Unveiling Mixed Cryoglobulinemia in Suspected Sepsis Without a Source.

Cryoglobulinemia is an uncommon condition characterized by the presence of cryoprecipitable immune complexes in circulation, leading to clinical symptoms like purpura, muscle weakness, and joint pain. Specifically, mixed cryoglobulinemia involves the formation of these complexes due to rheumatoid factors, mainly IgM, occasionally IgG or IgA. Previously, Hepatitis C (HCV) was a common cause of mixed cryoglobulinemia, as the chronic HCV infection triggered immune responses that resulted in cryoglobulin formation. However, the emergence of direct-acting antivirals (DAAs) for HCV treatment has shifted the landscape, with autoimmune and lymphoproliferative disorders becoming more prominent etiological factors for mixed cryoglobulinemia. This case report features a 67-year-old woman with a history of Hepatitis C-related cirrhosis. She presented at the emergency department with signs of septic shock and widespread joint pain, particularly in the knees, shoulders, and neck. Effective sepsis management was achieved using antibiotics, albumin infusion, and midodrine. Nonetheless, significant cervical and bilateral knee pain persisted. Further examination uncovered hypocomplementemia and positive results for rheumatoid factors (IgA, IgM, IgG) and cryoglobulin agglutination, confirming the diagnosis of mixed cryoglobulinemia. This case emphasizes the importance of considering mixed cryoglobulinemia in chronic Hepatitis C patients displaying fatigue and joint pain, even in the absence of the traditional clinical manifestations. Moreover, the case underscores the dual benefits of DAA treatment for Hepatitis C in individuals with mixed cryoglobulinemia by achieving viral eradication and alleviating cryoglobulinemia-related symptoms, thus preventing further organ damage.

Molecular Challenges and Opportunities in Climate Change-Induced Kidney Diseases.

As temperatures continue to modify due to weather changes, more regions are being exposed to extreme heat and cold. Physiological distress due to low and high temperatures can affect the heart, blood vessels, liver, and especially, the kidneys. Dehydration causes impaired cell function and heat itself triggers cellular stress. The decline in circulating plasma volume by sweat, which stresses the renal and cardiovascular systems, has been related to some molecules that are crucial players in preventing or provoking cellular damage. Hypovolemia and blood redistribution to cutaneous blood vessels reduce perfusion to the kidney triggering the activation of the renin-angiotensin-aldosterone system. In this review, we expose a deeper understanding of the modulation of molecules that interact with other proteins in humans to provide significant findings in the context of extreme heat and cold environments and renal damage reversal. We focus on the molecular changes exerted by temperature and dehydration in the renal system as both parameters are heavily implicated by weather change (e.g., vasopressin-induced fructose uptake, fructogenesis, and hypertension). We also discuss the compensatory mechanisms activated under extreme temperatures that can exert further kidney injury. To finalize, we place special emphasis on the renal mechanisms of protection against temperature extremes, focusing on two important protein groups: heat shock proteins and sirtuins.

Bacterial Brain Abscesses in a Patient With Transposition of the Great Arteries and Interventricular Communication.

Brain abscesses are localized infections in the brain's parenchyma, characterized by inflammation, pus formation, and the development of a surrounding capsule. These lesions typically occur due to underlying factors such as immunosuppression, ear and sinus infections, and contamination during neurosurgery. While brain abscesses are a life-threatening complication of cyanotic heart defects, they are rarely reported, with only sporadic cases previously documented. This article presents the case of an eight-year-old male patient with an uncorrected transposition of the great arteries, who was evaluated for symptoms including headache, fever, and neurological focalization. Diagnostic imaging revealed three lesions consistent with brain abscesses. Furthermore, the causal agents were identified as Streptococcus intermedius and Fusobacterium spp., representing oral microorganisms. Additionally, the patient exhibited poor oral hygiene and dental caries in multiple teeth. This article discusses and integrates the possible pathophysiological mechanisms that allowed a localized dental infection to spread hematogenously and cause brain abscesses in this patient. Prompt management of the infectious source is crucial to prevent a poor prognosis associated with brain abscesses. Therefore, this case emphasizes the importance of regular dental assessments and thromboprophylaxis for patients with underlying cardiomyopathies that cause right-to-left shunting to prevent potential complications.

