Pathophysiology, Volume 30, Issue 2 (June 2023) – 15 articles

Vestibulo-atactic syndrome (VAS), which represents a combination of motor and vestibular disorders, can be manifested as a clinical complication of breast cancer treatment and has a significant impact on patients’ quality of life. The identification of novel potential biomarkers that might help to predict the onset of VAS and its progression could improve the management of this group of patients. In the current study, the levels of intercellular cell adhesion molecule 1 (ICAM-1), platelet/endothelial cell adhesion molecule 1 (PECAM-1), NSE (neuron-specific enolase), and the antibodies recognizing NR-2 subunit of NMDA receptor (NR-2-ab) were measured in the blood serum of BC survivor patients with vestibulo-atactic syndrome (VAS) and associated with the brain connectome data obtained via functional magnetic resonance imaging (fMRI) studies. A total of 21 patients were registered in this open, single-center trial and compared to age-matched healthy female volunteers (control group) (n = 17). BC patients with VAS demonstrated higher serum levels of ICAM-1, PECAM-1, and NSE and a lower value of NR-2-ab, with values of 654.7 ± 184.8, 115.3 ± 37.03, 49.9 ± 103.9, and 0.5 ± 0.3 pg/mL, respectively, as compared to the healthy volunteers, with 230.2 ± 44.8, 62.8 ± 15.6, 15.5 ± 6.4, and 1.4 ± 0.7 pg/mL. According to the fMRI data (employing seed-to-voxel and ROI-to-ROI methods), in BC patients with VAS, significant changes were detected in the functional connectivity in the areas involved in the regulation of postural-tonic reflexes, the coordination of movements, and the regulation of balance. In conclusion, the detected elevated levels of serum biomarkers may reveal damage to the CNS neurons and endothelial cells that is, in turn, associated with the change in the brain connectivity in this group of patients. Full article

Antioxidant protection is one of the key reactions of cardiomyocytes (CMCs) in response to myocardial damage of various origins. The thioredoxin interacting protein (TXNIP) is an inhibitor of thioredoxin (TXN). Over the recent few years, TXNIP has received significant attention due to its wide range of functions in energy metabolism. In the present work, we studied the features of the redox-thiol systems, in particular, the amount of TXNIP and glutathione synthetase (GS) as markers of oxidative damage to CMCs and antioxidant protection, respectively. This study was carried out on 38-week-old Wistar-Kyoto rats with insulin-dependent diabetes mellitus (DM) induced by streptozotocin, on 38- and 57-week-old hypertensive SHR rats and on a model of combined hypertension and DM (38-week-old SHR rats with DM). It was found that the amount of TXNIP increased in 57-week-old SHR rats, in diabetic rats and in SHR rats with DM. In 38-week-old SHR rats, the expression of TXNIP significantly decreased. The expression of GS was significantly higher compared with the controls in 57-week-old SHR rats, in DM rats and in the case of the combination of hypertension and DM. The obtained data show that myocardial damage caused by DM and hypertension are accompanied by the activation of oxidative stress and antioxidant protection. Full article

Acute kidney injury (AKI) is associated with a worse prognosis in coronavirus disease 2019 (COVID-19) patients. Identification of AKI, particularly in COVID-19 patients, is important for improving patients’ management. The study aims to assess risk factors and comorbidities of AKI in COVID-19 patients. We systematically searched PubMed and DOAJ databases for relevant studies involving confirmed COVID-19 patients with data on risk factors and comorbidities of AKI. The risk factors and comorbidities were compared between AKI and non-AKI patients. A total of 30 studies involving 22385 confirmed COVID-19 patients were included. Male (OR: 1.74 (1.47, 2.05)), diabetes (OR: 1.65 (1.54, 1.76)), hypertension (OR: 1.82 (1.12, 2.95)), ischemic cardiac disease (OR: 1.70 (1.48, 1.95)), heart failure (OR: 2.29 (2.01, 2.59)), chronic kidney disease (CKD) (OR: 3.24 (2.20, 4.79)), chronic obstructive pulmonary disease (COPD) (OR: 1.86 (1.35, 2.57)), peripheral vascular disease (OR: 2.34 (1.20, 4.56)), and history of nonsteroidal anti-inflammatory drugs (NSAID) (OR: 1.59 (1.29, 1.98)) were independent risk factors associated with COVID-19 patients with AKI. Patients with AKI presented with proteinuria (OR: 3.31 (2.59, 4.23)), hematuria (OR: 3.25 (2.59, 4.08)), and invasive mechanical ventilation (OR: 13.88 (8.23, 23.40)). For COVID-19 patients, male gender, diabetes, hypertension, ischemic cardiac disease, heart failure, CKD, COPD, peripheral vascular disease, and history of use of NSAIDs are associated with a higher risk of AKI. Full article

