Search Results (2,876)

The respiratory tract is a dynamic biological interface where microbiome, environmental exposure, epithelial integrity, and host metabolic regulation converge to maintain pulmonary homeostasis. Once considered sterile, the lung is now recognized as a low-biomass yet structured microbial ecosystem that contributes to immune calibration, colonization resistance, epithelial barrier function, and tissue resilience. Disruption of this equilibrium, known as pulmonary dysbiosis, has been increasingly associated with acute and chronic lung diseases, including cystic fibrosis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, asthma, bronchiectasis, and lung cancer. In parallel, mitochondria have emerged as central regulators of pulmonary cell function, extending beyond ATP production to control redox signaling, apoptosis, innate immunity, epithelial repair, and inflammatory responses. This review examines the bidirectional crosstalk between the respiratory microbiome and mitochondria as an integrated pathogenic axis in lung disease. Dysbiotic microbial communities and respiratory pathogens can induce mitochondrial stress through toxins, virulence factors, microbial metabolites, and pattern-recognition receptor activation, leading to mitochondrial alteration and the release of mitochondrial damage-associated molecular patterns. Conversely, dysfunctional mitochondria reshape the pulmonary microenvironment by altering oxygen consumption, nutrient availability, cytokine production, redox balance, and barrier repair, thereby favoring pathogen persistence and chronic inflammation. Understanding mitochondria–microbiome interactions may support precision medicine strategies that integrate microbial, metabolic, inflammatory, and bioenergetic biomarkers to improve the diagnosis, prognosis, and treatment of inflammatory-related lung diseases. Full article

Background: Peyronie’s Disease (PD) is a complex andrological condition that severely compromises patients’ quality of life. While a novel formulation of hyaluronic acid (HA) has recently gained traction for treating the acute inflammatory phase, clinical evidence regarding its role in stable-phase (chronic) PD is lacking. We aimed to assess the therapeutic outcomes and safety profile of Perovial^®, a specialized HA formulation, in patients with stable disease. Methods: A cohort of 47 patients with stable-phase PD was treated at a single andrological center between June and December 2025. The treatment protocol consisted of eight weekly injections targeted around the tunica albuginea plaque. Clinical efficacy was assessed 3 months post-treatment by comparing baseline data with the following outcome measures: change in penile curvature (Δ°), the international index of erectile function (IIEF-5) score, Peyronie’s Disease Questionnaire (PDQ) and Global Assessment of Peyronie’s Disease (GAPD). Results: At the 3-month follow-up visit, a statistically significant improvement in penile curvature was registered in 35 out of 47 patients (Δ° − 16) (p < 0.001). All patients had a significant improvement from baseline in terms of IIEF (20 vs. 24; p < 0.001) and in all PDQ domains. No major adverse events or complications were observed during the study period. At the GAPD questionnaire, 43 patients (91.2%) reported subjective improvement of penile curvature. Conclusions: Perilesional injection of Perovial^® seems a promising intervention in patients with stable-phase PD in terms of penile curvature reduction and patient-reported quality of life improvement. Full article

Background: Safe treatment options for ulcerative colitis, a chronic relapsing inflammatory bowel disease, remain limited, and the bioactive fraction of Rosa davurica Pall. root associated with its protective activity against Ulcerative colitis (UC) has not been characterized. Methods: This study evaluated the protective effects of the total root aqueous extract (WRP) and two process-defined fractions prepared by ethanol precipitation: the supernatant fraction (SRP) and crude polysaccharide precipitate fraction (PRP). These fractions were administered concurrently with Dextran sulfate sodium (DSS) during acute colitis induction in mice. Assessments included disease activity index, colon histopathology, intestinal barrier proteins, RT-qPCR analysis, fecal metabolomics, 16S rRNA sequencing, and UHPLC-MS/MS. Results: Compared to PRP, SRP significantly alleviated DSS-induced weight loss, colon shortening, perianal bleeding, and histological injury. SRP also reduced the mRNA levels of TNF-α, IL-6, IL-1β, MPO, NF-κB, NLRP3, GSDMD, and IL-18. SRP treatment increased Claudin-1 and ZO-1 protein expression, whereas Occludin expression showed no significant change. SRP treatment was associated with shifts in fecal metabolic profiles and gut microbiota composition in DSS-treated mice, including a change in the Firmicutes/Bacteroidota ratio toward the CON group pattern. UHPLC–MS/MS profiling resulted in the tentative annotation of 68 nonredundant constituents in SRP. Conclusions: Under the present experimental conditions, SRP demonstrated protective activity in DSS-induced acute colitis and represents a potentially important bioactive fraction of the R. davurica root aqueous extract. Its protective effects were accompanied by reduced inflammatory gene expression, partial enhancement of barrier-associated protein expression, and alterations in gut microbiota composition and fecal metabolic profiles. Full article