Self-oxygenation of engineered living tissues orchestrates osteogenic commitment of mesenchymal stem cells.

Oxygenating biomaterials can alleviate anoxic stress, stimulate vascularization, and improve engraftment of cellularized implants. However, the effects of oxygen-generating materials on tissue formation have remained largely unknown. Here, we investigate the impact of calcium peroxide (CPO)-based oxygen-generating microparticles (OMPs) on the osteogenic fate of human mesenchymal stem cells (hMSCs) under a severely oxygen deficient microenvironment. To this end, CPO is microencapsulated in polycaprolactone to generate OMPs with prolonged oxygen release. Gelatin methacryloyl (GelMA) hydrogels containing osteogenesis-inducing silicate nanoparticles (SNP hydrogels), OMPs (OMP hydrogels), or both SNP and OMP (SNP/OMP hydrogels) are engineered to comparatively study their effect on the osteogenic fate of hMSCs. OMP hydrogels associate with improved osteogenic differentiation under both normoxic and anoxic conditions. Bulk mRNAseq analyses suggest that OMP hydrogels under anoxia regulate osteogenic differentiation pathways more strongly than SNP/OMP or SNP hydrogels under either anoxia or normoxia. Subcutaneous implantations reveal a stronger host cell invasion in SNP hydrogels, resulting in increased vasculogenesis. Furthermore, time-dependent expression of different osteogenic factors reveals progressive differentiation of hMSCs in OMP, SNP, and SNP/OMP hydrogels. Our work demonstrates that endowing hydrogels with OMPs can induce, improve, and steer the formation of functional engineered living tissues, which holds potential for numerous biomedical applications, including tissue regeneration and organ replacement therapy.

Tunable and Compartmentalized Multimaterial Bioprinting for Complex Living Tissue Constructs.

Recapitulating inherent heterogeneity and complex microarchitectures within confined print volumes for developing implantable constructs that could maintain their structure in vivo has remained challenging. Here, we present a combinational multimaterial and embedded bioprinting approach to fabricate complex tissue constructs that can be implanted postprinting and retain their three-dimensional (3D) shape in vivo. The microfluidics-based single nozzle printhead with computer-controlled pneumatic pressure valves enables laminar flow-based voxelation of up to seven individual bioinks with rapid switching between various bioinks that can solve alignment issues generated during switching multiple nozzles. To improve the spatial organization of various bioinks, printing fidelity with the z-direction, and printing speed, self-healing and biodegradable colloidal gels as support baths are introduced to build complex geometries. Furthermore, the colloidal gels provide suitable microenvironments like native extracellular matrices (ECMs) for achieving cell growths and fast host cell invasion via interconnected microporous networks in vitro and in vivo. Multicompartment microfibers (i.e., solid, core-shell, or donut shape), composed of two different bioink fractions with various lengths or their intravolume space filled by two, four, and six bioink fractions, are successfully printed in the ECM-like support bath. We also print various acellular complex geometries such as pyramids, spirals, and perfusable branched/linear vessels. Successful fabrication of vascularized liver and skeletal muscle tissue constructs show albumin secretion and bundled muscle mimic fibers, respectively. The interconnected microporous networks of colloidal gels result in maintaining printed complex geometries while enabling rapid cell infiltration, in vivo.

Association of irisin levels with cardiac magnetic resonance, inflammatory, and biochemical parameters in patients with chronic heart failure versus controls.

BACKGROUND AND AIMS: Chronic heart failure (CHF) represents a significant cause of morbidity and mortality globally. Metabolic maladaptation has proven to be critical in the progression of this condition. Preclinical studies have shown that irisin, an adipomyokine involved in metabolic regulations, can induce positive cardioprotective effects by improving cardiac remodeling, cardiomyocyte viability, calcium delivery, and reducing inflammatory mediators. However, data on clinical studies identifying the associations between irisin levels and functional imaging parameters are scarce in CHF patients. The objective of this study was to determine the association of irisin levels with cardiac imaging measurements through cardiac magnetic resonance, inflammatory markers, and biochemical parameters in patients with CHF compared with control subjects. METHODS AND RESULTS: Thirty-two subjects diagnosed with CHF and thirty-two healthy controls were evaluated in a cross-sectional study. Serum irisin levels were significantly lower in patients with CHF than in controls. This is the first study to report a significant positive correlation between irisin levels and cardiac magnetic resonance parameters such as left ventricular ejection fraction, fraction shortening, and global radial strain. A negative correlation was demonstrated between irisin levels and brain natriuretic peptide, insulin levels, and Homeostatic model assessment for insulin resistance index. We did not observe significant correlations between irisin levels and inflammatory cytokines. CONCLUSIONS: Given the importance of fraction shortening and global radial strain as accurate markers of ventricular wall motion, these results support the hypothesis that irisin may play an essential role in maintaining an adequate myocardial wall architecture, deformation, and thickness.

