The Efficacy of Nanoparticle Delivery to Hypoxic Solid Tumors by ciRGD Co-Administration Depends on Neuropilin-1 and Neutrophil Levels.

The ability to improve nanoparticle delivery to solid tumors is an actively studied domain, where various mechanisms are looked into. In previous work, the authors have looked into nanoparticle size, tumor vessel normalization, and disintegration, and here it is aimed to continue this work by performing an in-depth mechanistic study on the use of ciRGD peptide co-administration. Using a multiparametric approach, it is observed that ciRGD can improve nanoparticle delivery to the tumor itself, but also to tumor cells specifically better than vessel normalization strategies. The effect depends on the level of tumor perfusion, hypoxia, neutrophil levels, and vessel permeability. This work shows that upon characterizing tumors for these parameters, conditions can be selected that can optimally benefit from ciRGD co-administration as a means to improve NP delivery to solid tumors.

Splenic Infarction: A Rare Complication of Infectious Mononucleosis.

Infectious mononucleosis (IM) is caused by Epstein-Barr virus (EBV), and the condition is characterized by sore throat, fever, lymphadenopathy, and atypical lymphocytosis. These infections are common in early childhood, with a second peak occurring in late adolescence. EBV is spread by contact with oral secretions. Most cases of IM are self-limited. However, there are associated complications, some of which can be serious and fatal. We report the case of a 20-year-old man with splenic infarction and exuberant peritonsillar abscess secondary to an EBV infection. This case highlights the importance of accurate diagnoses and frequent monitoring in IM patients, given the risk of airway obstruction.

Genetically encoded barcodes for correlative volume electron microscopy.

While genetically encoded reporters are common for fluorescence microscopy, equivalent multiplexable gene reporters for electron microscopy (EM) are still scarce. Here, by installing a variable number of fixation-stable metal-interacting moieties in the lumen of encapsulin nanocompartments of different sizes, we developed a suite of spherically symmetric and concentric barcodes (EMcapsulins) that are readable by standard EM techniques. Six classes of EMcapsulins could be automatically segmented and differentiated. The coding capacity was further increased by arranging several EMcapsulins into distinct patterns via a set of rigid spacers of variable length. Fluorescent EMcapsulins were expressed to monitor subcellular structures in light and EM. Neuronal expression in Drosophila and mouse brains enabled the automatic identification of genetically defined cells in EM. EMcapsulins are compatible with transmission EM, scanning EM and focused ion beam scanning EM. The expandable palette of genetically controlled EM-readable barcodes can augment anatomical EM images with multiplexed gene expression maps.

Influence of the Preparation Method on the Structural, Morphological and Dielectric Properties of FeNbO4 Ceramics.

In this work, iron niobate (FeNbO4) was prepared via two processes based on the sol-gel method: colloidal gel and polymeric gel. The obtained powders were submitted to heat treatments at different temperatures based on the results obtained via differential thermal analysis. The structures of the prepared samples were characterized via X-ray diffraction and the morphology was characterized via scanning electron microscopy. The dielectric measurements were performed in the radiofrequency region using the impedance spectroscopy technique and in the microwave range using the resonant cavity method. The influence of the preparation method was noticeable in the structural, morphological and dielectric properties of the studied samples. The polymeric gel method promoted the formation of monoclinic and orthorhombic iron niobate at lower temperatures. The differences in the samples' morphology were also remarkable, both in the size and shape of the grains. The dielectric characterization revealed that the dielectric constant and the dielectric losses had the same order of magnitude and similar trends. A relaxation mechanism was identified in all the samples.

Kala-Azar: A Case Report.

Leishmaniasis is a zoonosis caused by unicellular protozoans Leishmania. The transmission can be zoonotic or anthroponotic, depending on the species, and the main vector is the phlebotomine sandfly. The disease is endemic in the tropics of Asia and Africa but is considered rare in Portugal, especially in immunocompetent hosts. Its main clinical syndromes constitute cutaneous leishmaniasis, mucocutaneous disease, and visceral leishmaniasis. The latter is also known as kala-azar and is caused by the infection of the phagocytes of the reticuloendothelial system, causing the typical symptoms: fever, hepatosplenomegaly, and pancytopenia. The clinical manifestations are non-specific, frequently causing a delay in the diagnosis, especially in nonendemic areas and immunocompetent hosts. Early diagnosis and treatment are essential, given the high mortality rate in untreated patients. The diagnosis is based on the direct visualization of the protozoan and molecular methods, such as polymerase chain reaction tests. Amphotericin B is considered the first-line treatment. We present a case of visceral leishmaniasis in an immunocompetent patient with fever, hepatosplenomegaly, and pancytopenia.

