Pathophysiology, Volume 30, Issue 4 (December 2023) – 14 articles

In this meta-analysis, we examine the advantages of invasive strategies for patients diagnosed with chronic coronary heart disease (CHD) and preserved left ventricular (LV) function, as well as those with significant LV systolic dysfunction (LV ejection fraction (EF) < 45%). Material and methods: We conducted a systematic search to identify all randomized trials directly comparing invasive strategies with optimal medical therapy (OMT) in patients diagnosed with chronic CHD. Data from these trials were pooled using a random-effects meta-analysis. The primary outcome assessed was the all-cause mortality, while secondary endpoints included cardiovascular (CV) death, stroke, myocardial infarction (MI), and unplanned revascularization. This study was designed to assess the benefits of both invasive strategies and OMT in patients with preserved LV function and in those with LV systolic dysfunction. The statistical analysis of the data was conducted using the Review Manager (RevMan) software, version 5.4.1 (The Cochrane Collaboration, 2020). Results: Twelve randomized studies enrolling 13,912 patients were included in the final analysis. Among the patients with chronic CHD and preserved LV systolic function, revascularization did not demonstrate a reduction in all-cause mortality (8.52% vs. 8.45%, p = 0.45), CV death (3.41% vs. 3.62%, p = 0.08), or the incidence of MI (9.88% vs. 10.49%, p = 0.47). However, the need for unplanned myocardial revascularization was significantly lower in the group following the initial invasive approach compared to patients undergoing OMT (14.75% vs. 25.72%, p < 0.001). In contrast, the invasive strategy emerged as the preferred treatment modality for patients with ischemic LV systolic dysfunction. This approach demonstrated lower rates of all-cause mortality (40.61% vs. 46.52%, p = 0.004), CV death (28.75% vs. 35.82%, p = 0.0004), and MI (8.19% vs. 10.8%, p = 0.03). Conclusions: In individuals diagnosed with chronic CHD and preserved LV EF, the initial invasive approach did not demonstrate a clinical advantage over OMT. Conversely, in patients with ischemic LV systolic dysfunction, myocardial revascularization was found to reduce the risks of CV events and enhance the overall outcomes. These findings hold significant clinical relevance for optimizing treatment strategies in patients with chronic CHD, contingent upon myocardial contractility status. Full article

The aim of this systematic review was to answer the question of whether crack cocaine can induce cellular and molecular alterations and whether such alterations are somehow related to clinical lesions in the oral mucosa. The searches were undertaken in three electronic databases and conducted based on the PRISMA 2020 statement. Eleven studies published between 1994 and 2020 were analyzed. The quality of the included studies was assessed by two independent reviewers (TGP and DAR) through a confounder’s categorization methodology, in which final ratings were attributed (strong, moderate or weak) for each study. From 11 studies included, 7 evaluated the cellular/molecular impact of the addiction in a total of 492 individuals and compared to a control (non-exposure) group (n = 472). The main tests used for cellular alteration were MN and AgNORs. Cells from crack cocaine groups exhibited increased proliferation and MN counting. Only four studies evaluated the prevalence of oral lesions. All of them showed that individuals exposed to crack cocaine presented an increased number of oral lesions. Most studies showed good quality. In conclusion, our results demonstrate that crack use may induce changes at the cellular and molecular level and also exhibit an increased number of oral lesions. However, a correlation between such changes and oral mucosa lesions still needs further investigation and elucidation through other clinical studies in humans. Full article

The menisci increase the contact area of load bearing in the knee and thus disperse the mechanical stress via their circumferential tensile fibers. Traumatic meniscus injuries cause mechanical symptoms in the knee, and are more prevalent amongst younger, more active patients, compared to degenerative tears amongst the elderly population. Traumatic meniscus tears typically result from the load-and-shear mechanism in the knee joint. The treatment depends on the size, location, and pattern of the tear. For non-repairable tears, partial or total meniscal resection decreases its tensile stress and increases joint contact stress, thus potentiating the risk of arthritis. A longitudinal vertical tear pattern at the peripheral third red-red zone leads to higher healing potential after repair. The postoperative rehabilitation protocols after repair range from immediate weight-bearing with no range of motion restrictions to non-weight bearing and delayed mobilization for weeks. Pediatric and adolescent patients may require special considerations due to their activity levels, or distinct pathologies such as a discoid meniscus. Further biomechanical and biologic evidence is needed to guide surgical management, postoperative rehabilitation protocols, and future technology applications for traumatic meniscus injuries. Full article