There are several pathophysiological outcomes associated with substance abuse including metabolic disbalance, neurodegeneration, and disordered redox. Drug use in pregnant women is a topic of great concern due to developmental harm which may occur during gestation and the associated complications in the neonate after delivery. We sought to determine what the trajectory of drug use is like in children aged 0–4 years and mothers of neonates. Urine drug screen (UDS) results were obtained of our target demographic during 1998–2011 and 2012–2019 from LSU Health Sciences Center in Shreveport (LSUHSC-S). Statistical analysis was performed using R software. We observed an increase in cannabinoid-positive UDS results in both Caucasian (CC) and African American (AA) groups between 1998–2011 and 2012–2019 periods. Cocaine-positive UDS results decreased in both cohorts. CC children had higher UDS positive results for opiates, benzodiazepines, and amphetamines, while AA children had a higher percentage for illicit drugs such as cannabinoids and cocaine. Neonate’s mothers had similar UDS trends to that in children during 2012–2019. Overall, while percentage of positive UDS results for both AA and CC 0–4 year old children started to decline for opiate, benzodiazepine, and cocaine during 2012–2019, cannabinoid- and amphetamine (CC)-positive UDS steadily increased. These results suggest a shift in the type of drug use by mothers from opiates, benzodiazepines, and cocaine to cannabinoids and/or amphetamines. We also observed that 18-year-old females who tested positive for opiates, benzodiazepine, or cocaine had higher than average chances of testing positive for cannabinoids later in life. Full article

The primary aim of the study was to assess cerebral circulation in healthy young subjects during an ultra-short (45 min) session of ground-based microgravity modeled by “dry” immersion (DI), with the help of a multifunctional Laser Doppler Flowmetry (LDF) analyzer. In addition, we tested a hypothesis that cerebral temperature would grow during a DI session. The supraorbital area of the forehead and forearm area were tested before, within, and after a DI session. Average perfusion, five oscillation ranges of the LDF spectrum, and brain temperature were assessed. Within a DI session, in the supraorbital area most of LDF parameters remained unchanged except for a 30% increase in respiratory associated (venular) rhythm. The temperature of the supraorbital area increased by up to 38.5 °C within the DI session. In the forearm area, the average value of perfusion and its nutritive component increased, presumably due to thermoregulation. In conclusion, the results suggest that a 45 min DI session does not exert a substantial effect on cerebral blood perfusion and systemic hemodynamics in young healthy subjects. Moderate signs of venous stasis were observed, and brain temperature increased during a DI session. These findings must be thoroughly validated in future studies because elevated brain temperature during a DI session can contribute to some reactions to DI. Full article

In addition to mandibular advancement devices, dental expansion appliances are an important clinical approach for achieving an increased intra-oral space that promotes airflow and lessens the frequency or severity of apneic events in patients diagnosed with obstructive sleep apnea (OSA). It has been thought that dental expansion in adults must be preceded by oral surgery; however, in this paper, we examine the results of a new technique for slow maxillary expansion without any surgical procedures. The palatal expansion device, DNA (Daytime-Nighttime Appliance), was reviewed in this retrospective study, particularly regarding its effects on measurements of transpalatal width, airway volume, and apnea-hypopnea indices (AHI) as well as its common modalities and complications. The DNA effectively reduced AHI by 46% (p = 0.00001) and significantly increased both airway volume and transpalatal width (p < 0.00001). After DNA treatment, 80% of patients showed some improvement in AHI scores with 28% of patients having their OSA symptoms completely resolved. Compared to the use of mandibular appliances, this approach is intended to create a sustained improvement in airway management that can reduce or eliminate dependence on continuous positive airway pressure (CPAP) or other OSA treatment devices. Full article

