performed after obtaining ethical clearance from the Institutional Ethics Committee. T2DM patients consulting the Medicine Outpatient Department (OPD) of BRD Medical College Gorakhpur during a two-month period (from 20 July 2023 to 19 September 2023) with age >40 years and duration of T2DM >10 years. Multistage random sampling was done to recruit study participants, and 308 patients participated in the study. Informed consent was obtained from the recruited participants. The chi-square or Fisher's exact test (whichever was applicable) was used to explore the association between categorical variables. Correlation statistics were calculated using Spearman correlation among the NT-proBNP, EF, and other relevant variables. The Statistical Package for Social Sciences (SPSS) (version 21; IBM SPSS Statistics for Windows, Armonk, NY) was used for the analysis, and a two-sided p-value of < 0.05 was considered significant. Results Three hundred and eight diabetic patients satisfying inclusion and exclusion criteria were enrolled as study participants and completed the study. The mean age of the total study subjects was 60.82 ± 9.23 years. There were 161 (52.3%) male and 147 (47.7%) female participants, and about half (153/308, 49.7%) of the participants belonged to the age group 40-60 years. There was a statistically significant association (p = 0.01) between NT-proBNP and glycated hemoglobin. Statistically highly significant (p < 0.001) associations were found between NT-proBNP with duration of T2DM and EF. There was a strong negative correlation (correlation coefficient = -0.743) between EF and NT-proBNP, and this correlation was statistically highly significant with a p-value < 0.001. Conclusion Elevated NT-proBNP levels and impaired EF were found in a significant proportion of these patients, indicating an increased risk of cardiovascular complications. This study highlights a significant association between NT-proBNP and EF in patients with T2DM in those without overt heart failure symptoms. Furthermore, longer T2DM duration and higher HbA1c levels were found to be associated with elevated NT-proBNP levels, while longer T2DM duration and elevated NT-proBNP were linked to lower EF. These findings have important clinical implications, as they suggest that monitoring NT-proBNP levels in patients with T2DM without clinical features of overt heart failure may help identify those at risk for decreased EF and potentially prevent heart failure.

Procoagulant Extracellular Vesicles Alter Trophoblast Differentiation in Mice by a Thrombo-Inflammatory Mechanism.

Procoagulant extracellular vesicles (EV) and platelet activation have been associated with gestational vascular complications. EV-induced platelet-mediated placental inflammasome activation has been shown to cause preeclampsia-like symptoms in mice. However, the effect of EV-mediated placental thrombo-inflammation on trophoblast differentiation remains unknown. Here, we identify that the EV-induced thrombo-inflammatory pathway modulates trophoblast morphology and differentiation. EVs and platelets reduce syncytiotrophoblast differentiation while increasing giant trophoblast and spongiotrophoblast including the glycogen-rich cells. These effects are platelet-dependent and mediated by the NLRP3 inflammasome. In humans, inflammasome activation was negatively correlated with trophoblast differentiation marker GCM1 and positively correlated with blood pressure. These data identify a crucial role of EV-induced placental thrombo-inflammation on altering trophoblast differentiation and suggest platelet activation or inflammasome activation as a therapeutic target in order to achieve successful placentation.

Placental thromboinflammation impairs embryonic survival by reducing placental thrombomodulin expression.

Excess platelet activation by extracellular vesicles (EVs) results in trophoblast inflammasome activation, interleukin 1ß (IL-1ß) activation, preeclampsia (PE), and partial embryonic lethality. Embryonic thrombomodulin (TM) deficiency, which causes embryonic lethality hallmarked by impaired trophoblast proliferation, has been linked with maternal platelet activation. We hypothesized that placental TM loss, platelet activation, and embryonic lethality are mechanistically linked to trophoblast inflammasome activation. Here, we uncover unidirectional interaction of placental inflammasome activation and reduced placental TM expression: although inflammasome inhibition did not rescue TM-null embryos from lethality, the inflammasome-dependent cytokine IL-1ß reduced trophoblast TM expression and impaired pregnancy outcome. EVs, known to induce placental inflammasome activation, reduced trophoblast TM expression and proliferation. Trophoblast TM expression correlated negatively with IL-1ß expression and positively with platelet numbers and trophoblast proliferation in human PE placentae, implying translational relevance. Soluble TM treatment or placental TM restoration ameliorated the EV-induced PE-like phenotype in mice, preventing placental thromboinflammation and embryonic death. The lethality of TM-null embryos is not a consequence of placental NLRP3 inflammasome activation. Conversely, EV-induced placental inflammasome activation reduces placental TM expression, promoting placental and embryonic demise. These data identify a new function of placental TM in PE and suggest that soluble TM limits thromboinflammatory pregnancy complications.

Proteomics and Visual Health Research: Proteome of the Human Sclera Using High-Resolution Mass Spectrometry.

Eye disorders and resulting visual loss are major public health problems affecting millions of people worldwide. In this context, the sclera is an opaque, thick outer coat covering more than 80% of the eye, and essential in maintaining the shape of the eye and protecting the intraocular contents against infection and the external environment. Despite efforts undertaken to decipher the scleral proteome, the functional and structural picture of the sclera still remain elusive. Recently, proteomics has arisen as a powerful tool that enables identification of proteins playing a critical role in health and disease. Therefore, we carried out an in-depth proteomic analysis of the human scleral tissue using a high-resolution Orbitrap Fusion Tribrid mass spectrometer. We identified 4493 proteins using SequestHT and Mascot as search algorithms in Proteome Discoverer 2.1. Importantly, the proteins, including radixin, synaptopodin, paladin, netrin 1, and kelch-like family member 41, were identified for the first time in human sclera. Gene ontology analysis unveiled that the majority of proteins were localized to the cytoplasm and involved in cell communication and metabolism. In sum, this study offers the largest catalog of proteins identified in sclera with the aim of facilitating their contribution to diagnostics and therapeutics innovation in visual health and autoimmune disorders. This study also provides a valuable baseline for future investigations so as to map the dynamic changes that occur in sclera in various pathological conditions.

Pacific Ciguatoxin Induces Excitotoxicity and Neurodegeneration in the Motor Cortex Via Caspase 3 Activation: Implication for Irreversible Motor Deficit.

Consumption of fish containing ciguatera toxins or ciguatoxins (CTXs) causes ciguatera fish poisoning (CFP). In some patients, CFP recurrence occurs even years after exposure related to CTXs accumulation. Pacific CTX-1 (P-CTX-1) is one of the most potent natural substances known that causes predominantly neurological symptoms in patients; however, the underlying pathogenies of CFP remain unknown. Using clinically relevant neurobehavioral tests and electromyography (EMG) to assess effects of P-CTX-1 during the 4 months after exposure, recurrent motor strength deficit occurred in mice exposed to P-CTX-1. We detected irreversible motor strength deficits accompanied by reduced EMG activity, demyelination, and slowing of motor nerve conduction, whereas control unexposed mice fully recovered in 1 month after peripheral nerve injury. Finally, to uncover the mechanism underlying CFP, we detected reduction of spontaneous firing rate of motor cortical neurons even 6 months after exposure and increased number of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Increased numbers of motor cortical neuron apoptosis were detected by dUTP-digoxigenin nick end labeling assay along with activation of caspase 3. Taken together, our study demonstrates that persistence of P-CTX-1 in the nervous system induces irreversible motor deficit that correlates well with excitotoxicity and neurodegeneration detected in the motor cortical neurons.