Normal Function Research Articles

Iodine-123-Iomazenil Single-Photon Emission Computed Tomography Revealed Recovery of Neuronal Viability in Association With Improvement of Cognitive Dysfunction After Revascularization in Moyamoya Disease.

Recent studies indicate that 123I-iomazenil (123I-IMZ) single-photon emission computed tomography (SPECT) can demonstrate neuronal viability. Although cognitive dysfunction has been recognized as an important issue in adult patients with moyamoya disease (MMD), no standard neuroradiological methods to define such conditions have been established. We examined the relationship between cognitive function and 123I-IMZ SPECT before and after revascularization in patients with MMD. The study participants were 16 adult patients with MMD whose cerebrovascular reactivities were decreased only on the surgical sides of combined revascularization. Cognitive function was examined using the Mini-Mental State Examination (MMSE; cutoff: 27) and the Frontal Assessment Battery (FAB; cutoff: 16) before and at 3 to 6 months after surgery. 123I-iodoamphetamine (123I-IMP) SPECT with acetazolamide challenge and 123I-IMZ SPECT were performed concurrently while evaluating cognitive function. The radioreactivities of 123I-IMZ SPECT in regions with decreased cerebrovascular reactivities on 123I-IMP SPECT were investigated using affected-to-contralateral side asymmetry ratio (IMZ-ACR). Twelve patients showed normal cognitive function (MMSE: 29.8 ± 0.4, FAB: 18 ± 0) before surgery. No evident laterality of 123I-IMZ uptake was seen (IMZ-ACR: 0.98 ± 0.04). Neither cognitive function nor 123I-IMZ SPECT worsened after surgery (MMSE: 29.8 ± 0.3, FAB: 18 ± 0, IMZ-ACR: 1.00 ± 0.04). By contrast, 4 patients presented cognitive dysfunction (MMSE: 24.3 ± 3.9, FAB: 14.8 ± 2.7) before revascularization. Preoperative imaging of these patients showed decreased 123I-IMZ uptake, and their IMZ-ACRs (0.83 ± 0.08) were significantly lower than those of the normal group. After revascularization, cognitive functions and 123I-IMZ uptake tended to ameliorate (MMSE: 27.5 ± 1.7, FAB: 16.3 ± 2.2, IMZ-ACR: 0.94 ± 0.09). Preoperative cognitive function was associated with 123I-IMZ uptake in adult patients with MMD. After revascularization, cognitive function could be recovered in the viable areas of the brain, which is consistent with 123I-IMZ SPECT findings.

The biological impact of deuterium and therapeutic potential of deuterium-depleted water

Since its discovery by Harold Urey in 1932, deuterium has attracted increased amounts of attention from the scientific community, with many previous works aimed to uncover its biological effects on living organisms. Existing studies indicate that deuterium, as a relatively rare isotope, is indispensable for maintaining normal cellular function, while its enrichment and depletion can affect living systems at multiple levels, including but not limited to molecules, organelles, cells, organs, and organisms. As an important compound of deuterium, deuterium-depleted water (DDW) possess various special effects, including but not limited to altering cellular metabolism and potentially inhibiting the growth of cancer cells, demonstrating anxiolytic-like behavior, enhancing long-term memory in rats, reducing free radical oxidation, regulating lipid metabolism, harmonizing indices related to diabetes and metabolic syndrome, and alleviating toxic effects caused by cadmium, manganese, and other harmful substances, implying its tremendous potential in anticancer, neuroprotective, antiaging, antioxidant, obesity alleviation, diabetes and metabolic syndrome treatment, anti-inflammatory, and detoxification, thereby drawing extensive attention from researchers. This review comprehensively summarizes the latest progress in deuterium acting on living organisms. We start by providing a snapshot of the distribution of deuterium in nature and the tolerance of various organisms to it. Then, we discussed the impact of deuterium excess and deprivation, in the form of deuterium-enriched water (DEW) and deuterium-depleted water (DDW), on living organisms at different levels. Finally, we focused on the potential of DDW as an adjuvant therapeutic agent for various diseases and disorders.

Prediction of Motor Recovery Using Diffusion Tensor Imaging and Regional Cerebral Blood Flow in Postoperative Brain Tumors.

