ABSTRACT
Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals. The comorbidity of the two neurological disorders represents a grave health threat to older populations. This review presents a brief background of the development of novel concepts and their clinical potentials. The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca2+ influx is critical for neuronal function. An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca2+ mainly via N-methyl-D-aspartate receptors, particularly of those at the extrasynaptic site. This Ca2+-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity. Furthermore, mild but sustained Ca2+ increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic, but gradually set off deteriorating Ca2+-dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways. Based on the Ca2+ hypothesis of Alzheimer's disease and recent advances, this Ca2+-activated "silent" degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis. The N-methyl-D-aspartate receptor subunit GluN3A, primarily at the extrasynaptic site, serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity. Ischemic stroke and Alzheimer's disease, therefore, share an N-methyl-D-aspartate receptor- and Ca2+-mediated mechanism, although with much different time courses. It is thus proposed that early interventions to control Ca2+ homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia. This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.
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Accurate information about locoregional treatments in breast cancer neoadjuvant systemic therapy (NST) trials is vital to support surgical decision-making and allow meaningful interpretation of long-term oncological outcomes. This systematic review (PROSPERO registration CRD42023470891) aimed to describe the current practice of outcome reporting in NST studies. A systematic search identified primary research studies published 01/01/2018-08/09/2023 reporting outcomes in patients receiving NST for breast cancer followed by locoregional treatment. Included were randomised controlled trials (RCTs) and non-randomised studies (NRS) with >250 participants reporting at least one locoregional treatment outcome. Outcomes were extracted verbatim and categorised using content analysis. Descriptive statistics were used to summarise results. Of the 3111 abstracts screened, 137 studies (22 RCTs and 115 NRS) reporting at least one locoregional outcome in 575,531 patients were included. The 137 studies reported a total of 510 surgical outcomes with a median of 3 (range 1-12) per study. No single outcome was reported in all studies. Type of breast (n = 129, 94.2 %) and axillary (n = 86, 62.8 %) surgery were reported most frequently. Only 34 % (n = 47) studies reported how treatment response was assessed and if/how this informed surgical decision-making. Only a fifth (n = 28) reported outcomes relating to surgical de-escalation. Only 72 studies (52.6 %) reported any radiation therapy (RT)-related outcome, most frequently whether RT had been received (n = 63/72, 87.5 %). Current reporting of locoregional treatment outcomes in NST studies is poor, inconsistent and urgently needs to be improved. A core outcome set and reporting guidelines may improve the quality and value of future research.
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Glioblastoma Multiforme (GBM) is an aggressive brain tumor with a high mortality rate. Direct reprogramming of glial cells to different cell lineages, such as induced neural stem cells (iNSCs) and induced neurons (iNeurons), provides genetic tools to manipulate a cell's fate as a potential therapy for neurological diseases. NeuroD1 (ND1) is a master transcriptional factor for neurogenesis and it promotes neuronal differentiation. In the present study, we tested the hypothesis that the expression of ND1 in GBM cells can force them to differentiate toward post-mitotic neurons and halt GBM tumor progression. In cultured human GBM cell lines, including LN229, U87, and U373 as temozolomide (TMZ)-sensitive and T98G as TMZ-resistant cells, the neuronal lineage conversion was induced by an adeno-associated virus (AAV) package carrying ND1. Twenty-one days after AAV-ND1 transduction, ND1-expressing cells displayed neuronal markers MAP2, TUJ1, and NeuN. The ND1-induced transdifferentiation was regulated by Wnt signaling and markedly enhanced under a hypoxic condition (2% O2 vs. 21% O2). ND1-expressing GBM cultures had fewer BrdU-positive proliferating cells compared to vector control cultures. Increased cell death was visualized by TUNEL staining, and reduced migrative activity was demonstrated in the wound-healing test after ND1 reprogramming in both TMZ-sensitive and -resistant GBM cells. In a striking contrast to cancer cells, converted cells expressed the anti-tumor gene p53. In an orthotopical GBM mouse model, AAV-ND1-reprogrammed U373 cells were transplanted into the fornix of the cyclosporine-immunocompromised C57BL/6 mouse brain. Compared to control GBM cell-formed tumors, cells from ND1-reprogrammed cultures formed smaller tumors and expressed neuronal markers such as TUJ1 in the brain. Thus, reprogramming using a single-factor ND1 overcame drug resistance, converting malignant cells of heterogeneous GBM cells to normal neuron-like cells in vitro and in vivo. These novel observations warrant further research using patient-derived GBM cells and patient-derived xenograft (PDX) models as a potentially effective treatment for a deadly brain cancer and likely other astrocytoma tumors.