The pathophysiology of myasthenia gravis (MG) has been largely elucidated over the past half century, and treatment methods have advanced. However, the number of cases of childhood-onset MG is smaller than that of adult MG, and the treatment of childhood-onset MG has continued to be based on research in the adult field. Research on pathophysiology and treatment methods that account for the unique growth and development of children is now desired. According to an epidemiological survey conducted by the Ministry of Health, Labour and Welfare of Japan, the number of patients with MG by age of onset in Japan is high in early childhood. In recent years, MG has been reported from many countries around the world, but the pattern of the number of patients by age of onset differs between East Asia and Western Europe, confirming that the Japanese pattern is common in East Asia. Furthermore, there are racial differences in autoimmune MG and congenital myasthenic syndromes according to immunogenetic background, and their pathophysiology and relationships are gradually becoming clear. In addition, treatment options are also recognized in different regions of the world. In this review article, I will present recent findings focusing on the differences in pathophysiology. Full article

It would be useful to develop a reliable method for the cuffless measurement of blood pressure (BP), as such a method could be made available anytime and anywhere for the effective screening and monitoring of arterial hypertension. The purpose of this study is to evaluate blood pressure measurements through a CardioQVARK device in clinical practice in different patient groups. Methods: This study involved 167 patients aged 31 to 88 years (mean 64.2 ± 7.8 years) with normal blood pressure, high blood pressure, and compensated high blood pressure. During each session, three routine blood pressure measurements with intervals of 30 s were taken using a sphygmomanometer with an appropriate cuff size, and the mean value was selected for comparison. The measurements were carried out by two observers trained at the same time with a reference sphygmomanometer using a Y-shaped connector. In the minute following the last cuff-based measurements, an electrocardiogram (ECG) with an I-lead and a photoplethysmocardiogram were recorded simultaneously for 3 min with the CardioQVARK device. We compared the systolic and diastolic BP obtained from a cuff-based mercury sphygmomanometer and smartphone-case-based BP device: the CardioQVARK monitor. A statistical analysis plan was developed using the IEEE Standard for Wearable Cuffless Blood Pressure Devices. Bland–Altman plots were used to estimate the precision of cuffless measurements. Results: The mean difference between the values defined by CardioQVARK and the cuff-based sphygmomanometer for systolic blood pressure (SBP) was 0.31 ± 3.61, while that for diastolic blood pressure (DBP) was 0.44 ± 3.76. The mean absolute difference (MAD) for SBP was 3.44 ± 2.5 mm Hg, and that for DBP was 3.21 ± 2.82 mm Hg. In the subgroups, the smallest error (less than 3 mm Hg) was observed in the prehypertension group, with a slightly larger error (up to 4 mm Hg) found among patients with a normal blood pressure and stage 1 hypertension. The largest error was found in the stage 2 hypertension group (4–5.5 mm Hg). The largest error was 4.2 mm Hg in the high blood pressure group. We, therefore, did not record an error in excess of 7 mmHg, the upper boundary considered acceptable in the IEEE recommendations. We also did not reach a mean error of 5 mmHg, the upper boundary considered acceptable according to the very recent ESH recommendations. At the same time, in all groups of patients, the systolic blood pressure was determined with an error of less than 5 mm Hg in more than 80% of patients. While this study shows that the CardioQVARK device meets the standards of IEEE, the Bland–Altman analysis indicates that the cuffless measurement of diastolic blood pressure has significant bias. The difference was very small and unlikely to be of clinical relevance for the individual patient, but it may well have epidemiological relevance on a population level. Therefore, the CardioQVARK device, while being worthwhile for monitoring patients over time, may not be suitable for screening purposes. Cuffless blood pressure measurement devices are emerging as a convenient and tolerable alternative to cuff-based devices. However, there are several limitations to cuffless blood pressure measurement devices that should be considered. For instance, this study showed a high proportion of measurements with a measurement error of <5 mmHg, while detecting a small, although statistically significant, bias in the measurement of diastolic blood pressure. This suggests that this device may not be suitable for screening purposes. However, its value for monitoring BP over time is confirmed. Furthermore, and most importantly, the easy measurement method and the device portability (integrated in a smartphone) may increase the self-awareness of hypertensive patients and, potentially, lead to an improved adherence to their treatment. Conclusion: The cuffless blood pressure technology developed in this study was tested in accordance with the IEEE protocol and showed great precision in patient groups with different blood pressure ranges. This approach, therefore, has the potential to be applied in clinical practice. Full article