Hemophagocytic Lymphohistiocytosis Secondary to Chronic Lymphocytic Leukemia Progression.

Hemophagocytic lymphohistiocytosis (HLH) is an acute, rare systemic hyperinflammatory disorder caused by a dysregulated immune cell function and massive cytokine release, often leading to multiple organ involvement and failure. Fever, hepatosplenomegaly, cytopenia, elevated liver enzymes, hypertriglyceridemia, and hyperferritinemia are the hallmarks of the disease. Its primary (genetic) form is typically observed in pediatric patients and its secondary, acquired form is seen in adult patients with an underlying autoimmune, malignant, or infectious disease. It is not frequently reported in patients with chronic lymphocytic leukemia (CLL) without an infectious or pharmacological trigger. We present a case of a 71-year-old patient with hemophagocytic lymphohistiocytosis due to the progression of chronic lymphocytic leukemia.

Mycoplasma pneumoniae Infection With Cavitated Lung Lesions: A Case Report.

Mycoplasma pneumoniae (MP) is a common etiologic agent involved in community-acquired atypical bacterial pneumonia. In severe cases, M. pneumoniae can cause cavitated lung lesions. We describe the case of a 55-year-old male seen at the emergency department with complaints of cough, fever, dyspnea, pleuritic chest pain, nausea, anorexia, asthenia, and night sweats. Cavitated lesions in the upper lobes of both lungs were documented on thoracic computed tomography (CT). An extensive investigation ruled out several infectious and non-infectious causes. The only positive result was a high immunoglobulin M (IgM) titer for M. pneumoniae. The patient was treated with azithromycin and exhibited rapid clinical improvement. Three months later, a repeat thoracic computed tomography showed the resolution of the cavitated lesions. In this rare case of M. pneumoniae pneumonia with cavitated lesions, early identification of the etiologic agent and prompt antibiotic therapy led to the resolution of the cavitated lung lesions.

A Rare and Surprising Case of Spontaneous Type B Carotid-Cavernous Fistula in an Internal Medicine Ward.

Carotid-cavernous fistulas are abnormal communications between the carotid arteries and the cavernous sinus. They can be spontaneous, which is rare, or acquired, most often post-traumatic. We describe the case of a 59-year-old woman with complaints of right-sided red eye and blurred vision that did not improve with antibiotic treatment for bacterial conjunctivitis, progressing to what appeared to be post-septal cellulitis. The patient had exuberant chemosis, diplopia, VI cranial nerve palsy, and elevated intraocular pressure in the right eye. Computed tomography of the orbits showed right-sided thickening of the soft tissues of the upper eyelid and the medial and lateral rectus muscles, and an enlargement of the ipsilateral superior ophthalmic vein. However, antibiotics did not cause any kind of improvement. After a laborious diagnostic march, the diagnosis of a rare case of Barrow type B spontaneous carotid-cavernous fistula was confirmed. The patient underwent confirmatory angiography with endovascular treatment at the same time, showing rapid improvement after the procedure, without any sequelae. It is of great importance that clinicians are alert to this diagnosis, as diagnostic and therapeutic delay can lead to severe ocular compromise. In patients with a presumptive diagnosis of conjunctivitis and/or orbital cellulitis that does not improve with antibiotic treatment, the differential diagnosis with this rare entity should be considered, so that the appropriate treatment can be timely instituted.

Gold nanoparticle delivery to solid tumors: a multiparametric study on particle size and the tumor microenvironment.

Nanoparticle (NP) delivery to solid tumors remains an actively studied field, where several recent studies have shed new insights into the underlying mechanisms and the still overall poor efficacy. In the present study, Au NPs of different sizes were used as model systems to address this topic, where delivery of the systemically administered NPs to the tumor as a whole or to tumor cells specifically was examined in view of a broad range of tumor-associated parameters. Using non-invasive imaging combined with histology, immunohistochemistry, single-cell spatial RNA expression and image-based single cell cytometry revealed a size-dependent complex interaction of multiple parameters that promoted tumor and tumor-cell specific NP delivery. Interestingly, the data show that most NPs are sequestered by tumor-associated macrophages and cancer-associated fibroblasts, while only few NPs reach the actual tumor cells. While perfusion is important, leaky blood vessels were found not to promote NP delivery, but rather that delivery efficacy correlated with the maturity level of tumor-associated blood vessels. In line with recent studies, we found that the presence of specialized endothelial cells, expressing high levels of CD276 and Plvap promoted both tumor delivery and tumor cell-specific delivery of NPs. This study identifies several parameters that can be used to determine the suitability of NP delivery to the tumor region or to tumor cells specifically, and enables personalized approaches for maximal delivery of nanoformulations to the targeted tumor.