To determine whether diffusion tensor image (DTI) parameters and regional cerebral blood flow (rCBF) serve to preoperatively predict postoperative motor outcomes in patients with brain tumors. We included 81 patients with brain tumors who underwent surgical treatment. Motor function was assessed using the manual muscle test in the upper and lower limbs at admission and discharge. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and their ratios (rFA, rMD, rAD, and rRD) were measured at the corona radiata, internal capsule, and cerebral peduncle of the corticospinal tract (CST). In addition, DTI and single photon emission computed tomography (SPECT) were synthesized to measure rCBF at the CST. Both DTI parameters and rCBF at the CST in the preoperative motor weakness group significantly differed from those of the preoperative normal function group. rFA at the cerebral peduncle and the internal capsule was considerably higher in those showing postoperative motor recovery than in those postoperative unchanged or with deteriorated motor function (P < 0.05). Moreover, there was significantly lower rMD and rRD at the internal capsule in the motor recovery group (P < 0.05, P < 0.01).Furthermore, rCBF was higher at all the cerebral peduncle, internal capsule, and corona radiate in the motor recovery group than in the unchanged and deteriorated motor function group (P < 0.05, P < 0.01, P < 0.01). The analysis of DTI parameters and rCBF is useful in predicting postoperative motor outcomes in patients with brain tumors.

From Classical to Modern Nonlinear Central Limit Theorems

In 1733, de Moivre, investigating the limit distribution of the binomial distribution, was the first to discover the existence of the normal distribution and the central limit theorem (CLT). In this review article, we briefly recall the history of classical CLT and martingale CLT, and introduce new directions of CLT, namely Peng’s nonlinear CLT and Chen–Epstein’s nonlinear CLT, as well as Chen–Epstein’s nonlinear normal distribution function.

Can central venous pressure help identify acute right ventricular dysfunction in mechanically ventilated critically ill patients?

ObjectiveTo investigate the relationship between central venous pressure (CVP) and acute right ventricular (RV) dysfunction in critically ill patients on mechanical ventilation.MethodsThis retrospective study enrolled mechanically ventilated critically ill who underwent transthoracic echocardiographic examination and CVP monitoring. Echocardiographic indices including tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and tricuspid lateral annular systolic velocity wave (S’) were collected to assess RV function. Patients were then classified into three groups based on their RV function and presence of systemic venous congestion as assessed by inferior vena cava diameter (IVCD) and hepatic vein (HV) Doppler: normal RV function (TAPSE ≥ 17 mm, FAC ≥ 35% and S’ ≥9.5 cm/sec), isolated RV dysfunction (TAPSE < 17 mm or FAC < 35% or S’ <9.5 cm/sec with IVCD ≤ 20 mm or HV S ≥ D), and RV dysfunction with congestion (TAPSE < 17 mm or FAC < 35% or S’ <9.5 cm/sec with IVCD > 20 mm and HV S < D).ResultsA total of 518 patients were enrolled in the study, of whom 301 were categorized in normal RV function group, 164 in isolated RV dysfunction group and 53 in RV dysfunction with congestion group. Receiver operating characteristic analysis revealed a good discriminative ability of CVP for identifying patients with RV dysfunction and congestion(AUC 0.839; 95% CI: 0.795–0.883; p < 0.001). The optimal CVP cutoff was 10 mm Hg, with sensitivity of 79.2%, specificity of 69.4%, negative predictive value of 96.7%, and positive predictive value of 22.8%. A large gray zone existed between 9 mm Hg and 12 mm Hg, encompassing 95 patients (18.3%). For identifying all patients with RV dysfunction, CVP demonstrated a lower discriminative ability (AUC 0.616; 95% CI: 0.567–0.665; p < 0.001). Additionally, the gray zone was even larger, ranging from 5 mm Hg to 12 mm Hg, and included 349 patients (67.4%).ConclusionsCVP may be a helpful indicator of acute RV dysfunction patients with systemic venous congestion in mechanically ventilated critically ill, but its accuracy is limited. A CVP less than10 mm Hg can almost rule out RV dysfunction with congestion. In contrast, CVP should not be used to identify general RV dysfunction.

