Search Results (69)

Background/Objectives: Asprosin is the endogenous ligand of the olfactory Olfr734 receptor linked to MASLD and glucose metabolism. Despite the involvement of asprosin in these processes, little has been published on the specific role of Olfr734 in liver function. The aim of this work is therefore to study the specific role of the olfactory Olfr734 receptor in MASLD and glucose metabolism. Methods: To achieve this objective, we performed a genetic inhibition specifically to inhibit Olfr734 in the livers of male mice. We then studied the progression of MASLD in DIO mice. In addition, we studied the glucose metabolism in hypoglycemia states and postprandial glucose production in standard diet-fed mice. Finally, analyses of liver biopsies from patients with obesity and with or without T2DM were conducted. Results: We found that hepatic Olfr734 levels vary according to changes in nutritional status and its knockdown effect in the liver is to increase the hepatic lipid content in DIO mice. Our results also showed that OLFR734 expression is involved in the adaptive response in terms of glucose production to nutrient availability. Finally, the hepatic human Olfr734 ortholog named OR4M1 has been observed to be at significantly higher levels in male patients with T2DM. Conclusions: This study increases understanding of the mechanisms by which the modulation of Olfr734 expression affects liver function. Full article

Background: Protein carbonylation is an irreversible post-translational modification that is considered indicative of oxidative damage. Objective: The purpose of the study was to examine by an immunohistochemical method for the first time the extent and localization of protein carbonylation in biopsies of gingiva from periodontitis patients with or without diabetes mellitus (DM). Methods: These were processed for immunohistochemical staining of the carbonylated proteins, using the ENVISIOM FLEX Mini Kit, high pH, and anti-dinitrophenyl (DNP) antibody, a marker of oxidative damage to a given protein. The extent of protein carbonylation was semi-quantitatively estimated and evaluated by calculation of the Allred score (percentage of stained cells × intensity of staining). Results: The biopsies from periodontitis patients with diabetes mellitus (DM) exhibited higher staining scores as per the percentage of positively stained cells than the biopsies from patients with only periodontitis (means of 49.2 and 16.7, respectively), the difference being statistically significant (p = 0.036). The same trend was observed in the case of the combination of the above with the intensity of staining (score parameter) as well (means of 59.6 and 20.8, p = 0.036, respectively). Conclusions: An immunohistochemical method with the novelty of utilization for the first time of the anti-dinitrophenyl (DNP) antibody in gingival tissues was introduced and showed efficacy in detecting protein carbonylation indicative of oxidative stress and its impact in the pathogenesis of these two prevalent diseases of periodontitis and diabetes mellitus. Full article

Background and Objectives: The aim of our study was to assess the diagnostic accuracy of four imaging modalities—digital mammography (DM), digital breast tomosynthesis (DBT), ultrasound (US), and breast magnetic resonance imaging (MRI)—applied individually and in combination in early cancer detection in women with dense breasts. Methods: This single-center retrospective study was conducted from January 2021 to September 2024 at the Oncology Institute of Vojvodina in Serbia and included 168 asymptomatic and symptomatic women with dense breasts. Based on the exclusion criteria, the final number of women who were screened with all four imaging methods was 156. The reference standard for checking the diagnostic accuracy of these methods is the result of a histopathological examination, if a biopsy is performed, or a stable radiological finding in the next 12–24 months. Results: The findings underscore the superior diagnostic performance of breast MRI with the highest sensitivity (95.1%), specificity (78.7%), and overall accuracy (87.2%). In contrast, DM showed the lowest sensitivity (87.7%) and low specificity (49.3%). While the combination of DM + DBT + US demonstrated improved sensitivity to 96.3%, its specificity drastically decreased to 32%, illustrating as ensitivity–specificity trade-off. Notably, the integration of all four modalities increased sensitivity to 97.5% but decreased specificity to 29.3%, suggesting an overdiagnosis risk. DBT significantly improved performance over DM alone, likely due to enhanced tissue differentiation. US proved valuable in dense breast tissue but was associated with a high false-positive rate. Breast MRI, even when used alone, confirmed its status as the gold standard for dense breast imaging. However, its widespread use is constrained by economic and logistical barriers. ROC curve analysis further emphasized MRI’s diagnostic superiority (AUC = 0.958) compared with US (0.863), DBT (0.828), and DM (0.820). Conclusions: This study provides a unique, comprehensive comparison of all four imaging modalities within the same patient cohort, offering a rare model for optimizing diagnostic pathways in women with dense breasts. The findings support the strategic integration of complementary imaging approaches to improve early cancer detection while highlighting the risk of increased false-positive rates. In settings where MRI is not readily accessible, a combined DM + DBT + US protocol may serve as a pragmatic alternative, though its limitations in specificity must be carefully considered. Full article