Spinal Cord Infarction Presenting as Right-Sided Upper Back Pain: A Case Report.

Spinal cord infarction is a very rare event with a wide variety of symptoms at presentation. We describe the case of a 39-year-old man who presented to the emergency department with atypical chest pain. The initial investigations were non-diagnostic, and the patient was admitted for surveillance. On the second day of admission, he developed neurologic deficits; a second computed tomography showed a medullary infarction at levels C5-T2. Dual antiplatelet therapy was initiated. An extensive study on the underlying etiology was performed. It was considered to be an idiopathic event. The patient was discharged to a rehabilitation center for bladder training and motor training due to quadriplegia level D on Asia Impairment Scale with a C6 neurological level with left predominance and a hand grip deficit that disabled him to grab objects. This case report describes a rare event with a biphasic ictus at presentation. It highlights the difficulty in managing this pathology because of limited clinical data.

Isolated Left Ventricular Noncompaction Presenting With Heart Failure With Reduced Ejection Fraction and Intrahospital Cardiac Arrest: A Case Report and Literature Review.

Left ventricular noncompaction (LVNC) is characterized by a bilayered appearance of the myocardium with excessive trabeculations and deep intertrabecular recesses. Manifestations of this condition are widely variable, ranging from incidental findings in asymptomatic individuals to symptomatic heart failure, conduction abnormalities, tachyarrhythmia, and sudden cardiac death. Heart failure, ventricular arrhythmias, and systemic embolisms are the most frequent cardiovascular complications. We describe a case of a 53-year-old woman who presented to the emergency department with acute presentation of previously unknown heart failure with reduced ejection fraction and was diagnosed with LVNC. During hospitalization, the patient presented a defibrillated cardiac arrest rhythm, which was resuscitated after six minutes, and then treated with the placement of an implantable cardioverter defibrillator. After two years of follow-up with optimized medical therapy, the patient currently is asymptomatic and with a preserved ejection fraction.

Quincke's Disease Presenting After Cocaine Exposure.

Quincke's disease is a very rare form of upper airway angioedema, and it is characterized by a well-localized edematous reaction. Its epidemiology is not documented due to the rarity of this condition. Causes include allergic reactions, infectious diseases, and trauma, among others.  This article describes a rare case of a 27-year-old man who presented to the Emergency Department with isolated uvular edema associated with cocaine exposure.

A Suicide Attempt: Deltamethrin Intoxication.

Poisoning is a frequent cause of emergency department visits, with attempted suicide accounting for up to two-thirds of all fatalities from pesticide poisoning. Despite extensive pyrethroid use worldwide, relatively few cases of human poisoning have been reported in the literature. Although most pesticide use occurs in the developed world, 99% of all acute pesticide poisoning occurs in developing countries. Deltamethrin poisoning is uncommon, with fewer than 10 deaths reported following ingestion or occupational exposure. The present case report describes deltamethrin intoxication due to intentional oral ingestion in a suicide attempt, resulting in a life-threatening combination of seizures and coma due to non-convulsive status epilepticus. LEARNING POINTS: Up to two-thirds of all fatalities from pesticide poisoning are due to suicide.Organophosphate or organochloride poisoning can mimic pyrethroid poisoning.Poisoning with deltamethrin, which belongs to the pyrethroid family, is uncommon; there is no antidote, with supportive and symptom-directed treatment being the gold standard.

A Rare Case of Sarcoidosis With Urologic Symptoms As the Presenting Feature.