Dicyanisophorone-based viscosity fluorescent probe and its fluorescence imaging in cells and zebrafish

Cellular viscosity is a critical parameter for maintaining normal cellular functions, and its abnormalities are associated with the occurrence and development of various diseases. Therefore, real-time monitoring of cellular viscosity is of significant importance for understanding viscosity-related biological functions and revealing the pathological mechanisms of diseases. In this study, we developed a novel fluorescence probe (IP-HBO) by hybridizing dicyanisophorone with 2-(2-hydroxyphenyl)benzoxazole for monitoring of cellular microenvironment and viscosity changes in zebrafish. The probe IP-HBO combines the principles of molecular rotors and enhanced solid-state fluorescence properties, demonstrating highly specific responsiveness to viscosity, long-wavelength emission, large Stokes shift, and excellent photostability. It has been successfully employed for fluorescence imaging of viscosity in live HeLa cells and zebrafish. The construction of this probe provides a new tool for gaining insights into viscosity-related biological processes and disease mechanisms within cells.

Endoprosthetic replacement with preservation of the epiphysis for proximal tibial reconstruction after osteosarcoma resection in children: a case report

BackgroundLimb salvage surgery is an important method for treating malignant tumors of the bone involving the adjacent parts of the major joints in children. This technique allows for preservation of limb function, especially in the lower limb. However, the reconstruction of the proximal end of the tibia after removing the tumor mass with a rational scale to preserve the total knee joint and reduce limb length discrepancy presents a challenge.Case presentationWe present a case of osteosarcoma of the proximal tibia. After being treated with an extended tumor resection, the proximal tibia of the child was restructured using endoprosthetic replacement with epiphyseal preservation. This procedure preserves the entire articular surface and growth plate of the knee joint of the affected limb and provides a feasible alternative protocol for retaining the function and growth potential of the affected limb. The patient remained disease-free and normal limb motor function was observed during the 3.5 year follow-up since the initial surgery.ConclusionsPreservation of the epiphysis enabled our patient to perform better limb function after limb-saving surgery as a result of his undamaged knee joint and minimized limb-length discrepancy. We believe that endoprosthetic replacement with preservation of the epiphysis can provide the best strategy for reconstruction after resection of focal malignant tumors in long bones without epiphytic involvement.

Temporal and Dosage Impact of Magnesium Oxide Nanoparticles on Grass Carp: Unveiling Oxidative Stress, DNA Damage and Antioxidant Suppression

Magnesium oxide nanoparticles (MgO NPs) have gained significant importance in biomedicine and variety of nanotechnology-based materials used in the agriculture and biomedical industries. However, the release of different nanowastes in the water ecosystem becomes a serious concern. Therefore, this study was executed to evaluate the toxic impacts of MgO NPs on grass carp. A total of 60 grass carp were randomly divided in three groups (G0, G1, and G2). Fish reared in group G0 were kept as control while fish of groups G1 and G2 were exposed to 0.5mg/L and 0.7mg/L MgO NPs respectively, mixed in water for 21 days. The 96h median lethal concentration (LC50) of MgO NPs was found to be 4.5mg/L. Evaluation of oxidative stress biomarkers, antioxidant enzymes, DNA damage in different visceral organs and the presence of micronuclei in erythrocytes were determined on days-7, 14, and 21 of the trial. Results revealed a dose and time-dependent significantly increased values of reactive oxygen species, lipid peroxidation product, DNA damage in multiple visceral organs and formation of micronuclei in the erythrocytes of treated fish (0.7mg/L). The results on antioxidant profile exhibited significantly lower amounts of total proteins, catalase, superoxide dismutase and peroxidase in visceral organs of the fish exposed to MgO NPs (0.5 and 0.7mg/L) at day 21 of trial compared to control group. In conclusion, it has been recorded that MgO NPs severely influence the normal physiological functions of the grass carp even at low doses.

Multimerization of TREM2 is impaired by Alzheimer's disease-associated variants.