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) ribonucleic acid (RNA) shedding is an important parameter for determining the optimal length of isolation period required for coronavirus disease 2019 (COVID-19) patients. However, the clinical (i.e., patient and disease) characteristics that could influence this parameter have yet to be determined. In this study, we aim to explore the potential associations between several clinical features and the duration of SARS-CoV-2 RNA shedding in patients hospitalized with COVID-19. A retrospective cohort study involving 162 patients hospitalized for COVID-19 in a tertiary referral teaching hospital in Indonesia was performed from June to December 2021. Patients were grouped based on the mean duration of viral shedding and were compared based on several clinical characteristics (e.g., age, sex, comorbidities, COVID-19 symptoms, severity, and therapies). Subsequently, clinical factors potentially associated with the duration of SARS-CoV-2 RNA shedding were further assessed using multivariate logistic regression analysis. As a result, the mean duration of SARS-CoV-2 RNA shedding was found to be 13 ± 8.44 days. In patients with diabetes mellitus (without chronic complications) or hypertension, the duration of viral shedding was significantly prolonged (≥13 days; p = 0.001 and p = 0.029, respectively). Furthermore, patients with dyspnea displayed viral shedding for longer durations (p = 0.011). The multivariate logistic regression analysis reveals that independent risk factors associated with the duration of SARS-CoV-2 RNA shedding include disease severity (adjusted odds ratio [aOR] = 2.94; 95% CI = 1.36–6.44), bilateral lung infiltrates (aOR = 2.79; 95% CI = 1.14–6.84), diabetes mellitus (aOR = 2.17; 95% CI = 1.02–4.63), and antibiotic treatment (aOR = 3.66; 95% CI = 1.74–7.71). In summary, several clinical factors are linked with the duration of SARS-CoV-2 RNA shedding. Disease severity is positively associated with the duration of viral shedding, while bilateral lung infiltrates, diabetes mellitus, and antibiotic treatment are negatively linked with the duration of viral shedding. Overall, our findings suggest the need to consider different isolation period estimations for specific clinical characteristics of patients with COVID-19 that affect the duration of SARS-CoV-2 RNA shedding. Full article

Aim of the study: The aim of this study was to perform a comparative analysis of severity of discordant aortic stenosis (AS) assessment using multiposition scanning and the standard apical window. Materials and Methods: All patients (n = 104) underwent preoperative transthoracic echocardiography (TTE) and were ranked according to the degree of AS severity. The reproducibility feasibility of the right parasternal window (RPW) was 75.0% (n = 78). The mean age of the patients was 64 years, and 40 (51.3%) were female. In 25 cases, low gradients were identified from the apical window not corresponding to the visual structural changes in the aortic valve, or disagreement between the velocity and calculated parameters was detected. Patients were divided into two groups: concordant AS (n = 56; 71.8%) and discordant AS (n = 22; 28.2%). Three individuals were excluded from the discordant AS group due to the presence of moderate stenosis. Results: Based on the comparative analysis of transvalvular flow velocities obtained from multiposition scanning, the concordance group showed agreement between the velocity and calculated parameters. We observed an increase in the mean transvalvular pressure gradient (ΔP_mean) and peak aortic jet velocity (V_max), ΔP_mean in 95.5% of patients, velocity time integral of transvalvular flow (VTI AV) in 90.9% of patients, and a decrease in aortic valve area (AVA) and indexed AVA in 90.9% of patients after applying RPW in all patients with discordant AS. The use of RPW allowed the reclassification of AS severity from discordant to concordant high-gradient AS in 88% of low-gradient AS cases. Conclusion: Underestimation of flow velocity and overestimation of AVA using the apical window may lead to misclassification of AS. The use of RPW helps to match the degree of AS severity with the velocity characteristics and reduce the number of low-gradient AS cases. Full article