Subject(s)
Cellular Reprogramming , Glioblastoma , Neurons , Glioblastoma/pathology , Glioblastoma/genetics , Glioblastoma/metabolism , Humans , Animals , Cell Line, Tumor , Neurons/metabolism , Neurons/drug effects , Mice , Cellular Reprogramming/drug effects , Brain Neoplasms/pathology , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Temozolomide/pharmacology , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/geneticsABSTRACT
INTRODUCTION: Neoadjuvant systemic anticancer therapy (neoSACT) is increasingly used in the treatment of early breast cancer. Response to therapy is prognostic and allows locoregional and adjuvant systemic treatments to be tailored to minimise morbidity and optimise oncological outcomes and quality of life. Accurate information about locoregional treatments following neoSACT is vital to allow the translation of downstaging benefits into practice and facilitate meaningful interpretation of oncological outcomes, particularly locoregional recurrence. Reporting of locoregional treatments in neoSACT studies, however, is currently poor. The development of a core outcome set (COS) and reporting guidelines is one strategy by which this may be improved. METHODS AND ANALYSIS: A COS for reporting locoregional treatment (surgery and radiotherapy) in neoSACT trials will be developed in accordance with Core Outcome Measures in Effectiveness Trials (COMET) and Core Outcome Set-Standards for Development guidelines. Reporting guidance will be developed concurrently.The project will have three phases: (1) generation of a long list of relevant outcome domains and reporting items from a systematic review of published neoSACT studies and interviews with key stakeholders. Identified items and domains will be categorised and formatted into Delphi consensus questionnaire items. (2) At least two rounds of an international online Delphi survey in which at least 250 key stakeholders (surgeons/oncologists/radiologists/pathologists/trialists/methodologists) will score the importance of reporting each outcome. (3) A consensus meeting with key stakeholders to discuss and agree the final COS and reporting guidance. ETHICS AND DISSEMINATION: Ethical approval for the consensus process will be obtained from the Queen's University Belfast Faculty Ethics Committee. The COS/reporting guidelines will be presented at international meetings and published in peer-reviewed journals. Dissemination materials will be produced in collaboration with our steering group and patient advocates so the results can be shared widely. REGISTRATION: The study has been prospectively registered on the COMET website (https://www.comet-initiative.org/Studies/Details/2854).
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Breast Neoplasms , Neoadjuvant Therapy , Research Design , Humans , Breast Neoplasms/therapy , Female , Delphi Technique , Consensus , Outcome Assessment, Health CareABSTRACT
BACKGROUND: This article presents the use of blood speckle Imaging (BSI) as an echocardiographic approach for the pre- and post-operative evaluation of subaortic membrane resection and aortic valve repair. METHOD: BSI, employing block-matching algorithms, provided detailed visualization of flow patterns and quantification of parameters from ultrasound data. The 9-year-old patient underwent subaortic membrane resection and peeling extensions of the membrane from under the ventricular-facing surface of all three aortic valve leaflets. RESULT: Post-operatively, BSI demonstrated improvements in hemodynamic patterns, where quantified changes in flow velocities showed no signs of stenosis and trivial regurgitation. The asymmetric jet with a shear layer and flow reversal on the posterior aspect of the aorta was corrected resulting in reduced wall shear stress on the anterior aspect and reduced oscillatory shear index, which is considered a contributing element in cellular alterations in the structure of the aortic wall. CONCLUSION: This proof-of-concept study demonstrates the potential of BSI as an emerging echocardiographic approach for evaluating subaortic and aortic valvar repair. BSI enhances the quantitative evaluation of the left ventricular outflow tract of immediate surgical outcomes beyond traditional echocardiographic parameters and aids in post-operative decision-making. However, larger studies are needed to validate these findings and establish standardized protocols for clinical implementation.