The immune receptor triggering receptor expressed on myeloid cells 2 (TREM2) is among the strongest genetic risk factors for Alzheimer's disease (AD) and is a therapeutic target. TREM2 multimers have been identified in crystallography and implicated in the efficacy of antibody therapeutics; however, the molecular basis for TREM2 multimerization remains poorly understood. We used molecular dynamics simulations and binding energy analysis to determine the effects of AD-associated variants on TREM2 multimerization and validated with experimental results. TREM2 trimers remained stably bound, driven primarily by salt bridge between residues D87 and R76 at the interface of TREM2 units. This salt bridge was disrupted by the AD-associated variants R47H and R98W and nearly ablated by the D87N variant. This decreased binding among TREM2 multimers was validated with co-immunoprecipitation assays. This study uncovers a molecular basis for TREM2 forming stable trimers and unveils a novel mechanism by which TREM2 variants may increase AD risk by disrupting TREM2 oligomerization to impair TREM2 normal function. Triggering receptor expressed on myeloid cells 2 (TREM2) multimerization could regulate TREM2 activation and function. D87-R76 salt bridges at the interface of TREM2 units drive the formation of stable TREM2 dimers and trimers. Alzheimer's disease (AD)-associated R47H and R98W variants disrupt the D87-R76 salt bridge. The AD-associated D87N variant leads to complete loss of the D87-R76 salt bridge.

Effects of Endocrine-Disrupting Chemicals on Bone Health.

This comprehensive review critically examines the detrimental impacts of endocrine-disrupting chemicals (EDCs) on bone health, with a specific focus on substances such as bisphenol A (BPA), per- and polyfluoroalkyl substances (PFASs), phthalates, and dioxins. These EDCs, by interfering with the endocrine system's normal functioning, pose a significant risk to bone metabolism, potentially leading to a heightened susceptibility to bone-related disorders and diseases. Notably, BPA has been shown to inhibit the differentiation of osteoblasts and promote the apoptosis of osteoblasts, which results in altered bone turnover status. PFASs, known for their environmental persistence and ability to bioaccumulate in the human body, have been linked to an increased osteoporosis risk. Similarly, phthalates, which are widely used in the production of plastics, have been associated with adverse bone health outcomes, showing an inverse relationship between phthalate exposure and bone mineral density. Dioxins present a more complex picture, with research findings suggesting both potential benefits and adverse effects on bone structure and density, depending on factors such as the timing and level of exposure. This review underscores the urgent need for further research to better understand the specific pathways through which EDCs affect bone health and to develop targeted strategies for mitigating their potentially harmful impacts.

FORMATION OF EFFECTIVE BUSINESS ENVIRONMENT IN GEORGIA WITH THE ASSISTANCE OF

Besik Kvachantiradze E-mail: b.kvatchantiradze@gmail.com PhD Students,Batumi Shota Rustaveli state University Batumi, Georgia https://orcid.org/0000-0003-2833-1007 Abstract: The article discusses the stages of formation of the business environment of Georgia and the ways of its improvement with the cooperation of the European Union. Strengthening relations with the European Union has been the main goal of Georgia's foreign policy for years. Small and medium-sized enterprises, which are the basis of the successful development of the European Union, in recent decade have been operating in close collaboration with large businesses. Therefore, in our opinion, it is interesting to analyze the ratio of large, medium and small enterprises in the European Union. Since Georgia has taken the direction to European development, a number of reforms have been implemented in the country to encourage small and medium-sized businesses, which in turn has a possitive effect on the development of the country's overall economy. In addition to the state support for small businesses in the European Union, all member states have their own national system for stimulating the development of small businesses, the purpose of which is to create an economic climate that will contribute to the creation of economic conditions and normal functioning. This, in the first place, includes the creation of national institutions and the organization of financial assistance, training system for enterprise manager and entrepreneurs who want to start independent activities. Under taking European experience and mechanisms into consideration, a number of projects were implemented in Georgia, which contributed to the expansion and development of Georgian small and medium-sized businesses, in addition, retraining of the Georgian workforce and adjusting working conditions to European standards. Moreover, Georgia can greatly accelerate its economic development, strengthen its competitiveness and achieve its goals - through sustainable growth and job creation. Cooperation with the European Union offers Georgia great opportunities for learning, innovation and integration into the global economy. The article offers recommendations and suggestions that focus on creating closer relations with the European Union and attracting more foreign investment, which will ensure the economic prosperity of the country. Keywords: Business environment, small and medium business, cooperation with the European Union. JEL classification: O1, G2, E4

Melatonin via MTNR1B regulates METTL3 to protect ileum cell differentiation.