Background/Objectives: Epicardial adipose tissue (EAT) is metabolically active and is in dynamic crosstalk with the surrounding cardiomyocytes, modulating their function and metabolism. Oxidative stress is a key contributor to cell death and cardiac remodeling, is a hallmark of diabetes (DM) and cardiovascular disease, such as coronary artery disease (CAD). However, little is known about these processes in EAT from patients undergoing cardiac surgery. This study investigates changes in mitochondrial dynamics, reactive oxygen species (ROS) production, and antioxidant defense levels in EAT compared to subcutaneous adipose tissue (SAT) in patients undergoing cardiac surgery, with a focus on the impact of DM and CAD. Methods: Adipose tissue biopsies were collected from 128 patients undergoing surgical cardiac intervention. Mitochondrial dynamics and oxidative stress markers were analyzed. Results: EAT exhibited increased expression of mitochondrial fusion markers [mitofusin 1 (p ≤ 0.001), mitofusin 2 (p = 0.038), and optic atrophy 1 (p ≤ 0.001)], as well as fission markers [fission 1 (p ≤ 0.001) and dynamin-related protein 1 (p ≤ 0.001)] relative to SAT. Additionally, ROS levels (dihydroethidium, p = 0.004) were elevated, while lipid peroxidation (malondialdehyde, p ≤ 0.001) was reduced in EAT compared to SAT. Reduced glutathione (GSH) levels (p ≤ 0.001) and the redox buffer ratio between reduced and oxidized glutathione (GSH/GSSG, p ≤ 0.001) were significantly increased in EAT. Interestingly, glutathione peroxidase activity (p ≤ 0.001) and the antioxidant defense markers catalase (p ≤ 0.001) and superoxide dismutase 2 (p = 0.001) were significantly reduced in EAT compared to SAT. Conclusions: The findings provide a unique molecular insight into the mitochondrial dynamics and oxidative stress profiles of EAT, highlighting potential avenues for a novel diagnostic method and therapeutic strategies for cardiac disease. Full article

Background: Wolfram syndrome (WFS), also known as DIDMOAD, is a rare monogenic neurodegenerative disorder characterized by four key components: non-autoimmune insulin-dependent diabetes mellitus (DM), optic atrophy, sensorineural hearing loss, and diabetes insipidus. Although it significantly affects quality of life, gonadal dysfunction, particularly hypogonadism, remains underrecognized. Methods: In total, 45 patients (25 men, 20 women) with genetically confirmed WFS from a single tertiary-care center were prospectively followed to assess gonadal function. Men underwent hormonal evaluations, semen analysis, imaging tests, and testicular biopsies. In women, data on age at menarche, menstrual irregularities, and age at menopause were recorded. Hormonal analyses, including anti-Müllerian hormone (AMH) levels, and imaging tests were also conducted. Results: Hypogonadism was identified in 19 men (76.0%), of whom 17 (68.0%) had hypergonadotropic hypogonadism and 2 (8.0%) had hypogonadotropic hypogonadism. Testicular biopsies showed seminiferous tubule damage, Sertoli cell predominance, and reduced Leydig cells. Azoospermia was observed in 12 patients, whereas others presented with oligozoospermia, teratozoospermia, or asthenozoospermia. Most patients exhibited low testosterone levels along with elevated LH and FSH, suggesting primary testicular failure, except for two cases of hypogonadotropic hypogonadism. Correlations between biomarkers, onset age and severity have been analyzed and provide important insights regarding medical treatment. In women, menstrual irregularities were universal, with 20% experiencing premature menopause. Four patients had low AMH levels, with ovarian atrophy in three and a postmenopausal uterus in two, indicating early hypogonadism risk. Conclusions: Gonadal dysfunction is a significant yet overlooked feature of WFS, requiring systematic evaluation during puberty and beyond. Proper management is essential to mitigate metabolic disturbances and psychological impacts, including infertility distress, relationship challenges, and quality of life concerns. Addressing sexual health is crucial as WFS patients live longer and aspire to establish relationships or start families. Full article