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Stroke and late-onset Alzheimer's disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background and recent progresses that are important and informative for the comorbidity of stroke and late-onset AD and related dementia (ADRD). Glutamatergic NMDA receptor (NMDAR) activity and NMDAR-mediated Ca2+ influx are essential for neuronal function and cell survival. An ischemic insult, however, can cause rapid increases in glutamate concentration and excessive activation of NMDARs, leading to swift Ca2+ overload in neuronal cells and acute excitotoxicity within hours and days. On the other hand, mild upregulation of NMDAR activity, commonly seen in AD animal models and patients, is not immediately cytotoxic. Sustained NMDAR hyperactivity and Ca2+ dysregulation lasting from months to years, nevertheless, can be pathogenic for slowly evolving events, i.e. degenerative excitotoxicity, in the development of AD/ADRD. Specifically, Ca2+ influx mediated by extrasynaptic NMDARs (eNMDARs) and a downstream pathway mediated by transient receptor potential cation channel subfamily M member (TRPM) are primarily responsible for excitotoxicity. On the other hand, the NMDAR subunit GluN3A plays a "gatekeeper" role in NMDAR activity and a neuroprotective role against both acute and chronic excitotoxicity. Thus, ischemic stroke and AD share an NMDAR- and Ca2+-mediated pathogenic mechanism that provides a common receptor target for preventive and possibly disease-modifying therapies. Memantine (MEM) preferentially blocks eNMDARs and was approved by the Federal Drug Administration (FDA) for symptomatic treatment of moderate-to-severe AD with variable efficacy. According to the pathogenic role of eNMDARs, it is conceivable that MEM and other eNMDAR antagonists should be administered much earlier, preferably during the presymptomatic phases of AD/ADRD. This anti-AD treatment could simultaneously serve as a preconditioning strategy against stroke that attacks ≥ 50% of AD patients. Future research on the regulation of NMDARs, enduring control of eNMDARs, Ca2+ homeostasis, and downstream events will provide a promising opportunity to understand and treat the comorbidity of AD/ADRD and stroke.
Subject(s)
Alzheimer Disease , Ischemic Stroke , Stroke , Animals , Receptors, N-Methyl-D-Aspartate/metabolism , Alzheimer Disease/metabolism , Ischemic Stroke/drug therapy , Memantine/pharmacology , Memantine/therapeutic useABSTRACT
Our recent investigation revealed that deficiency of N-methyl-D-aspartate (NMDA) receptor subunit GluN3A (NR3A) is a trigger for chronic neuronal hyperactivity and disruptionFfepspof Ca2+ homeostasis, leading to sporadic Alzheimer's disease (AD) phenotypes. The identification of the amyloid-independent pathogenesis was a surprise considering that GluN3A is a much less known NMDA receptor subunit with obscure function in aging adulthood, while the new concept of degenerative excitotoxicity as a decade-long pathogenic mechanism of AD/dementia remains to be further delineated. With negative observations in GRIN3A-/- mouse, Verhaeghe et al. in their letter challenge the "odd" idea that lasting GluN3A deficiency is detrimental and responsible for the spontaneous progression of AD and cognitive decline. We now discuss the potential mouse strain hypothesis and experimental data in these two investigations, and provide additional evidence that further supports the validity and specificity of GluN3A deficiency in the development of AD and associated dementia.
Subject(s)
Alzheimer Disease , Mice , Animals , Alzheimer Disease/genetics , Neurons , Receptors, N-Methyl-D-Aspartate/geneticsABSTRACT
Introduction: Rib fractures are a common sequelae of chest trauma and are associated with significant morbidity. The erector spinae nerve block (ESB) has been proposed as an alternative first-line regional technique for rib fractures due to ease of administration and minimal complication profile. We aimed to investigate the current literature surrounding this topic with a focus on pain and respiratory outcomes. Methods: A comprehensive literature search was performed on the Medline, Embase, Web of Science, Scopus, and Cochrane databases. Keywords of "erector spinae block" and "rib fractures" were used to form the search strategy. Papers published in English investigating ESB as an analgesic intervention for acute rib fracture were included. Exclusion criteria were operative rib fixation, or where the indication for ESB was not rib fracture. Results: There were 37 studies which met the inclusion criteria for this scoping review. Of these, 31 studies reported on pain outcomes and demonstrated a 40% decrease in pain scores post administration within the first 24 hours. Respiratory parameters were reported in 8 studies where an increase in incentive spirometry was demonstrated. Respiratory complication was not consistently reported. ESB was associated with minimal complications; only 5 cases of haematoma and infection were (incidence 0.6%) reported, none of which required further intervention. Discussion: Current literature surrounding ESB in rib fracture management provides a positive qualitative evaluation of efficacy and safety. Improvements in pain and respiratory parameters were almost universal. The notable outcome from this review was the improved safety profile of ESB. The ESB was not associated with complications requiring intervention even in the setting of anticoagulation and coagulopathy. There still remains a paucity of large cohort, prospective data. Moreover, no current studies reflect an improvement in respiratory complication rates compared to current techniques. Taken together, these areas should be the focus of any future research.