Background/Objectives: Anthracycline-induced cardiotoxicity may compromise cancer treatment and long-term outcomes. Although differences in the cardiotoxicity profile of epirubicin and doxorubicin have been reported, direct comparative pharmacovigilance evidence remains limited. This study compared their cardiovascular adverse reaction reporting profiles using EudraVigilance (EV) data. Methods: Aggregated Individual Case Safety Reports submitted up to 12 July 2026 on the European portal were analyzed. Descriptive analyses assessed demographic characteristics, report origin, reporter type, System Organ Class distribution, seriousness, and clinical outcomes. Cardiotoxicity-related preferred terms (PTs) were identified using the Standardized MedDRA Queries “Cardiac failure”, “Cardiomyopathy”, and “Myocardial infarction”. Comparative disproportionality analysis was restricted to reports submitted by healthcare professionals. Reporting odds ratios and 95% confidence intervals were calculated for PTs with at least five reports for each drug. Results: Overall, 52,257 reports for doxorubicin and 31,049 for epirubicin were identified. Cardiac disorders were reported in 4459 doxorubicin cases and 1406 epirubicin cases, with over 97% classified as serious. Among 51 cardiotoxicity-related PTs, doxorubicin showed significantly higher reporting odds for cardiogenic shock, congestive, chronic, acute, and left ventricular cardiac failure, decreased ejection fraction, cardiomyopathy, cardiotoxicity, toxic cardiomyopathy, acute myocardial infarction, myocardial infarction, and increased troponin. The strongest disproportionality signals were observed for cardiogenic shock, toxic cardiomyopathy, cardiomyopathy, and cardiotoxicity. Conclusions: Doxorubicin was associated with a more pronounced pattern of cardiotoxicity-related reporting and disproportionality signals than epirubicin in the EV database. These findings highlight potential differences in the cardiovascular safety profiles of the two anthracyclines and provide signals that warrant further investigation, while underscoring the importance of cardiovascular risk assessment and monitoring in patients receiving anthracycline therapy. However, disproportionality signals do not establish incidence, absolute risk, or causality and require confirmation in prospective comparative studies. Full article

Carboplatin, a second-generation platinum-based therapy, is widely indicated for first-line treatment of selected solid tumors. Furthermore, it represents a well-established alternative to cisplatin in populations characterized by chronic kidney disease (CKD) or clinical frailty. The renal profile of carboplatin toxicity is most commonly linked to hypomagnesemia, and less frequently to acute kidney injury (AKI) or a persistent decline in GFR. While hypomagnesemia is the most frequent renal adverse effect, severe episodes that impact anticancer treatment are uncommon. Reductions in GFR carry significant clinical implications because they directly affect carboplatin dosing and drive cumulative hematologic toxicity that leads to adverse clinical events, which may be more relevant in older and sarcopenic patients. Carboplatin toxicity is highly dependent on systemic exposure and is quantified by the area under the concentration–time curve (AUC). Inaccurate estimation of GFR, particularly when using the Cockcroft–Gault (CG) equation, frequently leads to GFR overestimation and carboplatin overdose. Thus, precise dose adjustment according to GFR is of the utmost importance. In this review, we examine the renal complications associated with carboplatin, including the reported incidence and clinical patterns of kidney injury, with particular emphasis on dose-adjustment strategies based on GFR, encompassing patients with CKD and those receiving dialysis, as well as practical considerations for the prevention and management of carboplatin nephrotoxicity. Full article

