High glucose promotes osteogenic differentiation of human lens epithelial cells through hypoxia-inducible factor (HIF) activation.

Cataract, a leading cause of blindness, is characterised by lens opacification. Type 2 diabetes is associated with a two- to fivefold higher prevalence of cataracts. The risk of cataract formation increases with the duration of diabetes and the severity of hyperglycaemia. Hydroxyapatite deposition is present in cataractous lenses that could be the consequence of osteogenic differentiation and calcification of lens epithelial cells (LECs). We hypothesised that hyperglycaemia might promote the osteogenic differentiation of human LECs (HuLECs). Osteogenic medium (OM) containing excess phosphate and calcium with normal (1 g/L) or high (4.5 g/L) glucose was used to induce HuLEC calcification. High glucose accelerated and intensified OM-induced calcification of HuLECs, which was accompanied by hyperglycaemia-induced upregulation of the osteogenic markers Runx2, Sox9, alkaline phosphatase and osteocalcin, as well as nuclear translocation of Runx2. High glucose-induced calcification was abolished in Runx2-deficient HuLECs. Additionally, high glucose stabilised the regulatory alpha subunits of hypoxia-inducible factor 1 (HIF-1), triggered nuclear translocation of HIF-1α and increased the expression of HIF-1 target genes. Gene silencing of HIF-1α or HIF-2α attenuated hyperglycaemia-induced calcification of HuLECs, while hypoxia mimetics (desferrioxamine, CoCl2) enhanced calcification of HuLECs under normal glucose conditions. Overall, this study suggests that high glucose promotes HuLEC calcification via Runx2 and the activation of the HIF-1 signalling pathway. These findings may provide new insights into the pathogenesis of diabetic cataracts, shedding light on potential factors for intervention to treat this sight-threatening condition.

Predictors of persistent pain after extracorporeal shockwave lithotripsy for painful chronic calcific pancreatitis.

BACKGROUND: Extracorporeal shockwave lithotripsy (ESWL) and/or endoscopic retrograde cholangiopancreatography (ERCP) are recommended as first-line therapy for painful uncomplicated chronic pancreatitis with obstructed main pancreatic duct (MPD) in the pancreas head/body. However, predictors of pain relief after ESWL are unknown. We evaluated independent predictors of persistent pain in patients who underwent ESWL for chronic pancreatitis. METHODS: 640 consecutive adult patients with chronic pancreatitis, who underwent successful ESWL with ERCP and pancreatic duct (PD) stent placement, were followed for 12 months. The pain was assessed at baseline and at 12 months using the Izbicki Pain Score, with a score decrease of >50% considered pain relief. Independent predictors of pain relief were derived from logistic regression analysis. RESULTS: Of 640 patients (mean age 36.71 [SD 12.19] years; 60.5% men), 436 (68.1%) had pain relief and 204 (31.9%) had persistent pain. On univariate analysis, older age, male sex, alcohol and tobacco intake, longer duration of symptoms, dilated MPD and MPD stricture were associated with persistent pain at 12 months (P<0.05). Consumption of alcohol (odds ratio [OR] 1.93, 95%CI 1.26-2.97), tobacco (OR 4.09, 95%CI 2.43-6.90), duration of symptoms (OR 1.02, 95%CI 1.01-1.04), MPD size (OR 1.22, 95%CI 1.11-1.33), and MPD stricture (OR 8.50, 95%CI 5.01-14.42) were independent predictors of persistent pain. CONCLUSIONS: Alcohol, tobacco, duration of symptoms, MPD size and stricture were independent predictors of persistent pain after successful ESWL. A multidisciplinary team approach that includes behavioral therapy and surgical options should be considered for such patients.

Calcinosis in Juvenile Dermatomyositis-Epidemiology, Pathogenesis, Clinical Features, and Treatment: A Systematic Review.