Background/Objectives: The possibility of progressive liver fibrosis remains even when alanine aminotransferase (ALT) levels are <30 IU/L. Therefore, we aimed to investigate factors that can predict fibrosis progression in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) with ALT levels ≤ 30 U/L. Methods: This multicenter retrospective cohort study was conducted using data collected between December 1994 and December 2021. Among the 1381 patients with MASLD (CLIONE study) who underwent liver biopsy, we performed decision-tree analysis on factors for stage ≥ 3 in 115 with ALT levels ≤ 30 U/L. Of the 818 patients with MASLD (Kawasaki cohort) who underwent liver biopsy, we included 174 with ALT levels ≤ 30 U/L for validation. Results: In the decision-tree analysis of patients with stage ≥ 3 with ALT levels ≤ 30 U/L, 57% of patients with a fibrosis-4 (FIB-4) index ≥ 2.67 and 70% with both FIB-4 index ≥ 2.67 and type-2 diabetes mellitus (DM) were detected. However, no cases of stage ≥ 3 were observed among patients without type-2 DM with ALT ≤ 30 U/L and a FIB-4 index < 2.67. After verifying the decision-tree analysis, the model construction and validation datasets showed a close correlation. Conclusions: Among patients with MASLD with ALT levels ≤ 30 U/L, those with an FIB-4 index ≥ 2.67, particularly with comorbid type-2 DM, should consider consultation with a hepatologist. Full article

A 71-year-old Caucasian woman presented with lesions on both elbows. A physical examination revealed arcuate plaques with raised erythematous edges and central clearing. Comedones and cysts were evident on the border of the lesions. The dermatoscopic view showed the presence of pores, in addition to granuloma annulare changes. The biopsies showed changes according to granuloma annulare, but the granulomas were closely related to comedones and cysts. Furthermore, the presence of elastophagocytosis via multinucleated Langhans-type giant cells was evident. Verhoeff–van Gieson staining highlighted the transepithelial elimination of elastic fibers in the bottom of some cysts. The presence of comedones or cysts is exceptional in granuloma annulare. Only four similar cases have been reported. Although all previous cases showed lesions in sun-exposed areas over photodamaged skin, only our case showed transepithelial elimination of elastic fibers. Diabetes mellitus (DM) could play a role in the pathogenesis of this variant of actinic granuloma annulare, because most cases are associated with uncontrolled DM and the lesions improve after DM is controlled. Full article

Background: Hydroxyurea (HU) is a widely used chemotherapeutic agent for myeloproliferative disorders, yet its long-term use can rarely trigger a dermatomyositis-like (DM-like) eruption characterized solely by cutaneous manifestations without muscle involvement or serologic markers. This study presents a case of HU-induced DM-like eruption and reviews the literature regarding this rare occurrence. Methods: A 77-year-old woman with polycythemia vera on long-term HU therapy developed a progressively worsening, erythematous, scaly, and crusted eruption on the face, neck, and anterior thorax. Comprehensive clinical evaluations, laboratory tests (including normal muscle enzymes and negative autoimmune panels), and skin biopsies were performed. In parallel, a systematic literature review was conducted using databases such as PubMed, Scopus, and Google Scholar, incorporating case reports and series published prior to January 2025 that provided detailed individual clinical data. Results: The patient exhibited hallmark DM-like cutaneous features—interface dermatitis with basal vacuolar degeneration and prominent dermal mucin deposition—without evidence of muscle weakness or positive myositis-specific antibodies. The literature review of 23 cases revealed a median latency of 5 years from HU initiation to skin eruption, with the dorsal hands most frequently affected. HU discontinuation, often combined with systemic and topical corticosteroids (and, in some cases, steroid-sparing agents), resulted in lesion resolution in over 90% of cases, with a median healing time of approximately 3 months. Conclusions: HU-induced DM-like eruption, though infrequent, is a distinct clinical entity requiring prompt recognition and management. The main treatment is the discontinuation of HU, which, when supplemented by appropriate corticosteroid therapy, leads to significant clinical improvement. Ongoing dermatologic surveillance is recommended for patients on long-term HU therapy due to the potential risk of premalignant skin changes. Full article