Background/Objectives: α-Phellandrene (α-PHEL) is a monoterpene found in essential oils and is known for its antinociceptive and anti-inflammatory properties. This study investigated the antinociceptive effects of free α-PHEL and β-cyclodextrin-associated α-PHEL (α-PHEL/β-CD) in a Complete Freund’s adjuvant (CFA)-induced model of chronic inflammatory pain. Methods: Mechanical allodynia and hyperalgesia were evaluated in female Wistar rats using the von Frey and Randall–Selitto tests, respectively. Locomotor activity and motor performance were evaluated in male Swiss mice. Animals received α-PHEL (6.25–100 mg/kg) and α-PHEL/β-CD (3.12–12.5 mg/kg), as well as vehicle (2% Tween 80/0.9% saline) and dexamethasone (0.5 mg/kg, p.o.), with evaluations conducted in the von Frey test at intervals of 1 to 24 h. The antihyperalgesic effect was evaluated using α-PHEL, α-PHEL/β-CD, vehicle, and diclofenac (5 mg/kg, p.o.), with assessments in the Randall–Selitto test from 1 to 6 h. Over 10 days, the animals were treated and evaluated daily to determine the effect during repeated treatment. The involvement of the opioid pathway was assessed using naloxone, whereas the serotonergic pathway was investigated using PCPA and ketanserin in the von Frey test. Motor coordination was tested in the rotarod, and exploratory behavior was assessed in the open field. Results: α-PHEL reduced CFA-induced hyperalgesia and allodynia in both acute and chronic phases. The α-PHEL/β-CD preparation produced significant antinociceptive effects at all tested doses during repeated administration. Naloxone and 5-HT₂A receptor blockade reduced the antinociceptive effect of α-PHEL, while α-PHEL and the α-PHEL/β-CD preparation did not alter locomotor activity or motor coordination. Conclusions: The α-PHEL/β-CD preparation exhibits antinociceptive activity in inflammatory pain without affecting locomotor activity or motor coordination. The findings with free α-PHEL suggest the possible contribution of opioid and serotonergic pathways to its antinociceptive effect. Full article

Traumatic injury remains a critical global health challenge, with polytrauma frequently leading to multi-organ failure and mortality. A severe complication of polytrauma is acute kidney injury (AKI), which is driven by a massive systemic inflammatory response following the initial insult. This inflammation is exacerbated by the upregulation of phosphodiesterase 4 (PDE4) enzymes; therefore, PDE4 inhibition represents a rational therapeutic strategy. Roflumilast is an FDA-approved PDE4 inhibitor currently used for chronic obstructive pulmonary disease (COPD). This study evaluated the hypothesis that roflumilast can mitigate inflammation and prevent AKI in a polytrauma rat model. Anesthetized male Sprague–Dawley rats were randomly assigned to either a vehicle control group (n = 9) or a roflumilast treatment group (0.2 mg/kg, n = 10). All animals underwent a polytrauma protocol—including soft tissue injury, fibula fracture, and pressure-controlled hemorrhage—followed by whole blood resuscitation and a 72-h observation period. Rats treated with roflumilast demonstrated higher survival rates compared to injury controls (70% vs. 33%). Furthermore, roflumilast treatment significantly lowered blood urea nitrogen (BUN, p < 0.05) and renal levels of Kidney Injury Molecule-1 (KIM-1, p < 0.05). Roflumilast also significantly reduced levels of circulating High Mobility Group Box 1 (HMGB1) (p < 0.05) and the proinflammatory cytokine macrophage inflammatory protein-1 alpha (MIP-1α) (p < 0.05). These findings suggest that roflumilast is a promising therapeutic agent for mitigating trauma-induced AKI. Full article

Cardiovascular disease remains Europe’s leading cause of death and disability despite mature evidence for prevention, acute and chronic treatment, rehabilitation, and secondary prevention. This structured critical narrative review evaluates whether the European Safe Hearts Plan can convert this evidence into coordinated, measurable, and accountable cardiovascular pathways. We appraise the plan’s ten flagship actions by evidence maturity and implementation readiness; distinguish shared system functions from disease-specific delivery for acute coronary syndromes, heart failure, and atrial fibrillation; compare selected European Society of Cardiology and American Heart Association/American College of Cardiology recommendations; and propose a core indicator set and staged Cyprus pilot. Guideline-supported interventions should be standardised and audited, whereas screening technologies, digital health, artificial intelligence, and novel phenotyping require governed implementation and prospective assessment of patient outcomes, costs, equity, and unintended consequences. Cyprus is presented as a bounded implementation setting rather than a directly generalisable European model. The plan should be judged through a limited set of clinical, implementation, and equity indicators, including premature cardiovascular mortality, risk factor control, guideline-directed therapy, rehabilitation participation, registry completeness, reach, and fidelity. Full article