PURPOSE OF REVIEW: We performed a systematic review of the literature on the epidemiology, pathogenesis, clinical and laboratory characterization, and treatment of calcinosis in patients with juvenile dermatomyositis (JDM). A qualitative systematic review was conducted from January 1975 to April 2023 according to the PRISMA protocol using three electronic databases: PubMed, Web of Science, and Scopus. Studies were analyzed based on the following eligibility criteria: at least one combination of the terms described in the search strategy appeared in the title, written in English, Portuguese, or Spanish, and addressed the epidemiology, pathogenesis, diagnosis, and treatment of calcinosis in juvenile dermatomyositis. Systematic or scoping reviews, letters, clinical images, book chapters, abstracts, inflammatory myopathy in other connective tissue diseases, idiopathic inflammatory myopathies in adults, and purely qualitative studies were excluded. RECENT FINDINGS: Seventy-five studies were included. According to the literature, calcinosis is common in women, around five years old, with three years of disease in association with osteoarticular, cutaneous, pulmonary manifestations, and fever. The pathogenesis is still unknown, but the participation of interleukin 1 and 6, tumor necrosis factor alpha, and innate immunity dysregulation seem to be involved. Common autoantibodies are anti-NXP-2, anti-MDA-5, and anti-Mi-2, and their treatment remains controversial. Prospective, randomized, controlled studies are needed to evaluate treatment protocols and map the natural history of this serious complication. Calcinosis seems to be more common in White female children with muscle weakness, fever, arthritis, severe pulmonary, and skin involvement with anti-NXP-2, anti-MDA-5, and anti-Mi-2 autoantibodies. The multitargets and aggressive treatment is recommended.

A large post-stenting intramural hematoma in the left anterior descending artery caused by a small intimal calcium spur; should we respect the calcium shape?

Coronary heavy calcification (HC) poses a sturdy challenge to percutaneous coronary intervention (PCI). Scores considering calcification length, thickness, or circumferential extent, are widely accepted to dictate upfront calcium modification to improve PCI outcomes. Although often marginalized, calcification shape (morphology) may require consideration during procedure planning in selected cases. This case demonstrates how a focal but spur-shaped calcification led to a massive proximal left anterior descending (LAD) dissecting intramural hematoma.

Progressive calcification of bioprosthetic mitral valve observed during pregnancy resulting from in vitro fertilization: a case report.

BACKGROUND: Women with pre-existing cardiac conditions who undergo assisted reproductive technologies (ART) are believed to be at a heightened risk of cardiovascular events during both the treatment and pregnancy phases. An unresolved question within this context pertains to whether the ART procedure itself constitutes a risk factor for individuals with bioprosthetic heart valves (BHV). Additionally, there is ongoing controversy regarding whether pregnancies expedite the process of structural valve degeneration (SVD) in BHV. The purpose of this study is to present the developmental process of BHV calcification, which is considered the primary cause of SVD, during a pregnancy resulting from in vitro fertilization and embryo transfer (IVF-ET), an ART modality, and to elucidate the underlying mechanisms. CASE PRESENTATION: At 7 + 3 weeks of gestation in a twin pregnancy resulting from IVF-ET, a 27-year-old woman with a bioprosthetic mitral valve manifesting severe mitral stenosis and moderate pulmonary arterial hypertension, was suspected of SVD. Despite undergoing fetal reduction, she experienced progressive calcification of the bioprosthetic valve, increasing pulmonary arterial pressure and ultimately deteriorated into heart failure. An elective cesarean section and redo valve replacement was subsequently administered to improve her cardiovascular condition. As a result, a healthy young boy was delivered and the dysfunctional BHV was replaced with a mechanical valve. She did not report any discomfort during the 3-month follow-up. CONCLUSION: The progressive calcification of the BHV was observed during IVF pregnancy, indicating a potential connection between fertility therapy, pregnancy and calcification of BHV. Pregnant women with pre-implanted BHV should be treated with caution, as any medical interventions during ART and pregnancy can have a significant impact on both maternal and fetal outcomes. Thus, involving a multidisciplinary team in decision-making early on, starting from the treatment of the original heart disease, throughout the entire process of ART and pregnancy, is crucial.

Calcifications in the descending thoracic aorta predict postoperative anastomotic leakages after esophagectomy for cancer.