Background: As the impacts of diabetes-induced reproductive damage are now evident in young people, we are now in urgent need to devise new ways to protect and enhance the reproductive health of diabetic people. The present study aimed to evaluate the protective effects of enalapril (an ACE inhibitor) and paricalcitol (a vitamin D analog), individually or in combination, on streptozotocin (STZ)-diabetes-induced testicular dysfunction in rats and to identify the possible mechanisms for this protection. Material and methods: This study was carried out on 50 male Sprague-Dawley rats; 10 normal rats were allocated as a non-diabetic control group. A total of 40 rats developed diabetes after receiving a single dose of STZ; then, the diabetic rats were divided into four groups of equivalent numbers assigned as diabetic control, enalapril-treated, paricalcitol-treated, and combined enalapril-and-paricalcitol-treated groups. The effects of mono and combined therapy with paricalcitol and enalapril on testicular functions, sperm activity, glycemic state oxidative stress, and inflammatory parameters, as well as histopathological examinations, were assessed in comparison with the normal and diabetic control rats. Results: As a result of diabetes induction, epididymal sperm count, sperm motility, serum levels of testosterone, follicle-stimulating hormone (FSH) as well as luteinizing hormone (LH), and the antioxidant enzyme activities, were significantly decreased, while abnormal sperm (%), insulin resistance, nitric oxide (NO), malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were significantly increased, along with severe distortion of the testicular structure. Interestingly, treatment with paricalcitol and enalapril, either alone or in combination, significantly improved the sperm parameters, increased antioxidant enzyme activities in addition to serum levels of testosterone, FSH, and LH, reduced insulin resistance, IL-6, and TNF-α levels, and finally ameliorated the diabetes-induced testicular oxidative stress and histopathological damage, with somewhat superior effect for paricalcitol monotherapy and combined therapy with both drugs compared to monotherapy with enalapril alone. Conclusions: Monotherapy with paricalcitol and its combination therapy with enalapril has a somewhat superior effect in improving diabetes-induced testicular dysfunction (most probably as a result of their hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic properties) compared with monotherapy with enalapril alone in male rats, recommending a synergistic impact of both drugs. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes autism, Asperger’s syndrome, and pervasive developmental disorder. ASD is characterized by poor interpersonal relationships and strong attachment. The correlations between activated or inactivated gene products, which occur as a result of genetic mutations affecting neurons in ASD patients, and ASD symptoms are now of critical concern. Here, for the first time, we describe the process in which that the respective ASD-associated mutations (Arg676-to-Cys [R676C] and Ser951-to-Cys [S951C]) of semaphorin-5A (Sema5A) localize Sema5A proteins themselves around the plasma membrane in the N1E-115 cell line, a model line that can achieve neuronal morphological differentiation. The expression of each mutated construct resulted in the promotion of excessive elongation of neurite-like processes with increased differentiation protein markers; R676C was more effective than S951C. The differentiated phenotypes were very partially neutralized by an antibody, against Plexin-B3 as the specific Sema5A receptor, suggesting that the effects of Sema5A act in an autocrine manner. R676C greatly increased the activation of c-Jun N-terminal kinase (JNK), one of the signaling molecules underlying process elongation. In contrast, the blocking of JNK signaling, by a chemical JNK inhibitor or an inhibitory construct of the interaction of RhoG with Elmo1 as JNK upstream signaling molecules, recovered the excessive process elongation. These results suggest that ASD-associated mutations of Sema5A, acting through the JNK signaling cascade, lead to excessive differentiated phenotypes, and the inhibition of JNK signaling recovers them, revealing possible therapeutic targets for recovering the potential molecular and cellular phenotypes underlying certain ASD symptoms. Full article