Background: Myocardial infarction (MI) causes spatially heterogeneous loss of contractility and progressive extracellular matrix remodeling, altering left ventricular mechanics from the acute phase through chronic remodeling. This review integrates current understanding of infarct, border-zone, and remote-myocardial microstructure with organ-scale mechanics and patient-specific computational modeling. Methods: A narrative review and perspective were conducted using the literature identified through PubMed/MEDLINE, Scopus, and Web of Science, supplemented by targeted searches of IEEE Xplore and Google Scholar. Experimental, imaging, computational, and translational studies were synthesised, with emphasis on post-MI constitutive behaviour, finite-element and growth-and-remodeling models, imaging-informed personalization, inverse parameter estimation, identifiability, model calibration, verification and validation, and uncertainty quantification. No quantitative synthesis was performed because of substantial heterogeneity in study populations, imaging modalities, constitutive formulations, boundary conditions, calibration procedures, and reported outcomes. Results: Contemporary post-MI models can reproduce ventricular volumes, regional strain patterns, and selected haemodynamic measures, while enabling counterfactual simulations of infarct stiffness, border-zone contractility, and loading interventions. However, clinically credible prediction remains constrained by limited in vivo observability of regional tissue properties, poor parameter identifiability, confounding between material properties and loading conditions, and incomplete treatment of measurement, parameter, and model-form uncertainty. Conclusions: The novelty of this review lies in framing post-MI patient-specific modeling as an identifiability- and uncertainty-limited inverse problem rather than solely as a model-fitting exercise. It proposes that translation toward decision-grade prediction requires parsimonious models aligned with a defined clinical context of use, constrained by microstructure-informed priors, multimodal pressure–volume–strain data, longitudinal validation, and routine reporting of parameter identifiability and predictive uncertainty. Full article

Periodontitis is a chronic dysbiotic inflammatory disease increasingly recognized as a contributor to systemic inflammatory burden and cardiovascular risk. Consensus and mechanistic literature support an association between periodontitis and atherosclerotic cardiovascular disease, while recent interventional evidence suggests that intensive periodontal treatment can improve endothelial function, reduce systemic inflammation and oxidative stress, and favorably influence the progression of carotid intima-media thickness. Among candidate mediators, interleukin-6 (IL-6) is especially compelling because it participates in local periodontal inflammation, hepatic acute-phase activation, endothelial dysfunction, oxidative stress, and the biology of atherosclerotic cardiovascular disease. CXCL10 has emerged as a relevant adjunctive chemokine because it is detectable in saliva, serum, gingival crevicular fluid, and inflamed periodontal tissues. In addition, it has also been implicated in atherosclerosis and adverse cardiac remodeling. Proteogenomic evidence suggests that CXCL10 may act as a potential downstream mediator of IL-6-associated signaling in atherosclerosis. Haptoglobin 2-2 (Hp2-2), while not itself a primary cytokine driver, may function as a host-susceptibility modifier, as the Hp2-2 phenotype has been associated with impaired hemoglobin scavenging, HDL dysfunction, endothelial dysfunction, oxidative vulnerability, and higher cardiovascular risk, particularly in dysglycemic states. This review proposes an IL-6-centered model linking chronic periodontal inflammation to cardiovascular risk, with CXCL10 positioned as an inflammatory recruitment amplifier and Hp2-2 as a genotype-defined modifier of vascular susceptibility. The translational implications of this framework for precision oral–systemic risk assessment, integration of salivary and blood-based biomarkers, and future biomarker-guided intervention studies are discussed. Full article

