Current perspective on infections and mitigation strategies in primary systemic vasculitis.

PURPOSE OF REVIEW: The purpose of this review is to summarize and evaluate most recent evidence on the epidemiology of infections and associated risk factors in patients with primary systemic vasculitides (PSV), as well as discuss mitigation strategies including the risk of antibiotic prophylaxis. RECENT FINDINGS: Infections remain one of the leading causes of mortality in patients with PSV, with rates of severe infection ranging from 16 to 40% in different cohorts. Older age, frailty, renal and pulmonary involvement, and higher burden of comorbidities have been recognized as important patient-associated risk factors. Treatments including higher cumulative doses of glucocorticoids are associated with an increased risk of infections, and recent studies show the potential benefit of interventions such as reduced-dose glucocorticoid regimens. Existing mitigation strategies include screening, vaccination, and infection prophylaxis. The latter remains particularly important for Pneumocystis jirovecii pneumonia; however, the benefit-risk ratio seems to be less clear outside of induction phase (i.e., high dose of glucocorticoids) and optimal treatment duration remains less clear. Patients with PSV are at increased risk of infections, due to disease itself, comorbidities, and treatment side effects. Awareness of the timing and types of infection, as well as mitigation strategies are imperative to ensure treatment success and survival for patients.

In Vivo Evaluation of Sgc8-c Aptamer as a Molecular Imaging Probe for Colon Cancer in a Mouse Xenograft Model.

Recent biotechnological applications in the field of clinical oncology led to the identification of new biomarkers as molecular targets of cancer, and to broad developments in the field of personalized medicine. Aptamers are oligonucleotides (ssDNA or RNA) that are selected to specifically recognize a molecular target with high affinity and specificity. Based on this, new horizons for their use as molecular imaging probes are being explored. The objective of this work was to evaluate the Sgc8-c aptamer conjugated with Alexa Fluor 647 fluorophore as an imaging probe in a colon tumor xenograft mouse model, with potential application in molecular imaging. In this study, the LS174T cell line was used to induce colorectal adenocarcinoma in nude mice. After confirmation of PTK7 overexpression by immunohistochemistry, in vivo studies were performed. Pharmacokinetic, in vivo and ex vivo biodistribution imaging, and a competition assay were evaluated by fluorescence imaging. In vivo visualization of the probe in the tumors was assessed two hours after aptamer probe administration, exhibiting excellent tumor-to-background ratios in biodistribution studies and high specificity in the competition test. Our results demonstrated the functionality of Scg8-c as an imaging probe for colon cancer, with potential clinical applications.

Isolation and molecular characterization of four novel Neospora caninum strains.

Neospora caninum causes neosporosis, a leading cause of bovine abortion worldwide. Uruguay is a developing economy in South America that produces milk to feed seven times its population annually. Naturally, dairy production is paramount to the country's economy, and bovine reproductive failure impacts it profoundly. Recent studies demonstrated that the vast majority of infectious abortions in dairy cows are caused by N. caninum. To delve into the local situation and contextualize it within the international standing, we set out to characterize the Uruguayan N. caninum strains. For this, we isolated four distinct strains and determined by microsatellite typing that these represent three unique genetic lineages, distinct from those reported previously in the region or elsewhere. An unbiased analysis of the current worldwide genetic diversity of N. caninum strains known, whereby six typing clusters can be resolved, revealed that three of the four Uruguayan strains group closely with regional strains from Argentina and Brazil. The remaining strain groups in an unrelated genetic cluster, suggesting multiple origins of the local strains. Microsatellite typing of N. caninum DNA from fetuses opportunistically collected from local dairy farms correlated more often with one of the isolates. Overall, our results contribute to further understanding of genetic diversity among strains of N. caninum both regionally and worldwide.

Establishment of an environmental microbiological monitoring program in a mice barrier facility.

Rodents used in biomedical research are maintained behind barriers to exclude microbial contaminants. Several check points have to be monitored to eliminate the potential of introducing adventitious agents into the facility. Microbiological monitoring of a mouse facility environment enables to evaluate the efficiency of sanitization and cleaning procedures, air quality, and technician good practices. At our SPF mouse facility, we implemented an environmental microbiological monitoring program based in sedimentation and swabbing, inexpensive and easy to use methods. The aim of this work was to evaluate the results and the efficiency of the monitoring program after seven years. The median for bacteria and fungi counts in the SPF sampled areas was ≤2 CFU/2 h for settle plates and <1 CFU per swabbing plate, satisfying the requirements for grade C of the EU-GMP, with some modifications. The environmental monitoring program was useful to detect early warning of problems and enabled us to define a safe range of microbiological counts. In addition, SPF status defined for our mice was maintained throughout this study, confirmed by our HM program. This work could encourage directors and technicians of other mouse facilities in Latin America and rest of the world to implement this kind of program.