Primary Varicella or Herpes Zoster? An Educational Case Report From the Primary Care Clinic.

Varicella-zoster virus is a pathogenic virus that can present itself as a primary infection or secondary infection, also known as herpes zoster. Recently, there has been a re-emergence of this vaccine-preventable disease due to gaps in vaccination. Primary varicella in immunocompetent adults is highly uncommon, and it could result in severe complications within this population. Given this delicate scenario, family physicians should be well trained to recognize the characteristic cutaneous lesions of varicella and dictate adequate management for these patients to obtain the best possible outcome and prevent life-threatening complications. We present the case of a 43-year-old immunocompetent woman with the onset of a generalized pruritic dermatosis characterized primarily by the presence of macules, vesicles, and crusts. The patients' lesions were compatible with primary varicella, and serological studies confirmed the diagnosis. Given the absence of acute complications in this individual, supportive treatment and close follow-up were the therapeutic modalities. This article focuses on the educational discussion of the primary differential diagnosis, evaluation for possible complications, and management of this uncommon clinical scenario. We also reinforce the importance of immunization in preventing re-emergent diseases as a critical element within primary care management.

Current Insights on the Role of Irisin in Endothelial Dysfunction.

Endothelial dysfunction is a crucial physiopathological mechanism for cardiovascular diseases that results from the harmful impact of metabolic disorders. Irisin, a recently discovered adipomyokine, has been shown to exert beneficial metabolic effects by increasing energy consumption, improving insulin sensitivity, and reducing the proinflammatory milieu. Multiple preclinical models have assessed irisin's possible role in the development of endothelial dysfunction, displaying that treatment with exogenous irisin can decrease the production of oxidative stress mediators by up-regulating Akt/mTOR/Nrf2 pathway, promote endothelial-dependent vasodilatation through the activation of AMPK-PI3K-AkteNOS pathway, and increase the endothelial cell viability by activation of ERK proliferation pathway and downregulation of Bad/Bax/Caspase 3 pro-apoptotic pathway. However, there is scarce evidence of these mechanisms in clinical studies, and available results are controversial. Some have shown negative correlations of irisin levels with the burden of coronary atherosclerosis and leukocyte adhesion molecules' expression. Others have demonstrated associations between irisin levels and increased atherosclerosis risk and higher carotid intima-media thickness. Since the role of irisin in endothelial damage remains unclear, in this review, we compare, contrast, and integrate the current knowledge from preclinical and clinical studies to elucidate the potential preventive role and the underlying mechanisms and pathways of irisin in endothelial dysfunction. This review also comprises original figures to illustrate these mechanisms.

Effects of electrically conductive nano-biomaterials on regulating cardiomyocyte behavior for cardiac repair and regeneration.