The objective of this study was to determine how housing temperature and genetic diversity affect the onset and severity of allogeneic T cell-induced tissue damage in mice subjected to reduced intensity conditioning (RIC). We found that adoptive transfer of allogeneic CD4⁺ T cells from inbred donors into sub-lethally irradiated inbred recipients (I→I) housed at standard housing temperatures (ST; 22–24 °C) induced extensive BM and spleen damage in the absence of injury to any other tissue. Although engraftment of T cells in RIC-treated mice housed at their thermo-neutral temperature (TNT; 30–32 °C) also developed similar BM and spleen damage, their survival was markedly and significantly increased when compared to their ST counterparts. In contrast, the adoptive transfer of allogeneic T cells into RIC-treated outbred CD1 recipients failed to induce disease in any tissue at ST or TNT. The lack of tissue damage was not due to defects in donor T cell trafficking to BM or spleen but was associated with the presence of large numbers of B cells and myeloid cells within these tissues that are known to contain immunosuppressive regulatory B cells and myeloid-derived suppressor cells. These data demonstrate, for the first time, that housing temperature affects the survival of RIC-treated I→I mice and that RIC-conditioned outbred mice are resistant to allogeneic T cell-induced BM and spleen damage. Full article

Prematurity is one of the most crucial risk factors negatively affecting the maturation of the auditory system. Children born preterm demonstrate high rates of hearing impairments. Auditory processing difficulties in preterm children might be a result of disturbances in the central auditory system development and/or sensory deprivation due to peripheral hearing loss. To investigate auditory processing in preterm children, we utilized a set of psychoacoustic tests to assess temporal processing and speech intelligibility. A total of 241 children aged 6–11 years old (136 born preterm and 105 healthy full-term children forming the control group) were assessed. The preterm children were divided into three groups based on their peripheral hearing status: 74 normal hearing (NH group); 30 children with bilateral permanent sensorineural hearing loss (SNHL group) and 32 children with bilateral auditory neuropathy spectrum disorder (ANSD group). The results showed significantly worse performance in all tests in premature children compared with full-term children. NH and SNHL groups showed significant age-related improvement in speech recognition thresholds in noise that might signify a “bottom-up” auditory processing maturation effect. Overall, all premature children had signs of auditory processing disorders of varying degrees. Analyzing and understanding the auditory processing specificity in preterm children can positively contribute to the more effective implementation of rehabilitation programs. Full article