Prevalence of High-Risk Genotypes of Human Papillomavirus: Women Diagnosed with Premalignant and Malignant Pap Smear Tests in Southern Ecuador.

Human papillomavirus (HPV) is the primary infectious agent for the development of cervical cancer, although the presence of the virus alone is insufficient for viral development and proliferation; this can be attributed to the increase in potential oncogenic risk, along with other risk factors. In the present investigation, the prevalence of high-risk HPV was determined from samples of premalignant or malignant cervical cytology in women from the southern region of Ecuador. The kit we used was able to detect genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. In addition, 64.5% of the analyzed samples were positive for HPV, with genotypes 16 and 18 being the most prevalent (16 was detected in 148 samples and 18 in 108). Genotypes 58 and 51 were the third most frequent simple and multiple infections, respectively. The data are very similar to those obtained worldwide, suggesting that the strategy of sex education, and the use of vaccines as primary prevention agents, could significantly decrease the incidence and mortality rate of cervical cancer in the southern region of Ecuador.

[Central Venous Catheters with Subcutaneous Reservoir with Implementation Braquial: An Alternative to Consider]. / Catéteres venosos centrales con reservorio subcutáneo de implantación braquial.

Administering treatments in patients with malignancies must be performed by nursing professionals with experience and knowledge of the pathology being treated, drugs, techniques and devices used for administration. The implantation of a venous access device with subcutaneous reservoir offers the possibility of multiple and long-term frequent injections and also blood extraction from a less invasive way. They are aesthetically more acceptable than external catheters, they have a lower risk of accidental release and infection, they require less care and they allow extra-hospital treatment. Another advantage to consider is that they cause less limitations in daily life, which is associated with an increased quality of life. Placement of devices with camera of brachial location, was done by the first time by venotomy technique with many doubts; however, the results of placement success and the decreased complications, improved significantly when the placement began performing by vascular radiology services using fluoroscopy and ultrasound. Particularly striking is the success rate (between 99% and 100%) with a 0% rate of placement complications (hemorrhage, pneumothorax). The infection rate is not flashy, remaining within normal parameters in relation to the pectoral systems. The rates of deep vein thrombosis (DVT) are assumable and they are consistent with other related studies. These devices are particularly useful in patients with abnormalities of chest wall such as dermal carcinoma and tumor shell in patients with breast cancer (tumour the bottom shell). And also when there are open wounds in the chest area, such as tracheotomy or fibrosis caused by radiation therapy, or in the presence of scars of flaps after surgery in head and neck cancer (or when it is expected that the patient will receive this surgery), severe kyphosis, obese patients and patients with respiratory failure.

Imaging Challenges and Developments in Large-vessel Vasculitis.

Vascular imaging is an integral part of large-vessel vasculitis (LVV) evaluation and management. Several imaging modalities are currently employed in clinical practice including vascular ultrasound, computed tomography angiography, MRI and magnetic resonance angiography, and 18F-fluorodeoxyglucose PET. Well-established roles for imaging in LVV include disease diagnosis and assessment of luminal lesions reflecting vascular damage. The ability of imaging to determine treatment response, monitor disease activity, and predict future arterial damage is an area of active research.

New insights into phenotype and genotype relationships in Neospora caninum.

The successful isolation of four new Neospora caninum strains from different regions and with different backgrounds (obtained from an abortion storm or congenitally infected and asymptomatic calves) allowed us previously to characterize natural isolates, finding differences in phenotype and microsatellites. Given the variability observed, we wondered in this work whether these differences had consequences in virulence, invasion and vertical transmission using cell cultures and murine neosporosis models. In addition, we performed the genomic analysis and SNP comparative studies of the NcURU isolates. The results obtained in this work allowed us to establish that NcURU isolates are of low virulence and have unique phenotypic characteristics. Likewise, sequencing their genomes has allowed us to delve into the genetic singularities underlying these phenotypes, as well as the common mutated genes. This work opens a new perspective for diagnostic purposes and formulating possible vaccines based on attenuated strains.

Trypanosoma cruzi Isolates Naturally Adapted to Congenital Transmission Display a Unique Strategy of Transplacental Passage.