Myocardial infarction (MI) represents one of the most prevalent cardiovascular diseases, with a highly relevant and impactful role in public health. Despite the therapeutic advances of the last decades, MI still begets extensive death rates around the world. The pathophysiology of the disease correlates with cardiomyocyte necrosis, caused by an imbalance in the demand of oxygen to cardiac tissues, resulting from obstruction of the coronary flow. To alleviate the severe effects of MI, the use of various biomaterials exhibit vast potential in cardiac repair and regeneration, acting as native extracellular matrices. These hydrogels have been combined with nano sized or functional materials which possess unique electrical, mechanical, and topographical properties that play important roles in regulating phenotypes and the contractile function of cardiomyocytes even in adverse microenvironments. These nano-biomaterials' differential properties have led to substantial healing on in vivo cardiac injury models by promoting fibrotic scar reduction, hemodynamic function preservation, and benign cardiac remodeling. In this review, we discuss the interplay of the unique physical properties of electrically conductive nano-biomaterials, are able to manipulate the phenotypes and the electrophysiological behavior of cardiomyocytes in vitro, and can enhance heart regeneration in vivo. Consequently, the understanding of the decisive roles of the nano-biomaterials discussed in this review could be useful for designing novel nano-biomaterials in future research for cardiac tissue engineering and regeneration. STATEMENT OF SIGNIFICANCE: This study introduced and deciphered the understanding of the role of multimodal cues in recent advances of electrically conductive nano-biomaterials on cardiac tissue engineering. Compared with other review papers, which mainly describe these studies based on various types of electrically conductive nano-biomaterials, in this review paper we mainly discussed the interplay of the unique physical properties (electrical conductivity, mechanical properties, and topography) of electrically conductive nano-biomaterials, which would allow them to manipulate phenotypes and the electrophysiological behavior of cardiomyocytes in vitro and to enhance heart regeneration in vivo. Consequently, understanding the decisive roles of the nano-biomaterials discussed in the review could help design novel nano-biomaterials in future research for cardiac tissue engineering and regeneration.

Educative Hybrid Intervention as a Strategy for Reintegration to the Clinical Courses of Undergraduate Students in COVID-19 Pandemic.

The SARS-CoV-2 pandemic generated the need to modify the current clinical educational model with the challenge of promoting safety and the continuity of clinical education through the use of virtual platforms. Since clinical training in hospital institutions cannot be substituted, a strategic training plan was developed to guarantee protection, safety, and academic continuity for students upon returning to clinical clerkships. The objective of this project was to develop and evaluate the impact of a massive hybrid training plan as an educative strategy to give the theoretical and practical knowledge required for the safe return of undergraduate students to their respective clinical activities in the context of this pandemic. An academic program was designed through a massive hybrid strategy to train 616 undergraduate students studying clinical cycles by presential, virtual, synchronous, and asynchronous activities. To know the program's impact, a study based on an initial evaluation and a final evaluation was carried out to evaluate the acquisition of the critical knowledge and skills of the program. A significant difference was found between the means of the initial and final evaluations (p <0.001), as well as a high impact of the intervention (d 1.6). Significant improvements in the areas of COVID-19 initial management (p <0.001) and personal protective equipment use (p <0.001) were seen in the post-test when compared to the initial evaluation. Both a quantitative and a qualitative analysis were carried out, finding positive results on the course design, quality of didactic resources, and instructors' performance. Massive hybrid training is an effective strategy to facilitate the reintegration of undergraduate students into their face-to-face clinical rotations.

Metabolic shift precedes the resolution of inflammation in a cohort of patients undergoing bariatric and metabolic surgery.

Bariatric and metabolic surgery has shown to promote weight loss and reduce systemic inflammation. However, the sequence and timing of events regarding metabolic improvement and inflammation resolution has been rarely explored. Furthermore, data on inflammatory markers of Th17 and Th1 cell responses after bariatric surgery is scarce. We conducted a prospective study in subjects with obesity that underwent bariatric and metabolic surgery, with follow-ups at 3 and 6 months. Anthropometric and metabolic markers such as insulin levels, HOMA-IR, and lipid parameters declined significantly 3 months after surgery; while hs-CRP, TNF-α, IL-1ß, IL-6, and IL-8 serum concentrations decreased 6 months after the procedure. Concentrations of Th1 signature and driver cytokines, particularly IFN-γ, IL-12, and IL-18, and of Th17 driver IL-23 also decreased significantly after 6 months. Significant positive correlations between triglyceride levels and hs-CRP, IL-1ß, and IFN-γ concentrations, and between Apo B and IFN-γ levels were observed 6 months after bariatric and metabolic surgery. In addition, BMI was associated with hs-CRP and TNF-α concentrations. Fat mass correlated with hs-CRP, TNF-α, and IL-12. Analysis of the temporality of metabolic and inflammatory events suggests that improvement in the metabolic status occurs before resolution of systemic inflammation and may be a requisite for the later event.