In recent years, the elderly has become a rapidly growing proportion of the world’s population as life expectancy is extending. Immunosenescence and inflammaging contribute to the increased risk of chronic non-communicable and acute infectious diseases. Frailty is highly prevalent in the elderly and is associated with an impaired immune response, a higher propensity to infection, and a lower response to vaccines. Additionally, the presence of uncontrolled comorbid diseases in the elderly also contributes to sarcopenia and frailty. Vaccine-preventable diseases that threaten the elderly include influenza, pneumococcal infection, herpes zoster, and COVID-19, which contribute to significant disability-adjusted life years lost. Previous studies had shown that conventional vaccines only yielded suboptimal protection that wanes rapidly in a shorter time. This article reviews published papers on several vaccination strategies that were developed for the elderly to solve these problems: more immunogenic vaccine formulations using larger doses of antigen, stronger vaccine adjuvants, recombinant subunit or protein conjugated vaccines, newly developed mRNA vaccines, giving booster shots, and exploring alternative routes of administration. Included also are several publications on senolytic medications under investigation to boost the immune system and vaccine response in the elderly. With all those in regard, the currently recommended vaccines for the elderly are presented. Full article

To avoid criminal prosecution, clandestine chemists produce designer stimulants that mimic the pharmacological and psychoactive effects of conventional stimulants, such as methamphetamine. Following persistent or high-dose exposure, both acute vasoconstriction and loss of vascular homeostasis are reported dangers of conventional stimulants, and designer stimulants may pose even greater dangers. To compare the effects of a conventional stimulant and two designer stimulants on vascular contraction, this study examined the direct effects of 1,3-benzodioxolylbutanamine (BDB) and N-butylpentylone in comparison to methamphetamine on the function of human brain vascular smooth muscle cells (HBVSMCs). HBVSMCs suspended in collagen gels were exposed to varying concentrations of each drug, and the degree of constriction was assessed over one week. The MTT assay was used to measure the impact of the three drugs on the cellular metabolic activity as a marker of cellular toxicity. The highest concentration tested of either methamphetamine or N-butylpentylone produced a loss of HBVSMC contractility and impaired cellular metabolism. BDB showed a similar pattern of effects, but, uniquely, it also induced vasoconstrictive effects at substantially lower concentrations. Each drug produced direct effects on HBVSMC contraction that may be a mechanism by which the cardiovascular system is damaged following high-dose or persistent exposure, and this could be exacerbated by any sympathomimetic effects of these compounds in whole organisms. BDB appears to impact HBVSMC function in ways distinct from methamphetamine and N-butylpentylone, which may present unique dangers. Full article

Previous studies have yielded inconsistent results on whether glycated hemoglobin (HbA1c) and random blood glucose (RBG) are associated with mortality of coronavirus disease 2019 (COVID-19) patients with type 2 diabetes mellitus (T2DM). This study aimed to assess the association of HbA1c and RBG with mortality among COVID-19 patients with T2DM. A retrospective study was conducted on 237 patients with COVID-19 and T2DM (survival (n = 169) and non-survival groups (n = 68)). Data on socio-demography, comorbidities, clinical symptoms, laboratory examination, and mortality were collected. Patients in the non-survival group had an older age range as compared with those in the survival group (60 (52.3–65.0) vs. 56.0 (48.5–61.5) years, p = 0.009). There was no statistical gender difference between the two groups. After matching was done, chronic kidney disease, NLR, d-dimer, procalcitonin, and random blood glucose were higher in the non-survival group compared to the survival group (p < 0.05). HbA1c levels were similar in survivors and non-survivors (8.7% vs. 8.9%, p=0.549). The level of RBG was independently associated with mortality of COVID-19 patients with T2DM (p = 0.003, adjusted OR per 1-SD increment 2.55, 95% CI: 1.36–4.76). In conclusion, RBG was associated with the mortality of COVID-19 patients with T2DM, but HbA1c was not. Full article

Aging causes a reduction in testosterone and estrogen, which is linked to diminished bone mineral density. Hormone replacement therapy and its effect on the outcome of joint arthroplasties is unclear. The purpose of this study was to analyze the impact of testosterone replacement therapy (TRT) and estrogen replacement therapy (ERT) on the medical and joint outcomes of total hip (THA) and total knee arthroplasties (TKA). A retrospective cohort study was conducted using the PearlDiver database. Patients who received TRT or ERT perioperatively were matched to controls. Rates of 90-day medical complications and 2-year joint complications were queried. Patients who received TRT had an increased risk of revision, periprosthetic joint infection, and pooled joint complications within 2 years following a THA and increased rates of septic and aseptic revisions, and aseptic loosening after TKA compared to the control cohort. Patients receiving ERT had increased rates of aseptic loosening and pooled joint complications within 2 years following THA and increased rates of all-cause revisions and pooled joint complications after TKA. Patients who received TRT demonstrated significantly higher rates of revision rates and PJI. Patients who received perioperative ERT were significantly more likely to have increased risks of revision rates and joint infections. Full article