BACKGROUND: Anastomotic leak is one of the most feared complications of esophagectomy. Previous studies have suggested a potential link between aortic calcifications detected on routine preoperative CT scans and increased risk of anastomotic leak after esophagectomy. This study aims to investigate whether clinicians' assessment of aortic calcifications can predict the occurrence of anastomotic leaks in patients undergoing esophagectomy for cancer. METHODS: A long-term follow-up was conducted on consecutive patients with esophageal cancer who underwent elective open esophagectomy at a Finnish tertiary hospital. Aortic calcifications were evaluated based on CT scans and categorized on a 0-3 scale reflecting the number of calcifications in the affected segment of the aorta. Reviewers assessing the calcifications were blinded to clinical details and postoperative outcomes. RESULTS: The study included 97 patients (median age: 64 years and range: 43-78; 20% female), with a median follow-up time of 1307 (2-1540) days. Among them, 22 patients (23%) had postoperative anastomotic leak. We observed a significant association between calcifications in the descending aorta and a higher risk of anastomotic leak (p = 0.007), as well as an earlier occurrence of leak postoperatively (p = 0.013). However, there was no association between aortic calcifications and increased mortality. CONCLUSIONS: Presence of calcifications in the descending aorta is independently associated with an increased risk of anastomotic leaks following esophagectomy for cancer. Identifying patients at higher risk for this complication could facilitate appropriate pre- and postoperative interventions, as well as enable earlier diagnosis and treatment to mitigate the severity of the complication.

Persistent chronic calcific pancreatitis with intraductal calculi associated with secondary diabetes mellitus type 3 and diabetic ketoacidosis - A case report.

Diabetes mellitus type 3 refers to diabetes secondary to an existing disease or condition of the exocrine pancreas and is an uncommon cause of diabetes occurring due to pancreatogenic pathology. It accounts for 15-20% of diabetic patients in Indian and Southeast Asian continents. This is case report of a rare case of type 3 diabetes mellitus (T3DM) presenting with diabetic ketoacidosis (DKA). The patient was admitted for DKA along with complaint of hyperglycemia, blood glucose of 405 mg/dl with HbA1c level of 13.7%. Computed tomography evidence revealed chronic calcific pancreatitis with intraductal calculi and dilated pancreatic duct.

Impact of residual microcalcifcations on prognosis after neoadjuvant chemotherapy in breast cancer patients.

BACKGROUND: Residual microcalcifications after neoadjuvant chemotherapy (NAC) are challenging for deciding extent of surgery and questionable for impact on prognosis. We investigated changes in the extent and patterns of microcalcifications before and after NAC and correlated them with pathologic response. We also compared prognosis of patients depending on presence of residual microcalcifications after NAC. METHODS: A total of 323 patients with invasive breast carcinoma treated with neoadjuvant chemotherapy at Kangbuk Samsung Hospital and Samsung Medical center from March 2015 to September 2018 were included. Patients were divided into four groups according to pathologic response and residual microcalcifications. Non-pCRw/mic group was defined as breast non-pCR with residual microcalcifications. Non-pCRw/o mic group was breast non-pCR without residual microcalcifications. pCRw/mic group was breast pCR with residual microcalcifications. pCRw/o mic group was breast pCR without residual microcalcifications. The first aim of this study is to investigate changes in the extent and patterns of microcalcifications before and after NAC and to correlate them with pathologic response. The second aim is to evaluate oncologic outcomes of residual microcalcifications according to pathologic response after NAC. RESULTS: There were no statistical differences in the extent, morphology, and distribution of microcalcifications according to pathologic response and subtype after NAC (all p > 0.05). With a median follow-up time of 71 months, compared to pCRw/o mic group, the hazard ratios (95% confidence intervals) for regional recurrence were 5.190 (1.160-23.190) in non-pCRw/mic group and 5.970 (1.840-19.380) in non-pCRw/o mic group. Compared to pCRw/o mic group, the hazard ratios (95% CI) for distant metastasis were 8.520 (2.130-34.090) in non-pCRw/mic group, 9.120 (2.850-29.200) in non-pCRw/o mic group. Compared to pCRw/o mic, the hazard ratio (95% CI) for distant metastasis in pCRw/mic group was 2.240 (0.230-21.500) without statistical significance (p = 0.486). CONCLUSIONS: Regardless of residual microcalcifications, patients who achieved pCR showed favorable long term outcome compared to non-pCR group.

Eruptive syringomas associated with milia-like idiopathic calcinosis cutis.

An 11-year-old boy presented generalized eruptive syringomas (ESs) associated with multiple milia-like whitish palmar papules corresponding to dermal calcium deposits. A relationship between calcium deposits distribution to an underlying eccrine duct was noted on pathology. The observation of dermal calcium deposits and its association with generalized ESs may support a possible sweat duct origin of this uncommon and peculiar form of superficial calcinosis cutis.