Intestinal stem cells rapidly differentiate into various epithelial cells, playing a crucial role in maintaining intestinal homeostasis. Melatonin, a known endogenous molecule with anti-inflammatory and antioxidant properties, has its potential efficacy in ileum stem cells differentiation not fully understood to date. This study indicates that melatonin suppresses ileum inflammation and maintains normal differentiation of ileum stem cells through MTNR1B. Subsequent outcomes following treatment with MTNR1B inhibitors further substantiate these findings. Additionally, overexpression of METTL3 protein appears to be a potential instigator for promoting ileum inflammation and disruptions in cell differentiation. Treatment with the METTL3 inhibitor SAH significantly inhibits ileum inflammation and Wnt/β-catenin activity, thereby sustaining normal cellular differentiation functions. In summary, this study showed that melatonin may improve ileum inflammation and maintain cell differentiation functions by inhibiting abnormal METTL3 expression via MTNR1B.

Oxidative stress and type 2 diabetes: the development and the pathogenesis, Jordanian cross-sectional study

Accumulation of reactive oxygen species (ROS) can disrupt the antioxidant defense system, leading to oxidative stress that leads to pathological damage to vital human organs, including hormone-producing glands. Normal physiological function is subsequently disrupted and disorders such as Type 2 Diabetes Mellitus (T2DM) may develop. The critical role of the antioxidant defense system in counteracting ROS and mitigating oxidative stress is fundamental to understanding the pathogenesis of T2DM. In our study, we monitored the oxidant/antioxidant status in a selected Jordanian population to further elucidate this relationship. Our results show higher serum levels of Malondialdehyde (MDA); 0.230 ± 0.05 and 0.207 ± 0.06 μmol/l for the diabetic and the obese groups, respectively, relative to 0.135 ± 0.04 μmol/l for the non-obese healthy group. Lower activity of Catalase (CAT) was recorded among the diabetic (9.2 ± 3.2) and obese groups (11.0 ± 2.8), compared to the non-obese healthy group (12.1 ± 3.5). Significant elevations (P < 0.05) were observed in uric acid concentrations in diabetic and obese subjects: 451 ± 57 mg/dl and 430 ± 51, respectively, versus 342 ± 57 mg/dl in the non-obese healthy group. Moreover, no significant differences were obtained between all the studied groups for the serum albumin and total protein concentrations. Our findings demonstrate the potential role of oxidative stress in the development and occurrence of T2DM.

Clinical and Functional Studies of MTOR Variants in Smith-Kingsmore Syndrome Reveal Deficits of Circadian Rhythm and Sleep-Wake Behavior

Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent 9 MTOR pathogenic variants. We conducted a detailed natural history study and found pathophysiological deficits among individuals with SKS, in addition to the common neurodevelopmental symptoms. These symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, indicative of homeostatic imbalance. To characterize these variants, we developed cell models and characterized their functional consequences. We showed that these SKS variants display a range of mTOR activities and respond to the mTOR inhibitor, rapamycin, differently. For example, the R1480_C1483del variant we identified here and the previously known C1483F are more active than wild-type controls and less responsive to rapamycin. Further, we showed that SKS mutations dampened circadian rhythms and low-dose rapamycin improved the rhythm amplitude, suggesting that optimal mTOR activity is required for normal circadian function. As SKS is caused by gain of function mutations in MTOR, rapamycin was used to treat several patients. While higher doses of rapamycin caused delayed sleep-wake phase disorder in a subset of patients, optimized lower doses improved sleep. Our study expands the clinical and molecular spectrum of SKS and support further studies for mechanism-guided treatment options to improve sleep-wake behavior and overall health.

N-acetylcysteine may improve endometrial receptivity by modulating endometrial stromal cells in goats