Damage to the peripheral nervous system (PNS) is a common complication of breast cancer (BC) treatment, with 60 to 80% of breast cancer survivors experiencing symptoms of PNS damage. In the current study, the levels of brain-derived neurotrophic factor (BDNF), galectin-3 (Gal-3), and neurotrophin-3 (NT-3) were measured in the blood serum of BC patients by ELISA as potential biomarkers that might indicate the PNS damage. Sixty-seven patients were enrolled in this multi-center trial and compared to the aged-matched healthy female volunteers (control group) (n = 25). Intergroup comparison of biomarker levels (i.e., Gal-3 and BDNF) did not show significant differences in any of the studied subgroups. However, intriguingly, NT-3 levels were significantly higher in BC patients as compared to healthy volunteers, constituting 14.85 [10.3; 18.0] and 5.74 [4.56; 13.7] pg/mL, respectively (p < 0.001). In conclusion, NT-3 might be employed as a potential biomarker in BC patients with clinical manifestations of PNS damage. However, further studies to validate its correlation to the degree of peripheral nervous system lesions are of high value. Full article

Chronic inflammation is a crucial driver of carcinogenesis in pancreatic ductal adenocarcinoma (PDAC). Several studies have investigated the prognostic significance of cyclooxygenase−2 (COX−2) expression in PDAC patients, obtaining conflicting results. Nuclear factor kappa−B (NF−κB), specificity protein 1 (Sp1), and c−Jun are known as the transcription factors of the COX2 gene. This exploratory observational study investigated the association of the NF−κB, COX−2, Sp1, and c−Jun expressions with patient survival in PDAC. We used the immunohistochemical method to detect the PDAC tissue expressions of NF−κB (RelA/p65), COX−2, Sp1, and c−Jun. The expressions of these proteins were correlated with the overall survival (OS) and other clinicopathological characteristics of PDAC patients. We obtained 53 PDAC specimens from resections and biopsies. There were significant correlations between the four proteins’ expressions in the PDAC tissues. The expression of the cytoplasmic (aHR = 0.31; 95% CI 0.11–0.90; p = 0.032) or nuclear NF−κB (aHR = 0.22; 95% CI 0.07–0.66; p = 0.007) was independently associated with a better prognosis in the PDAC patients. COX−2, Sp1, and c−Jun showed no significant association with a prognosis in the PDAC patients. The PDAC patients who expressed NF−κB had a better prognosis than the other patients, which suggests that the role of inflammation in PDAC is more complex than previously thought. Full article

Total hip arthroplasty is a widely performed operation allowing disabled patients to improve their quality of life to a degree greater than any other elective procedure. Planning for a THA requires adequate patient assessment and preoperative characterizations of acetabular bone loss via radiographs and specific classification schemes. Some surgeons may be inclined to ream at a larger diameter thinking it would lead to a more stable press-fit, but this could be detrimental to the acetabular wall, leading to intraoperative fracture. In the attempt to reduce the incidence of intraoperative fractures, the current study aims to identify how increased reaming diameter degrades and weakens the acetabular rim strength. We hypothesized that there is proportionality between the reaming diameter and the reduction in acetabular strength. To test this hypothesis, this study used bone surrogates, templated from CT scans, and reamed at different diameters. The obtained bone surrogate models were then tested using an Intron 8874 mechanical testing machine (Instron, Norwood, MA) equipped with a custom-made fixture. Analysis of variance (ANOVA) was used to identify differences among reamed diameters while linear regression was used to identify the relationship between reamed diameters and acetabular strength. We found a moderate correlation between increasing reaming diameter that induced thinning of the acetabular wall and radial load damage. For the simplified acetabular model used in this study, it supported our hypothesis and is a promising first attempt in providing quantitative data for acetabular weakening induced by reaming. Full article