Early arthroscopic debridement of posterior cruciate ligament calcification after symptom presentation led to immediate recovery: a case report.

BACKGROUND: We report a rare case of posterior cruciate ligament (PCL) calcification, which has only been reported in two case studies on PubMed. CASE PRESENTATION: A 71-year-old man developed left popliteal pain in the morning without any history of trauma and the pain became severe that night. On the following day, he presented to our department. The patient could not flex his left knee at all due to pain and swelling. CT and MRI scans showed calcification behind the PCL with mild osteoarthritic changes and accumulation of synovial fluid in the joint. Synovial fluid analysis did not reveal any crystals. Blood tests at first admission showed inflammation, hyperglycemia, and low blood uric acid levels. Although the patient's knee joint was injected with steroids, his symptoms did not improve. Thus, we performed arthroscopic surgery two days after symptoms had appeared. Intraoperatively, we observed a white, soft tissue in the synovial membrane behind the PCL. Part of this tissue was collected for histological analysis, which revealed sparse fibers with calcium deposits. Immediately after surgery, the patient's symptoms were completely gone. Afterward, the patient remained asymptomatic one month after surgery. CONCLUSION: This is the first reported case of debridement of PCL calcification and ossification that was performed soon after symptoms appeared. In addition, we demonstrated that early debridement led to complete recovery.

Calcification of a Hydrophilic Acrylic Intraocular Lens after Glaucoma Surgery.

A Japanese woman in her 70s was referred to our hospital for the evaluation and treatment of high intraocular pressure (IOP) in her right eye. She had undergone bilateral cataract surgeries and the insertion of hydrophilic acrylic intraocular lenses (IOLs). We performed trabeculotomy and trabeculectomy to lower her right IOP; thereafter, a circular opacity was observed on the right eye's IOL surface. We removed the right IOL because that eye's vision had decreased due to IOL opacification. The analysis of the removed IOL revealed that the main opacity component was calcium phosphate. This is the first post-glaucoma-surgery IOL calcification case report.

Unraveling the Pathogenesis of Calcinosis in Systemic Sclerosis: A Molecular and Clinical Insight.

Dystrophic calcinosis, which is the accumulation of insoluble calcified crystalline materials within tissues with normal circulating calcium and phosphorus levels, is a frequent finding in systemic sclerosis (SSc) and represents a major burden for patients. In SSc, calcinosis poses significant challenges in management due to the associated risk of severe complications such as infection, ulceration, pain, reduction in functional capacity and quality of life, and lack of standardized treatment choices. The exact pathogenesis of calcinosis is still unknown. There are multifaceted factors contributing to calcinosis development, including osteogenic differentiation of cells, imbalance between promoter and inhibitors of mineralization, local disturbance in calcium and phosphate levels, and extracellular matrix as a template for mineralization. Several pathophysiological changes observed in SSc such as ischemia, exacerbated production of excessive reactive oxygen species, inflammation, production of inflammatory cytokines, acroosteolysis, and increased extracellular matrix production may promote the development of calcinosis in SSc. Furthermore, mitochondrial dynamics, particularly fission function through the activity of dynamin-related protein-1, may have an effect on the dystrophic calcinosis process. In-depth investigations of cellular mechanisms and microenvironmental influences can offer valuable insights into the complex pathogenesis of calcinosis in SSc, providing potential targeting pathways for calcinosis treatment.

An Unusual Presentation of Extrapulmonary Tuberculosis in a Fibrocalculous Pancreatic Diabetes Patient.

Fibrocalculous pancreatic diabetes (FCPD) mellitus is a distinct type of diabetes that arises from chronic calcification of the pancreas in young, nonalcoholic individuals, predominantly in tropical regions. The characteristic triad of FCPD includes diabetes, abdominal pain, and steatorrhea. Additional notable features of the disease are its early age of onset, the presence of large intraductal stones, rapid disease progression, and a heightened risk of developing pancreatic cancer. Tuberculosis (TB) is a health concern worldwide and is responsible for a major health burden in developing countries like India. TB involving any organ other than the lungs is diagnosed as extrapulmonary tuberculosis (EPTB). EPTB with musculoskeletal involvement is often a difficult and delayed diagnosis because of unusual clinical presentations.