The link between cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD) is well-established at both the epidemiological and pathophysiological levels. Among the common pathophysiological mechanisms involved in the development and progression of both diseases, oxidative stress and inflammation, insulin resistance, lipid metabolism deterioration, hepatokines, and gut dysbiosis along with genetic factors have been recognized to play a pivotal role. Pharmacologic interventions with drugs targeting common modifiable cardiometabolic risk factors, such as T2DM, dyslipidemia, and hypertension, are a reasonable strategy to prevent CVD development and progression of MASLD. Recently, a novel drug for metabolic dysfunction-associated steatohepatitis (MASH), resmetirom, has shown positive effects regarding CVD risk, opening new opportunities for the therapeutic approach of MASLD and CVD. This review provides current knowledge on the epidemiologic association of MASLD to CVD morbidity and mortality and enlightens the possible underlying pathophysiologic mechanisms linking MASLD with CVD. The role of cardiometabolic drugs such as anti-hypertensive drugs, hypolipidemic agents, glucose-lowering medications, acetylsalicylic acid, and the thyroid hormone receptor-beta agonist in the progression of MASLD is also discussed. Metformin failed to prove beneficial effects in MASLD progression. Studies on the administration of thiazolinediones in MASLD suggest effectiveness in improving steatosis, steatohepatitis, and fibrosis, while newer categories of glucose-lowering agents such as GLP-1Ra and SGLT-2i are currently being tested for their efficacy across the whole spectrum of MASLD. Statins alone or in combination with ezetimibe have yielded promising results. The conduction of long-duration, large, high-quality, randomized-controlled trials aiming to assess by biopsy the efficacy of cardiometabolic drugs to reverse MASLD progression is of great importance. Full article

Nasopharyngeal carcinoma (NPC) with paraneoplastic dermatomyositis (DM) is an exceptionally rare clinical phenomenon, particularly among European populations. This case report details a 46-year-old woman initially diagnosed with DM, later confirmed to have NPC. Such an association is more frequently documented in Asian populations, highlighting its unique presentation in this case. The patient first developed symptoms in December 2016, which progressed significantly by spring 2017, manifesting as progressive proximal muscle weakness, characteristic skin changes, and elevated muscle enzyme levels. Diagnostic workup, including electromyography and biopsy, confirmed DM. Persistent symptoms and secondary DM suspicion prompted further malignancy screening, which identified undifferentiated NPC with strong Epstein–Barr virus RNA positivity. Multimodal treatment comprising corticosteroids, hydroxychloroquine, chemotherapy, and radiotherapy led to temporary symptomatic improvement. Despite initial success, the patient’s condition deteriorated, and she passed away by the end of 2018. This case underscores the importance of comprehensive malignancy screening in DM patients, considering rarer cancers like NPC even in non-endemic regions. It emphasizes the role of multidisciplinary care and adherence to international guidelines for managing such complex cases. Recognizing NPC-associated DM remains critical for early intervention and tailored therapeutic approaches to improve clinical outcomes and survival. Full article

Acquired reactive perforating dermatosis (ARPD) is characterized by its onset after the age of 18 years, umbilicated papules or nodules with a central keratotic plug, and the presence of necrotic collagen tissue within an epithelial crater. ARPD is strongly associated with systemic diseases such as diabetes mellitus (DM) and chronic renal failure, which may contribute to ARPD through factors including microcirculatory disturbances and the deposition of metabolic byproducts, including advanced glycation end-products and calcium. Here, we report a case of ARPD that improved following DM treatment and catheter-based interventions for peripheral artery disease (PAD). The eruptions on the upper limbs significantly improved with DM management. On the other hand, lesions on the lower limbs showed marked improvement after the enhancement in arterial blood flow due to catheter surgeries, along with DM treatment. Although a few reports of ARPD improving with DM management exist, our case underscores the importance of adequate DM control in ARPD management. The inability to perform the biopsy of the lesions on the lower limbs is our limitation; however, these lesions, similar to those on the upper limbs, presented with a central keratotic plug and re-epithelialized without forming ulcers or erosions, suggesting they were also related to ARPD. To date, there has been little discussion on the relationship between blood flow impairment in major vessels and ARPD. However, hypertension and venous circulatory dysfunctions are considered to lead to ARPD, raising the possibility that PAD-induced microvascular disturbances might have facilitated lesion formation in the present case. Further accumulation of cases and research is needed to clarify the relationship between blood flow impairment in major vessels and ARPD. Full article