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BACKGROUND: Surgical approach is the most effective treatment for primary spontaneous pneumothorax. The two most widely adopted surgical methods are mechanical abrasion and apical pleurectomy, in addition to bullectomy. We performed a systematic review and meta-analysis to examine which technique is superior in treating primary spontaneous pneumothorax. METHODS: PubMed, MEDLINE and EMBASE databases were searched for studies published between January 2000 to September 2022 comparing mechanical abrasion and apical pleurectomy for treatment of primary spontaneous pneumothorax. The primary outcome was pneumothorax recurrence. Secondary outcomes included post-operative chest tube duration, hospital length of stay, operative time and intra-operative of blood loss. RESULTS: Eight studies were eligible for inclusion involving 1,613 patients. There was no difference in the rate of pneumothorax recurrence between pleural abrasion and pleurectomy (RR: 1.34; 95% CI: 0.94 to 1.92). However, pleural abrasion led to shorter hospital length of stay (MD: -0.25; 95% CI: -0.51 to 0.00), post-operative chest tube duration (MD: -0.30; 95% CI: -0.56 to -0.03), operative time (MD: -13.00; 95% CI -15.07 to 10.92) and less surgical blood loss (MD: -17.77; 95% CI: -24.36 to -11.18). CONCLUSION: Pleural abrasion leads to less perioperative patient burden and shorter hospital length of stay without compromising the rate of pneumothorax recurrence when compared to pleurectomy. Thus, pleural abrasion is a reasonable first choice surgical procedure for management of primary spontaneous pneumothorax.
Subject(s)
Pneumothorax , Thoracic Surgical Procedures , Humans , Pneumothorax/surgery , Pleura/surgery , Pleurodesis/methods , Recurrence , Thoracic Surgical Procedures/methods , Treatment Outcome , Thoracic Surgery, Video-Assisted/methodsSubject(s)
Amyloidosis , Humans , Amyloidosis/diagnosis , Amyloidosis/diagnostic imaging , Ventricular Function, Left , SoftwareABSTRACT
Although the automatic speech recognition (ASR) technology is increasingly used for commercial purposes, its impact on language learning has not been extensively studied. Underpinned by the sociocultural theory, the present work examined the effects of leveraging ASR technology to support English vocabulary learning in a tertiary flipped setting. A control group and an experimental group of college students participated in a 14-week study. Both groups had their English classes in a flipped fashion, but the experimental group was assigned with ASR-assisted oral tasks for pre-class self-learning. The pre- and post-intervention in-class task performance of both groups was audio-recorded and transcribed for data analysis. The triadic complexity-accuracy-fluency (CAF) framework was adopted to evaluate the participants' vocabulary learning. The between- and within-subjects effects were examined mainly through procedures of MANCOVA and mixed-design repeated measures ANCOVA. Results showed that on all the metrics of lexical complexity and speed fluency, the experimental group outperformed the control group, and had significant growth over time. On the other hand, the control group only improved significantly overtime on the G-index. On lexical accuracy, there was no significant difference between the two groups, and the within-subjects effect was not significant for either group. The findings lent some support to Skehan's Trade-off Hypothesis and discussions were conducted regarding the triarchic CAF framework.
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Objectives: This study sought to characterize coronary artery disease (CAD) among adults diagnosed with an anomalous aortic origin of a coronary artery (AAOCA). We hypothesized that coronaries with anomalous origins have more severe CAD stenosis than coronaries with normal origins. Methods: This single-center study of 763 adults with AAOCA consisted of 620 patients from our cardiac catheterization database (1958-2009) and 273 patients from electronic medical records query (2010-2021). Within left main, anterior descending, circumflex, and right coronary arteries, the CAD stenosis severity, assessed by invasive or computer tomography angiography, was modeled with coronary-level variables (presence of an anomalous origin) and patient-level variables (age, sex, comorbidities, and which of the four coronaries was anomalous). Results: Of the 763 patients, 472 (60%) had obstructive CAD, of whom, 142/472 (30%) had obstructive CAD only in the anomalous coronary. Multivariable modeling showed similar CAD stenosis severity between coronaries with anomalous versus normal origins (P = .8). Compared with AAOCA of other coronaries, the anomalous circumflex was diagnosed at older ages (59.7 ± 11.1 vs 54.3 ± 15.8 years, P < .0001) and was associated with increased stenosis in all coronaries (odds ratio, 2.7; 95% confidence interval, 2.2-3.4, P < .0001). Conclusions: Among adults diagnosed with AAOCA, the anomalous origin did not appear to increase the severity of CAD within the anomalous coronary. In contrast to the circumflex, AAOCA of the other vessels may contribute a greater ischemic burden when they present symptomatically at younger ages with less CAD. Future research should investigate the interaction between AAOCA, CAD, and ischemic risk to guide interventions.
