International journal of physiology, pathophysiology and pharmacology最新文献

Alpha-N-acetylgalactosaminidase (nagalase), a lysosomal enzyme encoded by the NAGA gene, plays a critical role in the degradation of glycoconjugates, modulation of immune responses, and regulation of vitamin D metabolism. Dysregulation of nagalase is associated with several pathological conditions, including Schindler disease, psychiatric disorders, viral infections, and notably, cancer. Elevated serum levels of nagalase, particularly the Naga6 isoform, have been observed in cancer patients and individuals with enveloped viral infections, contributing to immune evasion by impairing macrophage activation through Gc protein deglycosylation. Moreover, nagalase activity has been implicated in rare blood group changes observed in some malignancies. Although ELISA-based assays offer potential for quantifying nagalase, their clinical application is hindered by assay interferences and cross-reactivity. The immunotherapeutic potential of Gc protein-derived macrophage activating factor (GcMAF), in combination with vitamin D3 and ascorbate, has shown promise in enhancing anti-tumor immunity, particularly in prostate cancer. Nevertheless, conflicting data and methodological criticisms have led to skepticism regarding its efficacy. This review comprehensively explores the biochemical variants of nagalase, its physiological and pathological roles, its diagnostic utility as a biomarker, and emerging therapeutic strategies targeting its activity, including gene silencing and monoclonal antibody development. The findings underscore the need for rigorous clinical studies to validate the diagnostic and therapeutic potential of nagalase in oncology and immunology.

Background: The diagnosis and follow-up of Crohn's disease (CD) often require invasive instrumental examinations, which carry a high risk of iatrogenic injury. This study aimed to determine the frequency of ultrasound features in each stage of the Pediatric Crohn's Disease Activity Index (PCDAI).

Methods: This cross-sectional study included 22 pediatric patients with Crohn's disease. Disease activity was assessed using the PCDAI. The state of CD activity was categorized into four groups: remission (PCDAI scores less than 10), mild (PCDAI scores of 10-27.5), moderate (PCDAI scores of 30-37.5), and severe (PCDAI scores > 40). Clinical data collected included the thickness of the ascending colon loop, the thickness of the ileal loop, the number of lymph nodes, the short-axis diameter of lymph nodes (mm), spleen span, presence of free fluid, fistulas, liver echogenicity, vascularity around the loops, lumen narrowing, terminal ileum compression, mesenteric fat hypertrophy, intestinal wall and mesenteric fat echogenicity, and Superior Mesenteric Artery indices. These data were documented for analysis.

Results: As disease activity progressed from mild to severe, intestinal wall echogenicity, fat echogenicity, mesenteric fat, vascularity, and lumen narrowing significantly increased (P < 0.05). The mean ileal loop thickness also significantly increased (P = 0.005), rising from 2.12 ± 0.58 in mild cases to 4.49 ± 1.43 in severe cases. However, the mean ascending colon loop thickness, the number of lymph nodes, the short-axis diameter of lymph nodes, and spleen span were not statistically significant (P > 0.05). Changes in the superior mesenteric artery indices across the different PCDAI phases were also not statistically significant (P > 0.05).

Conclusions: Ultrasound is a convenient and reproducible tool for monitoring CD activity in pediatrics. This study demonstrated significant findings, including the increase in intestinal wall echogenicity, fat echogenicity, mesenteric fat hypertrophy, vascularity, and lumen narrowing as the disease activity progressed from mild to severe. Particularly, the mean ileal loop thickness showed a significant increase in the severe phase compared to the mild phase.