Introduction: The most frequent local complication of insulin injection is the occurrence of subcutaneous nodules due to incorrect injection technique. Injection into nodules negatively impacts metabolic compensation and the requirement for greater insulin doses due to its partial and erratic absorption. Despite these concepts being accepted by the scientific community, it is not yet clear whether injection into nodules is causally related to worsening chronic diabetes (DM) complications and the morphological nature of such nodules. Aim: This multicenter study aimed to evaluate the associations between structural characteristics of skin nodules and chronic DM complications. A secondary endpoint was to evaluate the histological structure of those nodules, looking for differences between lipohypertrophies (LH) and amyloid nodules (LIDA). Methods: For this purpose, 816 DM patients with LH and 1033 without LH underwent a clinical and ultrasound study comparing metabolic data, injection habits, and frequency of complications. Excisional biopsies of the skin nodules were performed in a small series of eight subjects. Results: Data observed confirm a strong relationship between LH and diabetes chronic complications other than poor glycemic control. Histology of biopsies from the skin nodules showed mild foreign-body-like inflammation, prevailing mega-adipocytes (65%), apoptosis, and fibrosis but could not detect any amyloid fibrils. In four cases, intra-nodular fluid was present with an insulin concentration several times higher than in blood. Conclusions: We confirmed LHs to be significantly associated with insulin administration errors, duration of insulin therapy, greater daily doses and duration of insulin administration, and the presence of micro- and macro-vascular DM complications. LH nodules displayed no typical morphological features and were indistinguishable from LIDA nodules with which they shared several histologic similarities, albeit within the frame of a general picture of LIDA inhomogeneity. Further targeted studies are warranted to clarify the remaining doubts. Full article

Background: Lupus podocytopathy (LP) is a non-immune complex-mediated glomerular lesion in systemic lupus erythematosus (SLE), characterized by the diffuse effacement of podocyte processes without immune complex deposition or with only mesangial immune complex deposition. LP is a rare cause of nephrotic syndrome in SLE patients with implications for prognosis and treatment. Case Report: We present the case of a 28-year-old woman with a medical history of type 1 diabetes mellitus (T1DM) who presented with lower limb edema, dyspnea, hypercholesterolemia, with nephrotic range proteinuria, without acute kidney injury, and laboratory findings compatible with auto-immune hemolytic anemia. They had negative infectious serology, positive antinuclear antibody (ANA), and an eye fundus examination showing diabetic retinopathy. A biopsy was performed to define the etiology of the renal involvement, which was compatible with LP. Following immuno-suppressive and antiproteinuric therapy, the patient evolved with the complete remission of the nephrotic syndrome. Conclusions: Lupus podocytopathy is an infrequent anatomopathological entity, so this case is presented as the first reported in Peru, and a literature review is made. Full article

Background: Diabetic Mastopathy (DMP) is an uncommon benign fibro-inflammatory condition that occurs in women with long-standing diabetes mellitus (DM), particularly type 1. It often mimics breast cancer (BC) in clinical and imaging presentations, leading to diagnostic challenges. Methods: A retrospective monocentric study was conducted, analyzing clinical, radiologic, and pathological data from 28 women diagnosed with DMP over 10 years at the European Institute of Oncology. Data on DM type, age at DMP diagnosis, associated autoimmune conditions, imaging features, and surgical outcomes were collected and compared with the existing literature. Results: The majority (82%) of the patients had type 1 DM, with most diagnosed with DMP before age 40. Common complications included retinopathy (46%) and neuropathy (35%). Imaging often suggested malignancy, necessitating core needle biopsies for diagnosis. Surgical intervention occurred in 55% of cases, with a recurrence rate of 32%. One case of BC was observed. Conclusions: DMP remains challenging due to its resemblance to BC. Conservative management is typical, but the recurrence rate post-surgery highlights the importance of ongoing monitoring. Although DMP does not significantly increase BC risk, caution is advised, especially for immunocompromised patients. Further studies are needed to comprehensively understand DMP’s relationship with BC. Full article

(1) Background: The worldwide endometrial cancer (EC) incidence is rising, amongst others linked to obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome, possibly due to low-grade adipose tissue inflammation. We studied immune cell infiltration in the endometrium in relation to diagnosis and obesity. (2) Methods: A cohort was created (n = 44) from postmenopausal women, lean (n = 15) and obese (n = 29), with bleeding complaints due to EC (n = 18) or benign pathology (n = 26). Endometrial biopsies were used to study the immune microenvironment and stained for macrophages (CD68 and CD163), T-cells (CD3 and CD8), and NK-cells (CD56). (3) Results: Malignant samples showed reduced intraepithelial CD3+ and CD8+ T-cells and increased stromal CD3+ T-cells. In obese patients, increased intraepithelial CD3+ and CD8+ T-cells were detected, especially in obese patients with T2DM. Epithelial CD56+ NK-cells were depleted in EC; however, no effect of obesity on NK-cell infiltration was observed. Stromal CD68+ cells were reduced in EC patients, whereas the CD163+ cells were increased. (4) Conclusions: Obesity and malignancy are associated with differences in immune cell presence. The alterations in immune cell infiltration seen in obese EC patients with and without diabetes suggest a complex interaction where obesity-related low-grade inflammation plays a central role. Full article