Objective. To evaluate the effect of NO added to the sweep gas of the oxygenator during cardiopulmonary bypass (CPB) on the liver and kidneys in pigs. Methods. An experiment was carried out on 10 pigs undergoing cardiac surgery using CPB. NO was added to the sweep gas of the oxygenator at a concentration of 100 ppm for the animals in the experimental group (CPB-NO, n = 5). Animals in the control group (CPB-contr, n = 5) did not receive NO in the sweep gas of the oxygenator. The CPB lasted 4 h, followed by postoperative monitoring for 12 h. To assess the injury to the liver and kidneys, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL) were determined initially, at weaning from the CPB, and 6 and 12 h after weaning from the CPB. The glomerular filtration rate (GFR) was evaluated initially, at weaning from the CPB, and 6 and 12 h after weaning from the CPB. A pathomorphological study of the liver and kidneys was performed using semiquantitative morphometry. Results. The long four-hour period of CPB deliberately used in our experiment caused liver and kidney injury. In the CPB-contr group, an increase in the ALT concentration was found: 43 (34; 44) U/L at baseline to 82 (53; 99) U/L 12 h after CPB, p < 0.05. The AST concentration in the CPB-contr group increased from 25 (17; 26) U/L at baseline to 269 (164; 376) U/L 12 h after CPB, p < 0.05. We found no significant increase in the ALT and AST concentrations in the CPB-NO group. There were no significant differences in ALT and AST concentrations between the CPB-NO and CPB-contr groups at all the study time-points. In the CPB-contr group, an increase in the creatinine level was found from 131 (129; 133) µmol/L at baseline to 273 (241; 306) µmol/L 12 h after CPB, p < 0.05. We found no significant increase in creatinine level in the CPB-NO group. Creatinine levels in the CPB-NO group were significantly lower than in the CPB-contr group 12 h after weaning from CPB: 183 (168; 196) vs. 273 (241; 306) µmol/L; p = 0.008. The GFR in the CPB-NO group was significantly higher than in the CPB-contr group 6 h after weaning from CPB: 78.9 (77.8; 82.3) vs. 67.9 (62.3; 69.2) mL/min; p = 0.016. GFR was significantly higher in the CPB-NO group than in the CPB-contr group 12 h after weaning from CPB: 67.7 (65.5; 68.0) vs. 50.3 (48.7; 54.9) mL/min; p = 0.032. We found no significant differences between the study groups in the level of NGAL. We found several differences between the groups in the pathomorphological study. Conclusions. NO added to the sweep gas of the oxygenator reduces creatinine levels and increases GFR during prolonged CPB injury. Further research is required. Full article

Despite the efforts to deliver the best evidence-based care, in-hospital death is an inevitable event among some patients hospitalized in cardiology departments. We conducted a retrospective evaluation of mortality events from inpatient admissions to the cardiology department between 2010 and 2019. Data were collected from morbidity and mortality meeting presentations that evaluated comorbidities, medical history, treatments, and causes of death for the overall cohort and according to age group and sex. There were 1182 registered deaths. The most common causes of death among patients were acute myocardial infarction (AMI, 53.0%), heart failure (HF, 11.7%), cardiac arrest (CA, 6.6%), HF with complication/defined cardiomyopathy (6.3%), and sepsis (4.4%). We observed a decline in deaths from AMI from 61.9% in 2010 to 46.7% in 2019, while there was a clear increase in deaths from HF (11.1% in 2010 to 25.9% in 2019). Compared to patients ≥65 years, younger patients were more likely to have died from CA (15.7% vs. 4.3%, p < 0.001) and other cardiac reasons (3.0% vs. 0.4%, p < 0.001). The majority of deaths were due to AMI, HF, and CA. We observed a significant declining trend in the proportion of deaths due to AMI in recent years, with an increase in deaths due to HF. Full article

One of the primary challenges regarding chronic kidney disease (CKD) diagnosis is the absence of reliable methods to detect early-stage kidney damage. A metabolomic approach is expected to broaden the current diagnostic modalities by enabling timely detection and making the prognosis more accurate. Analysis performed on urine has several advantages, such as the ease of collection using noninvasive methods and its lower protein and lipid content compared with other bodily fluids. This review highlights current trends in applied analytical methods, major discoveries concerning pathways, and investigated populations in the context of urine metabolomic research for CKD over the past five years. Also, we are presenting approaches, instrument upgrades, and sample preparation modifications that have improved the analytical parameters of methods. The onset of CKD leads to alterations in metabolism that are apparent in the molecular composition of urine. Recent works highlight the prevalence of alterations in the metabolic pathways related to the tricarboxylic acid cycle and amino acids. Including diverse patient cohorts, using numerous analytical techniques with modifications and the appropriate annotation and explanation of the discovered biomarkers will help develop effective diagnostic models for different subtypes of renal injury with clinical applications. Full article