Sarcoidosis is a multisystem idiopathic disease that can affect virtually any organ of the human body. However, genitourinary tract involvement is rare. We describe the case of a 33-year-old man with post-coital right scrotal pain. Scrotal ultrasound showed two vascularized nodular lesions in the right testicle and one in the left. A thoracic and abdominopelvic computed tomography scan showed micronodular infiltrate in the liver, spleen, lungs, and millimetric retroperitoneal and iliac lymph nodes. Levels of alpha-fetoprotein and human chorionic gonadotropin beta were normal. On positron emission tomography, the previously documented micronodular infiltrate exhibited features suggestive of an inflammatory etiology. The aspiration cytology of an iliac ganglion was described as normal, with no malignant cells. A liver biopsy revealed non-caseating epithelioid granulomas characteristic of granulomatous hepatitis. After exclusion of other causes of granulomatous inflammation, conjugation of clinical and histological features led us to the diagnosis of sarcoidosis with pulmonary, hepatic, splenic, and genitourinary involvement. This clinical report describes one of the rare occasions when the reproductive tract is affected by sarcoidosis and is the first organ to present signs of involvement by the disease, which reinforces the importance of considering sarcoidosis in the differential diagnosis of urologic conditions. The diagnosis of testicular sarcoidosis is challenging and the issue of its impact on fertility is particularly important.

Ultrasound-Guided Injection of a Tendon-Compatible Hyaluronic Acid Preparation for the Management of Partial Thickness Rotator Cuff Tear: A Case Report.

Partial-thickness rotator cuff (RC) tear constitutes the most common cause of shoulder pain and disability. Its management is challenging, and a conservative approach is suggested as a first-line treatment. Nonetheless, minimally invasive approaches have been described in clinical trials, such as ultrasound (US)-guided tendon-compatible hyaluronic acid (HA) injection preparation in the rupture site. HA is believed to fill the intradermal space and thus support the regeneration process by its integration in the damaged extracellular matrix. A reduced healing period required for a tendon tear when treated with a tendon-compatible HA preparation compared to placebo has been previously described in the literature, enabling a more rapid return to exercise. The current study aims to provide a thorough analysis of a regular CrossFit practitioner case with a partial-thickness bursal-side RC tear of the anterior Supraspinatus (SS) fibers with 7 mm on the anteroposterior axis and 5 mm on the longitudinal axis in magnetic resonance imaging (MRI), that caused pain, and limited functional status. Two US-guided injections of a specific high molecular weight (one million Daltons) tendon-compatible HA preparation (12 mg/1.2 mL) separated by six weeks were performed. A supervised rehabilitation protocol was then followed and training was progressively introduced. In the 12 weeks follow-up visits, a reduction in pain intensity was noticed as well as an improvement of the functional status. At the six months, one year, and two years follow-ups, no pain and a normal joint function were observed, despite engaging in continuous overload and overhead activities during CrossFit practice. MRI was performed one year after the intervention presenting a reduction of the injury size and only a partial intrasubstance tear of 4 mm was observed in the SS tendon. US imaging in the two years follow-up presented an additional reduction in tear size to 3.9 mm length. No adverse effects were reported. It is thus believed that US-guided injections of tendon-compatible HA on partial-thickness RC tears can be a feasible and effective treatment option in the management of this frequent pathology, and more studies, particularly randomized controlled trials, should be implemented to substantiate and validate this approach.

Fabrication of 3D scaffolds based on fully biobased unsaturated polyester resins by microstereo-lithography.

Additive Manufacturing (AM) technologies are an effective route to fabricate tailor made scaffolds for tissue engineering (TE) and regenerative medicine, with microstereo-lithography (µSLA) being one of the most promising techniques to produce high quality 3D structures. Here, we report the crosslinking studies of fully biobased unsaturated polyesters (UPs) with 2-hydroxyethyl methacrylate (HEMA) as the unsaturated monomer (UM), using thermal and µSLA crosslinking processes. The resulting resins were fully characterized in terms of their thermal and mechanical properties. Determination of gel content, water contact angle, topography and morphology analysis by atomic force microscopy and scanning electron microscopy were also performed. The results show that the developed UP resins (UPRs) have promising properties for µSLA.In vitrocytotoxicity assays performed with 3T3-L1 cell lines showed that the untreated scaffolds exhibited a maximum cellular viability around 60%, which was attributed to the acidic nature of the UPRs. The treatment of the UPRs and scaffolds with ethanol (EtOH) improved the cellular viability to 100%. The data presented in this manuscript contribute to improve the performance of biobased UPs in AM.

Progressive Multifocal Leukoencephalopathy in a Chemotherapy-Naive Patient With Chronic Lymphocytic Leukemia: A Case Report.