Effective management is one of the most important factors in mitigating postoperative endodontic pain (PEP). The purpose of this network meta-analysis was to compare the therapeutic effects and safety of different drugs commonly used for pain relief after non-surgical endodontic treatment. We searched the Scopus, PubMed, and Google Scholar databases until February 2024. Titles, abstracts, and full texts were identified according to predetermined criteria. Data were extracted from the selected publications, and a quality assessment was performed for the included studies. Sixteen RCTs with 2,021 participants were included in the meta-analysis. All included studies investigated the impact of NSAIDs on pain reduction in nonsurgical endodontic treatment. A statistically significant reduction in pain was observed at 8 h (pooled effect = -3.10, I² = 100%), 12 h (pooled effect = -1.69, I² = 99.2%), 24 h (pooled effect = -1.48, I² = 99.9%), 48 h (pooled effect = -1.42, I² = 99.4%), and 72 h (pooled effect = -0.64, I² = 73.1%) of follow-up. The funnel plot was symmetrical, and sensitivity analysis excluded one article in 72 h follow-up. Overall, this meta-analysis demonstrated that NSAIDs and corticostreoids are statistically effective in relieving pain after non-surgical endodontic treatment. However, owing to the significant differences between studies and heterogenicity, additional randomized controlled trials are needed to validate this correlation further.

Objectives: Clinically, liver regeneration is often impaired by infections causing endotoxemia, although mechanisms are unclear. Since energy supply is essential for liver regeneration, we assessed whether formoterol (FMT), a β₂-adrenergic agonist that increases peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), the master regulator of mitochondrial biogenesis (MB), restores liver regeneration after partial hepatectomy (PHX) in endotoxin (LPS)-treated mice.

Methods: Mice underwent sham-operation, two-thirds PHX, PHX with LPS injection (PHX+LPS, 5 mg/kg, i.p.), or PHX+LPS followed by FMT (0.1 mg/kg, i.p.) after 2 h.

Results: At 48 h after PHX, 5'-bromo-2'-deoxyuridine incorporation, mitotic cells, proliferating cell nuclear antigen, and cyclin-D1 markedly increased, signifying liver regeneration. By contrast, after PHX+LPS, liver regeneration was almost completely suppressed. FMT restored liver regeneration after PHX+LPS. PGC1α, mitochondrial transcription factor-A (controlling mitochondrial DNA replication/transcription), and mitochondrial oxidative phosphorylation proteins ATP synthase-β and NADH dehydrogenase-3 decreased after PHX+LPS, signifying suppressed MB. FMT largely reversed these effects. Mitochondrial oxidative stress stimulates inflammation by activating inflammasomes. In addition to promoting MB, PGC1α reportedly inhibits oxidative stress and inflammation. 8-Hydroxy-deoxyguanosine, NLRP3, and inflammatory cytokines increased after PHX+LPS, demonstrating increased oxidative stress and inflammasome activation. Many necro-inflammatory foci occurred in liver sections after PHX+LPS. FMT increased expression of antioxidant protein thioredoxin-2, decreased oxidative stress, and blunted inflammatory responses. Additionally, FMT decreased alanine aminotransferase release and necrosis caused by PHX+LPS.

Conclusions: FMT restores liver regeneration during endotoxemia and decreases liver injury and inflammation, most likely by increasing PGC1α. Therefore, FMT is a promising therapy for liver failure caused by loss of liver mass complicated with sepsis.

Cardiomyopathy associated with amphetamine-dextroamphetamine (Adderall) use is an emerging and under-recognized clinical concern, particularly in the context of chronic stimulant exposure. While most reported cases involve non-ischemic myocardial dysfunction, the potential for Adderall to accelerate atherosclerosis and contribute to ischemic cardiomyopathy remains unexplored. This case report aims to document the potential severity of Adderall-induced cardiomyopathy with concomitant coronary artery disease (CAD), examine the pathophysiological link between chronic stimulant exposure and accelerated atherosclerosis, and emphasize the need for vigilant cardiovascular monitoring in patients on long-term stimulant therapy. We report the case of a 43-year-old man with no known cardiovascular history who presented with progressive dyspnea and signs of heart failure. He disclosed a five-year history of high-dose Adderall use (45-65 mg daily) and tobacco consumption but had no prior history of hypertension, diabetes, or known CAD. Evaluation revealed a severely reduced left ventricular ejection fraction (10-15%), consistent with dilated cardiomyopathy. Coronary angiography unexpectedly revealed severe three-vessel CAD, necessitating urgent coronary artery bypass grafting (CABG). Postoperative recovery was uneventful, and the patient was initiated on guideline-directed heart failure therapy, with structured follow-up and strict recommendations for stimulant cessation and lifestyle modification. This case illustrates the multifactorial cardiotoxicity of chronic Adderall use, including direct myocardial injury, fibrotic remodeling, vasospasm, and accelerated coronary atherosclerosis. Unlike prior reports of reversible non-ischemic cardiomyopathy, this case required surgical revascularization, underscoring the irreversible nature of the damage in some patients. It uniquely highlights the synergistic contribution of stimulant-induced toxicity and underlying CAD to the development of severe cardiac dysfunction.