Abstract. Endometrial receptivity is essential for successful embryo implantation and pregnancy maintenance, and the achievement of normal physiological function of endometrial stromal cells (ESCs) is an important factor in the establishment of receptivity. N-acetylcysteine (NAC) was found to be beneficial as a small-molecule antioxidant for improving animal reproductive performance, but it is unclear whether NAC can improve receptivity by modulating ESCs in goats. In this study, we successfully isolated and cultured the ESCs of Qianbei Ma goats, used different concentrations of NAC to culture the ESCs of Qianbei Ma goats, and explored the effects of NAC on the biological functions of the ESCs of Qianbei Ma goats by using CCK-8, qRT-PCR, ELISA and flow cytometry. The results showed that 200 µmol L−1 NAC may promote the proliferation of ESCs in Qianbei Ma goats by increasing the expression of PCNA, Cyclin D2 (P&lt;0.01) and Cyclin E (P&lt;0.05) mRNAs. Meanwhile, 200 µmol L−1 NAC increased the cell viability (P&lt;0.01) and enhanced the superoxide dismutase (SOD) and glutathione reductase (GR) activities (P&lt;0.01) of ESCs in Qianbei Ma goats. In addition, 200 µmol L−1 NAC increased the mitochondrial membrane potential of ESCs (P&lt;0.01). Notably, 200 µmol L−1 NAC promoted the expression of the mRNA of the endometrial receptivity marker genes HOXA10, PTGS2, PGR (P&lt;0.01) and LIF (P&lt;0.05). Thus, our results suggest that NAC may benefit the establishment of endometrial receptivity in goats by regulating the proliferation, antioxidant properties, mitochondrial membrane potential and expression of endometrial receptivity marker genes in goat ESCs.

Thyroid dysfunction in Hashimoto's thyroiditis: a pilot study on the putative role of miR-29a and TGFβ1.

Hashimoto's thyroiditis (HT) is one of the most common causes of thyroid dysfunction in iodine sufficient worldwide areas, but its molecular mechanisms are not completely understood. To this regard, this study aimed to assess serum levels of miRNA-29a (miR-29a) and transforming growth factor beta 1 (TGFβ1) in HT patients with different patterns of thyroid function. A total of 29 HT patients, with a median age of 52 years (21-68) were included. Of these, 13 had normal thyroid function (Eu-HT); 8 had non-treated hypothyroidism (Hypo-HT); 8 had hypothyroidism on replacement therapy with LT4 (subst-HT). All patients had serum miR-29a assayed through qRT-PCR and serum TGFβ1 assayed by ELISA. Serum miR-29a levels were significantly down-regulated in patients with Hypo-HT compared to Eu-HT patients (P < 0.01) and subst-HT patients (P < 0.05). A significant negative correlation was detected between serum miR-29a levels and TSH levels (r = -0.60, P < 0.01). Serum TGFβ1 levels were significantly higher in Hypo-HT than both Eu-HT (P < 0.01) and subst-HT patients (P < 0.05). A negative correlation was observed between serum miR-29a and TGFβ1 (r = -0.75, P < 0.01). In conclusion, Hypo-HT patients had lower levels of serum miR-29a and higher levels of TGFβ1 in comparison with Eu-HT patients. Worthy of note, subst-HT patients showed restored serum miR-29a levels compared with Hypo-HT group, associated with lower serum TGFβ1. These novel findings may suggest a possible impact of replacement therapy with levothyroxine on serum miR-29a levels in HT.

Left atrial stiffness index – an early marker of left ventricular diastolic dysfunction in patients with coronary heart disease

AimsTo evaluate the correlation between left atrial stiffness index (LASI) and left ventricular diastolic function in patients with coronary heart disease (CHD) by Autostrain LA technique.MethodsThis was a retrospective analysis that included a total of 82 CHD patients who had suitable image quality for left atrial strain measurement. According to the 2016 ASE/EACVI guidelines for the echocardiographic assessment of diastolic dysfunction, the patients were divided into three groups: normal left ventricular diastolic function group (n = 26), indeterminate left ventricular diastolic function (n = 36), and left ventricular diastolic dysfunction (LVDD) (n = 20). The left atrial conduit strain (LAScd), Left atrial contractile strain (LASct), left atrial reservoir strain (LASr) and its derived parameters, including LASI and left atrial filling index (LAFI), were compared among the three groups. Furthermore, we conduct a correlation analysis between LASI and left ventricular diastolic function in patients with CHD.ResultsLASr and LAScd in normal group were higher than those in indeterminate group, LASr and LAScd in indeterminate group were higher than those in LVDD group, LASI in normal group was lower than that in indeterminate group, and LASI in indeterminate group was lower than that in LVDD group (P < 0.001). LASct in both normal and indeterminate groups was higher than that in LVDD group (P < 0.05). The LAFI of normal group was lower than that of indeterminate group and LVDD group (P < 0.001). LASI was positively correlated with E/e’(r = 0.822) (P < 0.001). LASr and E/e’ were negatively correlated (r = -0.637) (P < 0.001).ConclusionLASI is closely related to the changes of left ventricular diastolic function in CHD patients.