Chagas disease is mainly transmitted by vertical transmission (VT) in nonendemic areas and in endemic areas where vector control programs have been successful. For the present study, we isolated natural Trypanosoma cruzi strains vertically transmitted through three generations and proceeded to study their molecular mechanism of VT using mice. No parasitemia was detected in immunocompetent mice, but the parasites were able to induce an immune response and colonize different organs. VT experiments revealed that infection with different strains did not affect mating, pregnancy, or resorption, but despite low parasitemia, VT strains reached the placenta and resulted in higher vertical transmission rates than strains of either moderate or high virulence. While the virulent strain modulated more than 2,500 placental genes, VT strains modulated 150, and only 29 genes are shared between them. VT strains downregulated genes associated with cell division and replication and upregulated immunomodulatory genes, leading to anti-inflammatory responses and tolerance. The virulent strain stimulated a strong proinflammatory immune response, and this molecular footprint correlated with histopathological analyses. We describe a unique placental response regarding the passage of T. cruzi VT isolates across the maternal-fetal interphase, challenging the current knowledge derived mainly from studies of laboratory-adapted or highly virulent strains. IMPORTANCE The main findings of this study are that we determined that there are Trypanosoma cruzi strains adapted to transplacental transmission and completely different from the commonly used laboratory reference strains. This implies a specific strategy for the vertical transmission of Chagas disease. It is impressive that the strains specialized for vertical transmission modify the gene expression of the placenta in a totally different way than the reference strains. In addition, we describe isolates of T. cruzi that cannot be transmitted transplacentally. Taken together, these results open up new insights into the molecular mechanisms of this insect vector-independent transmission form.

A potential pesticides exposure index (PPEI) for developing countries: Applied in a transboundary basin.

The potential risk of pesticide exposure in developing countries needs further study as data are limited and simple tools to assess the risks on human health and the environment caused by pesticides are lacking. This article introduces a potential pesticides exposure index (PPEI) as a modeling tool to assess the risk of human and environmental pesticide exposure in agricultural basins. The PPEI is based on a number of factors including: human population centers and their proximity to agricultural crops, the toxicological properties of pesticides, and their application frequency. The index was applied to a region in southern Ecuador (approximately 7200 km2 ) where corn, rice, and sugarcane are the predominant crops, and where hot spots with the highest vulnerability to pesticide residues were identified. Of the total of 5326 neighborhoods for the entire study area, 1030 had high, 1124 had medium, and 1009 had low PPEI scores. Among the practical uses of PPEI are to help to assist regulatory agencies and academics evaluate the effects of land use policies on pesticide vulnerability. Also, it can be easily expanded to include other parameters, such as data from other agricultural crops, or frequency of pesticide application. The PPEI can be a valuable indicator of risk of pesticide exposure, as it is reliable and applicable to developing countries, where data and resources are limited. Integr Environ Assess Manag 2022;18:187-197. © 2021 SETAC.

Pin-Pointing the Key Hubs in the IFN-γ Pathway Responding to SARS-CoV-2 Infection.

Interferon gamma (IFN-γ) may be potential adjuvant immunotherapy for COVID-19 patients. In this work, we assessed gene expression profiles associated with the IFN-γ pathway in response to SARS-CoV-2 infection. Employing a case-control study from SARS-CoV-2-positive and -negative patients, we identified IFN-γ-associated pathways to be enriched in positive patients. Bioinformatics analyses showed upregulation of MAP2K6, CBL, RUNX3, STAT1, and JAK2 in COVID-19-positive vs. -negative patients. A positive correlation was observed between STAT1/JAK2, which varied alongside the patient's viral load. Expression of MX1, MX2, ISG15, and OAS1 (four well-known IFN-stimulated genes (ISGs)) displayed upregulation in COVID-19-positive vs. -negative patients. Integrative analyses showcased higher levels of ISGs, which were associated with increased viral load and STAT1/JAK2 expression. Confirmation of ISGs up-regulation was performed in vitro using the A549 lung cell line treated with Poly (I:C), a synthetic analog of viral double-stranded RNA; and in different pulmonary human cell lines and ferret tracheal biopsies infected with SARS-CoV-2. A pre-clinical murine model of Coronavirus infection confirmed findings displaying increased ISGs in the liver and lungs from infected mice. Altogether, these results demonstrate the role of IFN-γ and ISGs in response to SARS-CoV-2 infection, highlighting alternative druggable targets that can boost the host response.

PD-1/PD-L1 blockade abrogates a dysfunctional innate-adaptive immune axis in critical ß-coronavirus disease.

Severe COVID-19 is associated with hyperinflammation and weak T cell responses against SARS-CoV-2. However, the links between those processes remain partially characterized. Moreover, whether and how therapeutically manipulating T cells may benefit patients are unknown. Our genetic and pharmacological evidence demonstrates that the ion channel TMEM176B inhibited inflammasome activation triggered by SARS-CoV-2 and SARS-CoV-2-related murine ß-coronavirus. Tmem176b-/- mice infected with murine ß-coronavirus developed inflammasome-dependent T cell dysfunction and critical disease, which was controlled by modulating dysfunctional T cells with PD-1 blockers. In critical COVID-19, inflammasome activation correlated with dysfunctional T cells and low monocytic TMEM176B expression, whereas PD-L1 blockade rescued T cell functionality. Here, we mechanistically link T cell dysfunction and inflammation, supporting a cancer immunotherapy to reinforce T cell immunity in critical ß-coronavirus disease.