3D bioprinted human iPSC-derived somatosensory constructs with functional and highly purified sensory neuron networks.

Engineering three-dimensional (3D) sensible tissue constructs, along with the complex microarchitecture wiring of the sensory nervous system, has been an ongoing challenge in the tissue engineering field. By combining 3D bioprinting and human pluripotent stem cell (hPSC) technologies, sensible tissue constructs could be engineered in a rapid, precise, and controllable manner to replicate 3D microarchitectures and mechanosensory functionalities of the native sensory tissue (e.g. response to external stimuli). Here, we introduce a biofabrication approach to create complex 3D microarchitecture wirings. We develop an hPSC-sensory neuron (SN) laden bioink using highly purified and functional SN populations to 3D bioprint microarchitecture wirings that demonstrate responsiveness to warm/cold sense-inducing chemicals and mechanical stress. Specifically, we tailor a conventional differentiation strategy to our purification method by utilizing p75 cell surface marker and DAPT treatment along with neuronal growth factors in order to selectively differentiate neural crest cells into SNs. To create spatial resolution in 3D architectures and grow SNs in custom patterns and directions, an induced pluripotent stem cell (iPSC)-SN-laden gelatin bioink was printed on laminin-coated substrates using extrusion-based bioprinting technique. Then the printed constructs were covered with a collagen matrix that guided SNs growing in the printed micropattern. Using a sacrificial bioprinting technique, the iPSC-SNs were seeded into the hollow microchannels created by sacrificial gelatin ink printed in the gelatin methacryloyl supporting bath, thereby demonstrating controllability over axon guidance in curved lines up to several tens of centimeters in length on 2D substrates and in straight microchannels in 3D matrices. Therefore, this biofabrication approach could be amenable to incorporate sensible SN networks into the engineered skin equivalents, regenerative skin implants, and augmented somatosensory neuro-prosthetics that have the potential to regenerate sensible functions by connecting host neuron systems in injured areas.

An Uncommon Presentation of Pyogenic Granuloma.

Benign vascular neoplasms are common clinical problems encountered in the practice of primary care. Pyogenic granulomas are one of the most common benign vascular lesions in young adults. Although the physiopathological mechanism for the development of this condition is still not well understood, it has been commonly associated with several triggers such as treatment with retinoids, biological agents, invasive cutaneous therapies and trauma. The development of pyogenic granulomas on sites of vascular malformations like port wine stains has been described in the literature to occur rarely. Most of these types of cases have been studied to occur in the setting of pregnancy and after cryotherapy or pulsated laser therapy. The aim of this article is to present the case of a 21-year-old man with a recent appearance of a pyogenic granuloma within an underlying port wine stain in the posterior cervical region without any history of triggers or risk factors. Excision of the vascular lesion was done, and histopathological report confirmed the diagnosis. The objective of this manuscript is to discuss the possible mechanisms involved in the development of this uncommon presentation and to summarize the current literature related to this clinical scenario.

Light-controlled growth factors release on tetrapodal ZnO-incorporated 3D-printed hydrogels for developing smart wound scaffold.

Advanced wound scaffolds that integrate active substances to treat chronic wounds have gained significant recent attention. While wound scaffolds and advanced functionalities have previously been incorporated into one medical device, the wirelessly triggered release of active substances has remained the focus of many research endeavors. To combine multiple functions including light-triggered activation, anti-septic, angiogenic, and moisturizing properties, we have developed a 3D printed hydrogel patch encapsulating vascular endothelial growth factor (VEGF) decorated with photoactive and antibacterial tetrapodal zinc oxide (t-ZnO) microparticles. To achieve the smart release of VEGF, t-ZnO was modified by chemical treatment and activated through UV/visible light exposure. This process would also make the surface rough and improve protein adhesion. The elastic modulus and degradation behavior of the composite hydrogels, which must match the wound healing process, were adjusted by changing t-ZnO concentrations. The t-ZnO-laden composite hydrogels can be printed with any desired micropattern to potentially create a modular elution of various growth factors. The VEGF decorated t-ZnO-laden hydrogel patches showed low cytotoxicity and improved angiogenic properties while maintaining antibacterial functions in vitro. In vivo tests showed promising results for the printed wound patches, with less immunogenicity and enhanced wound healing.