SLCO1B1 and ABCG2 genotype-informed phenotypes are related to variation in ramipril exposure.

Ramipril is an angiotensin-converting enzyme inhibitor used for hypertension and heart failure management. To date, scarce literature is available on pharmacogenetic associations affecting ramipril. The goal of this study was to investigate the effect of 120 genetic variants in 34 pharmacogenes (i.e., genes encoding for enzymes like CYPs or UGTs and transporters like ABC or SLC) on ramipril pharmacokinetic variability and adverse drug reaction (ADR) incidence. Twenty-nine healthy volunteers who had participated in a single-dose bioequivalence clinical trial of two formulations of ramipril were recruited. A univariate and multivariate analysis searching for associations between genetic variants and ramipril pharmacokinetics was performed. SLCO1B1 and ABCG2 genotype-informed phenotypes strongly predicted ramipril exposure. Volunteers with the SLCO1B1 decreased function (DF) phenotype presented around 1.7-fold higher dose/weight-corrected area under the curve (AUC/DW) than volunteers with the normal function (NF) phenotype (univariate p-value [puv] <0.001, multivariate p-value [pmv] <0.001, β =0.533, R2=0.648). Similarly, volunteers with ABCG2 DF + poor function (PF) phenotypes presented around 1.6-fold higher AUC/DW than those with the NF phenotype (puv=0.011, pmv<0.001, β =0.259, R2=0.648). Our results suggest that SLCO1B1 and ABCG2 are important transporters to ramipril pharmacokinetics, and their genetic variation strongly alters its pharmacokinetics. Further studies are required to confirm these associations and their clinical relevance.

Identification and prognostic analysis of metabolic genes associated with TP53 mutation in multiple myeloma

ABSTRACT Background TP53 gene mutation is crucial in determining the prognosis of Multiple Myeloma (MM) patients. Understanding metabolic genes linked to TP53 mutation is vital for developing targeted therapies for these patients. Method We analyzed The Cancer Genome Atlas (TCGA) dataset to identify genes related to TP53 mutation and metabolism. Using univariate Cox regression and protein–protein interaction (PPI) analysis, we identified key genes. We categorized patients into high and low metabolism groups via non-negative matrix factorization (NMF) clustering, which led to the discovery of relevant differential genes. Integrating these with genes from the Gene Expression Omnibus (GEO) datasets and PPI interactions, we pinpointed crucial metabolic genes associated with TP53 mutation in MM. Additionally, we conducted prognostic analyses involving survival curves and receiver operating characteristic (ROC) charts. Results Our study reveals that the metabolic gene ribonucleotide reductase M2 (RRM2), linked to TP53 mutation, correlates positively with the International Staging System (ISS) stage in MM patients and is an independent prognostic risk factor. In the TCGA dataset, among the 767 patients, the 35 MM patients with TP53 mutation generally had poor survival outcomes. Specifically, the patients with both TP53 mutation and high RRM2 expression had a 2-year survival rate of only 38.87%, whereas those with normal TP53 function and low RRM2 expression had a 2-year survival rate of 86.31% (p < 0.001). Conclusion RRM2 significantly impacts MM prognosis and is associated with TP53 mutation, presenting itself as a potential therapeutic target and prognostic marker for MM.

Cardiopulmonary exercise testing in post-COVID-19 patients

Abstract Patients with prior COVID-19 infection can have residual symptoms and significant disability. In particular, some patients have abnormal lung function with reduced volumes and diffusion capacities. However, some patients have relatively normal lung function and chest x-rays but have significant dyspnea. These patients have been evaluated using cardiopulmonary exercise testing (CPET) to determine their peak O2 consumption and their cardiac and respiratory responses during standardized testing. In general, these studies demonstrate that the level of impairment correlates with the severity of the initial infection. In addition, some patients have little or no improvement in their VO2 over time. This test can provide some insight as to exact system limitations resulting in impairment. Six-minute walk tests provide alternative approaches for evaluating patients when CPET testing is not available. Most patients who have had prior COVID infection improve with standard pulmonary rehabilitation. Keywords: COVID-19 infection, dyspnea, cardiopulmonary exercise testing, rehabilitation