Sarcopenia is an age-associated progressive deterioration of skeletal muscle, not only affecting the muscle function of elderly individuals but also contributing to various health issues and increased mortality. Current diagnostic tools are faced with limitations, hindering their widespread clinical application. This review examines the potential of myokines, peptides released from contracting muscles, as innovative biomarkers for sarcopenia. We explore the wide range of auto-, para-, and endocrine functions of myokines and the pathways of their physiological action, as well as address ongoing research results on the role of myokines as biomarkers for the timely diagnosis of sarcopenic individuals. Of all myokines, the ones that show the highest potential include irisin, myostatin, follistatin and brain-derived neurotrophic factor (BDNF). Their physiological action is exerted through complex pathways involving multiple molecules. Most studies show that these molecules can be used as biomarkers for the timely diagnosis of sarcopenia, whether by using each one individually or as a panel of biomarkers. However, several studies showed no correlation between the plasma levels of these peptides and a sarcopenia diagnosis. Finally, a number of studies also exhibited gender-affected relationships. While the quality of studies is promising, research on the use of myokines as biomarkers of sarcopenia is needed to more accurately determine the cut-off plasma values of such markers. By overcoming the shortcomings of existing methodologies, utilizing myokines in daily clinical practice could offer a promising path toward more effective prevention, diagnosis, and treatment strategies, ultimately improving outcomes for the aging population.

Cardiac amyloidosis (CA) is a challenging acquired heart disease caused by the deposition of β-pleated amyloid proteins, often leading to nonspecific symptoms that complicate the diagnosis. This case report describes an 83-year-old male patient presenting with chest pain and cough, revealing significant cardiomegaly and pericardial effusion on imaging. Initial diagnostic modalities, including echocardiography and endomyocardial biopsy (EMB), have yielded inconclusive results. Despite a negative EMB result, further investigation using positron emission tomography/computed tomography ruled out cardiac sarcoidosis. A second EMB was performed to confirm the diagnosis of CA. This case underscores the importance of combining clinical symptoms with paraclinical assessments and advocating additional testing when discrepancies arise, highlighting the complexities in diagnosing CA. This case report emphasizes the necessity for clinicians to integrate clinical symptoms with diagnostic findings when assessing for cardiac amyloidosis. This illustrates the potential for false-negative biopsies and the importance of considering further testing to ensure an accurate diagnosis, ultimately enhancing diagnostic accuracy and patient management in cases of suspected cardiac amyloidosis.

Background: Type 2 diabetes mellitus (T2DM) increases the risk of fractures. This meta-analysis compared the effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i) on fracture risk in patients with T2DM.

Method: A systematic search of PubMed, Web of Science, Embase, and Google Scholar was conducted up to August 6, 2023. Seven cohort studies (n = 1,199,267 participants at baseline; n = 357,119 after propensity matching) comparing SGLT-2i use with DPP-4i use and reporting fracture outcomes were included. Data were extracted and analyzed using a random-effects model. Subgroup analyses were performed by age (<70 and ≥70 years) and sex.