Background/Objectives: Severe arterial calcification remains a major challenge during femoropopliteal endovascular intervention, limiting luminal gain and increasing the risk of vessel-wall injury, restenosis, and bailout stenting. Pulsatile intravascular lithotripsy (PIVL) is a novel calcium-modification technology that converts pneumatic pulses into short-duration hydraulic pressure waves delivered through a non-compliant balloon. POWER PAD I evaluated the first-in-human feasibility, safety, and procedural performance of PIVL in calcified femoropopliteal arterial disease. Methods: POWER PAD I was a prospective, single-arm, two-center feasibility study. Adults with Rutherford category 2–4 symptomatic peripheral arterial disease and moderately or severely calcified superficial femoral or popliteal lesions were treated with PIVL, followed by adjunctive therapy when clinically indicated. Angiographic and duplex ultrasound outcomes were assessed by an independent core laboratory, and adverse events were adjudicated by an independent clinical events committee. Results: Nine patients underwent treatment of 20 lesions. Mean age was 76.2 ± 12.6 years, 19 lesions were severely calcified, and five lesions were chronic total occlusions. Patient-level device and procedural success were each achieved in 8 of 9 patients; technical success was achieved in all patients. Mean diameter stenosis decreased from 76.5 ± 18.0% before treatment to 28.1 ± 6.9% after PIVL-containing lesion preparation and before adjunctive drug-coated-balloon angioplasty, and to 20.6 ± 5.8% after adjunctive therapy. Mean minimal luminal diameter increased from 1.3 ± 1.0 mm to 3.8 ± 0.5 mm after PIVL-containing lesion preparation and to 4.3 ± 0.6 mm at final angiography. No perforation, distal embolization, thrombus, abrupt closure, no-reflow, bailout stenting, or grade D or higher dissection occurred. Freedom from clinically driven target-lesion revascularization was 100% at 30 days and 6 months. Conclusions: PIVL-containing lesion preparation was feasible in heavily calcified superficial femoral and popliteal lesions and was associated with substantial acute luminal gain before adjunctive DCB therapy and no severe angiographic complications. Favorable 6-month clinical and patency outcomes were observed after the combined treatment strategy of PIVL vessel preparation and adjunctive DCB therapy; therefore, longer-term outcomes cannot be attributed to PIVL alone. Larger controlled studies are warranted. Full article

Acute and chronic inflammation underlies the pathogenesis of numerous diseases, including autoimmune disorders, atherosclerosis, infections, and cancer. Although non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are widely used to control inflammation, their clinical utility is limited by adverse effects such as gastrointestinal toxicity and immunosuppression. Specialized pro-resolving mediators (SPMs), a family of endogenous lipid mediators derived from omega-3 fatty acids, have emerged as promising therapeutics because they actively promote the resolution of inflammation without suppressing host immunity. However, their clinical translation is hindered by poor chemical stability, rapid metabolic degradation, and short circulation half-lives. To overcome these limitations, a variety of delivery platforms—including liposomes, extracellular vesicles, PLGA nanoparticles, and hydrogels—have been developed to improve SPM stability, pharmacokinetics, and therapeutic efficacy. This review summarizes the cellular targets of SPMs, current delivery challenges, and emerging strategies for cell- and tissue-specific SPM delivery. We also discuss future opportunities for targeted SPM therapies in the treatment of inflammatory diseases and cancer. Full article

Background/Objectives: Anticoagulation in advanced chronic kidney disease (CKD) remains challenging due to limited representation in clinical trials, resulting in uncertainty regarding optimal drug selection, dosing, and monitoring strategies. Methods: We conducted a cross-sectional, web-based survey of clinicians involved in CKD care and anticoagulation prescribing. The questionnaire explored respondent characteristics, methods of renal function estimation, anticoagulant selection across common CKD scenarios, anticoagulants’ dosing and monitoring practices, and approaches to anticoagulation in nephrotic syndrome. Results: Fifty-seven clinicians participated in the survey. Unfractionated heparin was the preferred agent for venous thromboembolism (VTE) prophylaxis in patients with stage 4 and 5 CKD, or on dialysis. For acute VTE treatment, anticoagulant choice varied by CKD severity, with unfractionated heparin, direct oral anticoagulants (DOACs), and low-molecular-weight heparin (LMWH) all reported to be used depending on stages of CKD. Warfarin and DOACs were commonly used for treatment of chronic VTE and atrial fibrillation (AF), with warfarin more frequently selected in patients receiving dialysis. Apixaban was the most frequently reported DOAC, typically at a dose of 2.5 mg twice daily in advanced CKD and dialysis. Renal function estimation methods varied, with Cockcroft–Gault most used overall, while nephrologists more frequently reported MDRD or CKD-EPI equations. Most respondents reported not routinely monitoring DOAC levels, and the majority indicated the absence of a structured multidisciplinary team (MDT) for managing anticoagulated CKD patients. Clinical practice varied according to specialty, experience, and healthcare setting, particularly in anticoagulant selection, dosing strategies, and use of risk stratification tools. Conclusions: Anticoagulation practices in advanced CKD are highly heterogeneous, reflecting persistent evidence gaps. While unfractionated heparin and warfarin remain central in patients with stage 5 CKD or on dialysis, DOAC use—particularly apixaban—has expanded, often with empiric dose reduction. These findings underscore the need for clearer guidance, standardized approaches to renal function assessment, multidisciplinary care pathways, and prospective studies focusing on anticoagulation use in CKD populations. Full article