Progressive multifocal leukoencephalopathy is a rare, progressive demyelinating disease of the central nervous system caused by reactivation and replication of the John Cunningham (JC) virus in cerebral oligodendrocytes. The JC virus is a small ubiquitous polyomavirus that can be detected in up to 50% of the adult population. It affects almost exclusively immunocompromised patients and is generally observed in patients with acquired immunodeficiency syndrome and patients with hematologic malignancies and autoimmune or chronic inflammatory diseases medicated with immunosuppressive and immunomodulatory drugs. However, it is rarely described in patients with hematologic malignancies, not undergoing chemotherapy or immunosuppressive therapy. It has a poor prognosis, and the treatment is based on restoring the immune system, given that no specific antiviral treatment is available. We present a case of a chemotherapy-naive patient with chronic lymphocytic leukemia associated with progressive multifocal leukoencephalopathy.

Therapeutic Options in Refractory Evans Syndrome: A Case Report.

Evans syndrome is a rare autoimmune disease, characterized by at least two immune cytopenias, most frequently anemia and thrombocytopenia and rarely immune neutropenia. It has a variable clinical presentation and is rarely diagnosed in adults. It can be idiopathic or secondary to lymphoproliferative disease, infections, autoimmune diseases, drugs, and immunodeficiencies in about 50% of cases. It is characterized by a chronic, relapsing, potentially fatal course due to its hemorrhagic complications as well as complications associated with the long-term immunosuppressive treatment required to control the disease, such as infectious diseases, and cardiovascular and renal complications. Its prognosis depends on the underlying cause. Because of its rarity, the treatment is empirical, based mostly on case series and recommendations for the treatment of other immune cytopenias. The underlying disease and demographic characteristics also play an important role in choosing the treatment, which should be adapted individually to each patient. We present a case of an elderly patient with idiopathic autoimmune hemolytic anemia and thrombocytopenia, refractory to various treatment options.

Neurosyphilis: The Great Imitator.

Syphilis is a sexually transmitted disease caused by spirochete Treponema pallidum, with a growing incidence documented in recent years. Its clinical course is divided into three phases - primary, secondary, and tertiary syphilis - and virtually any organ can be affected, resulting in diverse clinical manifestations, making the diagnosis challenging. Neurosyphilis is a progressive, destructive disease of the central nervous system (CNS) that can develop at any stage of the infection, leading to meningeal involvement, meningovascular disease, or parenchymal syphilis (including tabes dorsalis and general paresis). Its clinical manifestations are heterogeneous and vary from focal neurologic signs to neuropsychiatric manifestations. The diagnosis is based mainly on the clinical picture and study of cerebrospinal fluid. Neuroimaging is helpful and sometimes essential, with magnetic resonance imaging being the most sensitive radiologic method, although there are no pathognomonic radiologic signs. Treatment of all forms of neurosyphilis is based on parenteral penicillin. We present a case of neurosyphilis in a patient presenting with a subacute confusional state and initial imaging findings suggestive of metastatic CNS lesions.

PINK1: A Bridge between Mitochondria and Parkinson's Disease.

Mitochondria are known as highly dynamic organelles essential for energy production. Intriguingly, in the recent years, mitochondria have revealed the ability to maintain cell homeostasis and ultimately regulate cell fate. This regulation is achieved by evoking mitochondrial quality control pathways that are capable of sensing the overall status of the cellular environment. In a first instance, actions to maintain a robust pool of mitochondria take place; however, if unsuccessful, measures that lead to overall cell death occur. One of the central key players of these mitochondrial quality control pathways is PINK1 (PTEN-induce putative kinase), a mitochondrial targeted kinase. PINK1 is known to interact with several substrates to regulate mitochondrial functions, and not only is responsible for triggering mitochondrial clearance via mitophagy, but also participates in maintenance of mitochondrial functions and homeostasis, under healthy conditions. Moreover, PINK1 has been associated with the familial form of Parkinson's disease (PD). Growing evidence has strongly linked mitochondrial homeostasis to the central nervous system (CNS), a system that is replenished with high energy demanding long-lasting neuronal cells. Moreover, sporadic cases of PD have also revealed mitochondrial impairments. Thus, one could speculate that mitochondrial homeostasis is the common denominator in these two forms of the disease, and PINK1 may play a central role in maintaining mitochondrial homeostasis. In this review, we will discuss the role of PINK1 in the mitochondrial physiology and scrutinize its role in the cascade of PD pathology.