Symptomatic Calcifications after Mastectomy: A Rare Case Report with a Review of the Literature.

Introduction: Symptomatic calcifications of the breast or skin after breast cancer surgery and adjuvant radiotherapy are a rare entity, with only a few case reports published worldwide, reducing the patient's quality of life, whilst asymptomatic calcifications are a common finding on imaging methods. Case presentation: Herein, we present a rare case report of calcifications after mastectomy and post-mastectomy radiation therapy causing chronic inflammation with ulceration and fistula formation, with a two-step surgical approach consisting of excision with linear suture and excision with the reconstruction using a thoraco-epigastric flap. Conclusions: To our knowledge, this is the first publication proving the feasibility of this therapy in patients with symptomatic dystrophic calcifications of the skin or the breast. Moreover, the article provides an up-to-date review of published studies about symptomatic calcifications after breast cancer surgery and radiotherapy with a focus on the time of the clinical manifestation from the radiotherapy and the used radiotherapy scheme.

[Dystrophic calcification of the parotid salivary glands in Sjogren's disease]. / Distroficheskaya kal'tsifikatsiya okoloushnykh slyunnykh zhelez pri bolezni Shegrena.

This article discusses a rare clinical case of differential diagnosis between salivary stone disease and calcinosis, which developed against the background of autoimmune pathology. Diagnosis of these pathologies causes difficulties for practitioners, and treatment methods have fundamental differences. In this regard, the description of this case is relevant and significant. The algorithm of the main and additional research methods to confirm the diagnosis is described.

Stage-specific and location-specific cartilage calcification in osteoarthritis development.

OBJECTIVES: This study investigated the stage-specific and location-specific deposition and characteristics of minerals in human osteoarthritis (OA) cartilages via multiple nano-analytical technologies. METHODS: Normal and OA cartilages were serially sectioned for micro-CT, scanning electron microscopy with energy dispersive X-ray spectroscopy, micro-Raman spectroscopy, focused ion beam scanning electron microscopy, high-resolution electron energy loss spectrometry with transmission electron microscopy, nanoindentation and atomic force microscopy to analyse the structural, compositional and mechanical properties of cartilage in OA progression. RESULTS: We found that OA progressed by both top-down calcification at the joint surface and bottom-up calcification at the osteochondral interface. The top-down calcification process started with spherical mineral particle formation in the joint surface during early-stage OA (OA-E), followed by fibre formation and densely packed material transformation deep into the cartilage during advanced-stage OA (OA-A). The bottom-up calcification in OA-E started when an excessive layer of calcified tissue formed above the original calcified cartilage, exhibiting a calcified sandwich structure. Over time, the original and upper layers of calcified cartilage fused, which thickened the calcified cartilage region and disrupted the cartilage structure. During OA-E, the calcified cartilage was hypermineralised, containing stiffer carbonated hydroxyapatite (HAp). During OA-A, it was hypomineralised and contained softer HAp. This discrepancy may be attributed to matrix vesicle nucleation during OA-E and carbonate cores during OA-A. CONCLUSIONS: This work refines our current understanding of the mechanism underlying OA progression and provides the foothold for potential therapeutic targeting strategies once the location-specific cartilage calcification features in OA are established.

Genetic and Developmental Contributors to Aortic Stenosis.

Aortic stenosis (AS) remains one of the most common forms of valve disease, with significant impact on patient survival. The disease is characterized by left ventricular outflow obstruction and encompasses a series of stenotic lesions starting from the left ventricular outflow tract to the descending aorta. Obstructions may be subvalvar, valvar, or supravalvar and can be present at birth (congenital) or acquired later in life. Bicuspid aortic valve, whereby the aortic valve forms with two instead of three cusps, is the most common cause of AS in younger patients due to primary anatomic narrowing of the valve. In addition, the secondary onset of premature calcification, likely induced by altered hemodynamics, further obstructs left ventricular outflow in bicuspid aortic valve patients. In adults, degenerative AS involves progressive calcification of an anatomically normal, tricuspid aortic valve and is attributed to lifelong exposure to multifactoral risk factors and physiological wear-and-tear that negatively impacts valve structure-function relationships. AS continues to be the most frequent valvular disease that requires intervention, and aortic valve replacement is the standard treatment for patients with severe or symptomatic AS. While the positive impacts of surgical interventions are well documented, the financial burden, the potential need for repeated procedures, and operative risks are substantial. In addition, the clinical management of asymptomatic patients remains controversial. Therefore, there is a critical need to develop alternative approaches to prevent the progression of left ventricular outflow obstruction, especially in valvar lesions. This review summarizes our current understandings of AS cause; beginning with developmental origins of congenital valve disease, and leading into the multifactorial nature of AS in the adult population.