Background: Acute subdural hematoma (ASDH) and chronic subdural hematoma (ChSDH) differ substantially in their pathophysiology, clinical course, and outcomes. Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated in blood–brain barrier disruption, extracellular matrix remodeling, and inflammatory processes involved in both traumatic brain injury and ChSDH. However, direct comparisons of perioperative MMP profiles between ASDH and ChSDH and their relationships with clinical characteristics remain limited. The aim of this study was to compare perioperative MMP-2 and MMP-9 concentrations in patients with ASDH and ChSDH and explore their associations with selected clinically relevant parameters. Methods: Thirty patients undergoing surgical treatment for subdural hematoma were prospectively enrolled, including 10 patients with ASDH and 20 with ChSDH. Serum samples were collected before surgery and on postoperative day 3, and hematoma content was obtained intraoperatively. MMP-2 and MMP-9 concentrations were measured using enzyme-linked immunosorbent assay. Results: Patients with ASDH had significantly higher MMP-9 concentrations in hematoma content (p = 0.002) and postoperative serum (p = 0.029) than patients with ChSDH, whereas MMP-2 concentrations did not differ significantly between the groups. In the ChSDH group, both MMP-2 and MMP-9 concentrations were significantly lower in hematoma content than in preoperative and postoperative serum, while no significant perioperative changes were observed in patients with ASDH. Higher MMP-2 concentrations in hematoma content were associated with lower leukocyte counts and smaller midline shift, whereas higher hematoma MMP-9 concentrations were associated with lower APTT and CRP concentrations after FDR correction. These findings suggest distinct perioperative MMP-2 and MMP-9 profiles in acute and chronic subdural hematomas. Conclusions: This study provides a direct comparison of perioperative MMP-2 and MMP-9 profiles in serum and hematoma content between patients with ASDH and ChSDH while also exploring their associations with selected clinically relevant parameters. Full article

Background/Objectives: Kidney transplantation is the most effective treatment for pediatric patients with end-stage renal disease (ESRD), offering superior survival rates and quality of life compared to dialysis. However, long-term graft survival remains a complex clinical and surgical challenge. This systematic review aims to evaluate short- and long-term graft outcomes and comprehensively analyze the primary clinical, immunological, and procedural risk factors driving pediatric graft failure. Methods: A comprehensive search was conducted across the PubMed database, yielding 289 initial records. Following duplicate removal and systematic title and abstract screening, 108 full-text articles were evaluated for eligibility. Ultimately, 35 high-quality studies met the full inclusion criteria and were selected for final data synthesis and analysis. Results: Synthesized data revealed high short-term outcomes, with a 1-year graft survival rate of 94.60%. However, survival experienced a steady decline over time, dropping to 59.50% at the 10-year mark. Acute rejection episodes and delayed graft function (DGF) were identified as the primary immunological primary risk factors. Furthermore, specific donor characteristics, early surgical complications (such as vascular thrombosis), post-transplant infections affecting nearly 45% of patients, and adolescent non-adherence to immunosuppressive regimens were heavily associated with accelerated graft failure. Conclusions: While short-term success in pediatric kidney transplantation is highly encouraging, long-term graft longevity requires targeted clinical interventions. Optimizing outcomes necessitates precise, lifelong management strategies specifically focused on mitigating chronic rejection, preventing post-operative infections, and implementing multidisciplinary support systems to enhance patient adherence to immunosuppressive therapy. Full article