Results: In general, SGLT-2i therapy was linked to reduced fracture risk when compared to DPP-4i (OR: 0.89, 95% CI: 0.81-0.98). Heterogeneity was high (I² = 64.3%). Upon stratified analysis by age, no statistically significant difference was observed between the fracture risk in the <70 years and ≥70 years subgroups upon comparison of SGLT-2i with DPP-4i. No significant difference was also observed in the female subgroup.

Conclusion: This meta-analysis indicates SGLT-2i therapy could be linked with reduced overall fracture risk in comparison to DPP-4i in the general population of T2DM. The benefit was not seen in subgroup analysis based on age and sex. Additional research, ideally with increased cases within subgroups, is required to determine the impact of these drugs on fracture risk in patient subgroups.

Background: "Laterality", or "lateral preference" indicates how differently or rather 'differentially' one tends to use a pair of sense organs or limbs. The most widely studied aspect of laterality is handedness. However, research on footedness has not received the same level of attention. Previous studies primarily relied on questionnaires to determine limb dominance, which may not provide the most accurate assessments. The present study aims to generate reliable objective data regarding both upper and lower limb dominance by analyzing surface electromyography (sEMG) parameters. Additionally, it seeks to correlate these findings with perceived limb dominance as indicated by questionnaire responses.

Methods and material: It was a cross-sectional observational study. The physiological parameters were recorded in the Clinical Physiology Laboratory. 20 male, healthy participants of 19-20 years participated in the study voluntarily. After recording of their demographic data, the study participants were assessed twice to ascertain the dominance of both upper and lower limbs. At first, they responded to the study questionnaires to report self-determined dominance of upper and lower limbs. Following this, the performance of both upper and lower limbs was evaluated by recording of surface EMG of specific muscles of the limbs at rest and during sustained contraction using a pre-defined load till the onset of fatigue. On the basis of normality test, the data were expressed as median with interquartile range. Wilcoxon signed rank test was performed to compare the parameters of sEMG. SPSS software version 20.0 (IBM Inc., USA) was used to analyse the data. A two-tailed P value less than 0.05 was taken as the cut-off level of significance.

Results: Based on questionnaire analysis, out of 20 participants, one was left-handed and the rest were right-handed. Six participants were found to use both legs and the rest were right leg dominant. Following analysis, no significant difference between the parameters of surface EMG (sEMG) of the corresponding muscles of the two upper and lower limbs was found. Even no significant difference between the time to set fatigue in right and left upper and lower limbs was observed.

Conclusions: The result of the present study indicates that the dominant and the non-dominant limbs have attained differences in such a manner that it has not affected their performances significantly. However, their different, though sometimes overlapping aspects of motion and movements is helpful for the performance of a given task.

Radiopharmaceutical therapy (RPT) is an advanced targeted cancer treatment that delivers radiation through specialized radiolabeled compounds to selectively destroy cancer cells while minimizing damage to healthy tissues. This theranostic approach integrates diagnosis and therapy, enhancing treatment precision and improving the therapeutic index compared to conventional chemotherapy. RPT agents consist of a radioactive isotope conjugated to a targeting molecule, enabling specific binding to cancer-associated antigens or receptors. Upon binding, these agents induce cell death through DNA damage caused by ionizing radiation. The choice of radionuclide, including beta and alpha emitters, plays a crucial role in determining therapeutic efficacy and potential side effects. This study aims to provide a comprehensive analysis of RPT, focusing on its mechanisms of action, clinical applications, and emerging challenges. We discuss the therapeutic potential of various radionuclides and highlight key clinical trials demonstrating efficacy across different malignancies. Additionally, we address critical issues such as optimizing delivery systems, managing radiotoxicity, and refining the dose-response relationship. Future directions include the development of novel radiopharmaceuticals and personalized treatment approaches. Further investigation is essential to overcome existing limitations and maximize the clinical benefits of RPT for patients with advanced cancers. Our findings contribute to a deeper understanding of RPT and offer insights into strategies for improving therapeutic outcomes and patient care.