Inflammatory and Biomechanical Drivers of Endothelial-Interstitial Interactions in Calcific Aortic Valve Disease.

Calcific aortic valve disease is dramatically increasing in global burden, yet no therapy exists outside of prosthetic replacement. The increasing proportion of younger and more active patients mandates alternative therapies. Studies suggest a window of opportunity for biologically based diagnostics and therapeutics to alleviate or delay calcific aortic valve disease progression. Advancement, however, has been hampered by limited understanding of the complex mechanisms driving calcific aortic valve disease initiation and progression towards clinically relevant interventions.

Multi-Omics Approaches to Define Calcific Aortic Valve Disease Pathogenesis.

Calcific aortic valve disease sits at the confluence of multiple world-wide epidemics of aging, obesity, diabetes, and renal dysfunction, and its prevalence is expected to nearly triple over the next 3 decades. This is of particularly dire clinical relevance, as calcific aortic valve disease can progress rapidly to aortic stenosis, heart failure, and eventually premature death. Unlike in atherosclerosis, and despite the heavy clinical toll, to date, no pharmacotherapy has proven effective to halt calcific aortic valve disease progression, with invasive and costly aortic valve replacement representing the only treatment option currently available. This substantial gap in care is largely because of our still-limited understanding of both normal aortic valve biology and the key regulatory mechanisms that drive disease initiation and progression. Drug discovery is further hampered by the inherent intricacy of the valvular microenvironment: a unique anatomic structure, a complex mixture of dynamic biomechanical forces, and diverse and multipotent cell populations collectively contributing to this currently intractable problem. One promising and rapidly evolving tactic is the application of multiomics approaches to fully define disease pathogenesis. Herein, we summarize the application of (epi)genomics, transcriptomics, proteomics, and metabolomics to the study of valvular heart disease. We also discuss recent forays toward the omics-based characterization of valvular (patho)biology at single-cell resolution; these efforts promise to shed new light on cellular heterogeneity in healthy and diseased valvular tissues and represent the potential to efficaciously target and treat key cell subpopulations. Last, we discuss systems biology- and network medicine-based strategies to extract meaning, mechanisms, and prioritized drug targets from multiomics datasets.

Impact of Parathyroid Hormone Level on Intracoronary Calcification and Short- and Long-Term Outcomes in Dialysis Patients Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Dialysis patients have strong intracoronary calcification, accelerated by secondary hyperparathyroidism as well as atherosclerosis. We evaluated the association of intact parathyroid hormone (iPTH) level with intracoronary calcification evaluated by intravascular ultrasound (IVUS), and its impact on both stent expansion after percutaneous coronary intervention (PCI) and long-term clinical outcomes, in dialysis patients with coronary artery disease (CAD).Methods and Results: A total of 116 patients on dialysis, who underwent PCI with IVUS guidance between March 2012 and December 2020, were enrolled. Patients were divided into 2 groups based on their median iPTH level. The degree of intracoronary calcification was evaluated by calcification score using grayscale IVUS in the target lesions. Preprocedural calcification scores were significantly higher in the high iPTH group compared with the low iPTH group (2.9±1.1 vs. 2.1±0.7, P<0.001). After PCI, the high iPTH group had a significantly lower stent expansion index (0.6±0.2 vs. 0.7±0.1, P<0.001) and stent symmetry index (0.5±0.1 vs. 0.7±0.1, P<0.001) compared with the low iPTH group. The incidence of major adverse cardiac or cerebrovascular events within 3 years was significantly higher in the high iPTH group (log-rank P<0.05). CONCLUSIONS: High iPTH level is likely to increase intracoronary calcification, and cause inadequate stent expansion, which may be associated with increased risk of future adverse events in dialysis patients with CAD requiring PCI.