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Ischemic stroke is a leading cause of morbidity and mortality, with limited treatments that can facilitate brain regeneration. Neural progenitor cells (NPCs) hold promise for replacing tissue lost to stroke, and biomaterial approaches may improve their efficacy to overcome hurdles in clinical translation. The immune response and its role in stroke pathogenesis and regeneration may interplay with critical mechanisms of stem cell and biomaterial therapies. Cellular therapy can modulate the immune response to reduce toxic neuroinflammation early after ischemia. However, few studies have attempted to harness the regenerative effects of neuroinflammation to augment recovery. Our previous studies demonstrated that intracerebrally transplanted NPCs encapsulated in a chondroitin sulfate-A hydrogel (CS-A + NPCs) can improve vascular regeneration after stroke. In this paper, we found that CS-A + NPCs affect the microglia/macrophage response to promote a regenerative phenotype following stroke in mice. Following transplantation, PPARγ-expressing microglia/macrophages, and MCP-1 and IL-10 protein levels are enhanced. Secreted immunomodulatory factor expression of other factors was altered compared to NPC transplantation alone. Post-stroke depression-like behavior was reduced following cellular and material transplantation. Furthermore, we showed in cultures that microglia/macrophages encapsulated in CS-A had increased expression of angiogenic and arteriogenic mediators. Neutralization with anti-IL-10 antibody negated these effects in vitro. Cumulatively, this work provides a framework for understanding the mechanisms by which immunomodulatory biomaterials can enhance the regenerative effects of cellular therapy for ischemic stroke and other brain injuries.
Subject(s)
Brain Ischemia , Ischemic Stroke , Stroke , Animals , Biocompatible Materials , Brain/pathology , Brain Ischemia/metabolism , Brain Ischemia/therapy , Glycosaminoglycans , Immunity , Immunomodulation , Ischemia , Mice , Stem Cell Transplantation , Stroke/pathologyABSTRACT
STEM education has been regarded as an important educational initiative for cultivating students' twenty-first century skills. The present work aimed to explore ways to promote students' twenty-first century skills through an integrated STEM-based curriculum. Specifically, we designed and implemented an 8-week crossover program of STEM and community service education. In this program, students learned about STEM domain knowledge and community service issues. They then applied the knowledge to solve authentic problems faced by Hong Kong community-housing residents from disadvantaged groups. A mixed-method approach was employed to evaluate the effectiveness of the program in enhancing students' twenty-first century skills and attitudes, including (i) creative thinking, (ii) collaboration, (iii) perseverance, as well as their (iv) STEM career interests. The research participants were 121 secondary students from a government-subsidized school. The quantitative results showed that the participants' creative thinking, collaboration, and perseverance improved alongside their STEM career interests. These findings were further supported by the data gathered through focus-group interviews. This study provides theoretical and practical insights into the integration of STEM education with community service learning.
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Medical students learning to use artificial intelligence for medical practices is likely to enhance medical services. However, studies in this area have been lacking. The present study investigated medical students' perceptions of and behavioral intentions toward learning artificial intelligence (AI) in clinical practice based on the theory of planned behavior (TPB). A sum of 274 Year-5 undergraduates and master's and doctoral postgraduates participated in the online survey. Six constructs were measured, including (1) personal relevance (PR) of medical AI, (2) subjective norm (SN) related to learning medical AI, (3) perceived self-efficacy (PSE) of learning medical AI, (4) basic knowledge (BKn) of medical AI, (5) behavioral intention (BI) toward learning medical AI and (6) actual learning (AL) of medical AI. Confirmatory factor analysis and structural equation modelling were employed to analyze the data. The results showed that the proposed model had a good model fit and the theoretical hypotheses in relation to the TPB were mostly confirmed. Specifically, (a) BI had a significantly strong and positive impact on AL; (b) BI was significantly predicted by PR, SN and PSE, whilst BKn did not have a direct effect on BI; (c) PR was significantly and positively predicted by SN and PSE, but BKn failed to predict PR; (d) both SN and BKn had significant and positive impact on PSE, and BKn had a significantly positive effect on SN. Discussion was conducted regarding the proposed model, and new insights were provided for researchers and practitioners in medical education.
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Intention , Students, Medical , Artificial Intelligence , Humans , Learning , Surveys and QuestionnairesABSTRACT
Objectives: Anomalous aortic origin of the right coronary artery (AAORCA) may cause ischemia and sudden death. However, the specific anatomic indications for surgery are unclear, so dobutamine-stress instantaneous wave-free ratio (iFR) is increasingly used. Meanwhile, advances in fluid-structure interaction (FSI) modeling can simulate the pulsatile hemodynamics and tissue deformation. We sought to evaluate the feasibility of simulating the resting and dobutamine-stress iFR in AAORCA using patient-specific FSI models and to visualize the mechanism of ischemia within the intramural geometry and associated lumen narrowing. Methods: We developed 6 patient-specific FSI models of AAORCA using SimVascular software. Three-dimensional geometries were segmented from coronary computed tomography angiography. Vascular outlets were coupled to lumped-parameter networks that included dynamic compression of the coronary microvasculature and were tuned to each patient's vitals and cardiac output. Results: All cases were interarterial, and 5 of 6 had an intramural course. Measured iFRs ranged from 0.95 to 0.98 at rest and 0.80 to 0.95 under dobutamine stress. After we tuned the distal coronary resistances to achieve a stress flow rate triple that at rest, the simulations adequately matched the measured iFRs (r = 0.85, root-mean-square error = 0.04). The intramural lumen remained narrowed with simulated stress and resulted in lower iFRs without needing external compression from the pulmonary root. Conclusions: Patient-specific FSI modeling of AAORCA is a promising, noninvasive method to assess the iFR reduction caused by intramural geometries and inform surgical intervention. However, the models' sensitivity to distal coronary resistance suggests that quantitative stress-perfusion imaging may augment virtual and invasive iFR studies.
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A previously well, independent 20-year-old man presented with a 4-day history of progressive left lower limb pain with associated phlegmasia cerulea dolens. Duplex venous ultrasound examination and computed tomography venogram revealed extensive deep vein thrombus from the left popliteal vein to abnormal venous vasculature proximally. Notably, no infrarenal inferior vena cava was detected, with distal venous return channeled through lumbar and visceral collateral channels into the azygous system. Treatment included systemic anticoagulation, catheter-directed thrombolysis, and prolonged therapeutic anticoagulation. In the absence of other risk factors, anatomical abnormalities should be considered in young, well patients presenting with lower limb venous thrombosis.
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BACKGROUND: Calciphylaxis is a rare, often fatal disease resulting from calcification of dermal arterioles and capillaries. Usually diagnosed in patients with end-stage renal disease, this disorder typically presents as necrotic, nonhealing ulcers in acral or adipose areas. Here we report the case of an elderly man who was found to have calciphylaxis of the distal digits and penis, the latter of which is an uncommon site of disease that carries a particularly poor prognosis. CASE PRESENTATION: A 73-year-old African American man with multiple medical comorbidities including dialysis-dependent end-stage renal disease presented with worsening painful, necrotic lesions on his glans penis and several distal digits over the last 2 months. The wound on the glans was foul smelling with overlying purulence and had been unsuccessfully treated with amoxicillin-clavulanic acid. Discovery of diffuse intravascular calcification on computed tomography, in addition to a markedly elevated calcium-phosphate product immediately prior to the onset of his ulcers, led to the diagnosis of calciphylaxis. The patient was initiated on sodium thiosulfate without improvement in his lesions, and he died 3 months later after another prolonged hospitalization. CONCLUSIONS: While calciphylaxis is a rare disease, involvement of the distal digits and especially the penis is even more uncommon and portends a particularly poor prognosis: 6-month mortality rates are reportedly as high as 70%. This suggests that prompt recognition and management of the disease is required; however, despite receiving standard therapy, our patient failed to experience improvement in his disease and instead developed several more fingertip ulcers at blood glucose sample points during his hospitalization. A corollary of the case presented here is the need for more effective management of calciphylaxis, especially for patients in whom uncommon sites, such as the penis, are involved.