The risk and severity of stroke in patients with atrial fibrillation and gout: A National Representative Database study.

BACKGROUND: It has been shown that gout is associated with left atrium remodeling and a pro-inflammatory state leading to the development of atrial fibrillation (AF). There is limited evidence whether gout increases the risk of stroke in patients with AF. We assessed the incidence of gout and the risk of stroke in patients with AF. METHODS: This is a retrospective cohort study using the 2016 US National Inpatient Sample (NIS) based on ICD-10 codes. The outcomes of the study were the risk and severity of new stroke in patients with pre-existing AF and gout. RESULTS: In 2016, we identified 3 844 057 patients admitted to the hospitals in NIS with history of AF, of which 240 875 had history of gout. Patients with AF and gout have higher risk of new stroke (OR 2.07 [1.97-2.19], P < .001), and this risk remains significantly elevated after adjusting for CHADS2VASC score variables, chronic kidney disease, dyslipidemia, obesity, and race (OR 1.10 [1.01-1.11], P = .041). However, presence of gout in patients with AF was not associated with all-cause in-hospital mortality, need for mechanical ventilation, percutaneous gastrostomy tube insertion, or discharge to skilled nursing facility. CONCLUSION: Subjects with AF and gout compared to AF alone had an increased risk of new stroke, but presence of gout was not associated with stroke severity. There is a potential role of gout as a risk factor or a risk marker for stroke in subjects with AF.

A Nitroalkene Benzoic Acid Derivative Targets Reactive Microglia and Prolongs Survival in an Inherited Model of ALS via NF-κB Inhibition.

Motor neuron degeneration and neuroinflammation are the most striking pathological features of amyotrophic lateral sclerosis (ALS). ALS currently has no cure and approved drugs have only a modest clinically therapeutic effect in patients. Drugs targeting different deleterious inflammatory pathways in ALS appear as promising therapeutic alternatives. Here, we have assessed the potential therapeutic effect of an electrophilic nitroalkene benzoic acid derivative, (E)-4-(2-nitrovinyl) benzoic acid (BANA), to slow down paralysis progression when administered after overt disease onset in SOD1G93A rats. BANA exerted a significant inhibition of NF-κB activation in NF-κB reporter transgenic mice and microglial cell cultures. Systemic daily oral administration of BANA to SOD1G93A rats after paralysis onset significantly decreased microgliosis and astrocytosis, and significantly reduced the number of NF-κB-p65-positive microglial nuclei surrounding spinal motor neurons. Numerous microglia bearing nuclear NF-κB-p65 were observed in the surrounding of motor neurons in autopsy spinal cords from ALS patients but not in controls, suggesting ALS-associated microglia could be targeted by BANA. In addition, BANA-treated SOD1G93A rats after paralysis onset showed significantly ameliorated spinal motor neuron pathology as well as conserved neuromuscular junction innervation in the skeletal muscle, as compared to controls. Notably, BANA prolonged post-paralysis survival by ~30%, compared to vehicle-treated littermates. These data provide a rationale to therapeutically slow paralysis progression in ALS using small electrophilic compounds such as BANA, through a mechanism involving microglial NF-κB inhibition.

Bullous Lupus: An Atypical Case of Refractory Disease in a Patient with Sulfa Allergy.

Bullous systemic lupus erythematosus (BSLE) is a rare cutaneous autoimmune disorder characterized by rapid, widespread vesiculobullous lesions in patients with Systemic Lupus Erythematosus (SLE). BSLE can present as the initial manifestation of SLE and may be a marker of severe disease. In this case report, we present a case of a 22-year-old African American woman with BSLE and impaired renal function with subsequent nephrotic range proteinuria concerning for lupus nephritis and autoimmune hemolytic anemia, refractory to systemic corticosteroids, immunoglobulin, and mycophenolate mofetil, requiring dapsone after careful desensitization due to prior history of angioedema with sulfa drugs. This case highlights the importance of the prompt recognition of BSLE as the initial manifestations of SLE and illustrates the association of BSLE with severe disease and the benefit of concomitant use of dapsone with corticosteroids and other immunosuppressant drugs, even in patients with a history of sulfa allergy.

Lupus Never Fails to Deceive US: A Case of Rowell's Syndrome.

BACKGROUND: Rowell's syndrome is comprised of the presentation of erythema multiforme- (EM-) like lesions in association with lupus erythematosus (LE), along with serologies of speckled antinuclear antibodies (ANAs), positive rheumatoid factor (RF), positive anti-La/anti-Ro, and the clinical finding of chilblains. As per the redefined criteria by Zeitouni et al., three major criteria in addition to at least 1 minor criterion are necessary for diagnosis. Case Presentation. A 20-year-old male presented with a one-week history of worsening nonpruritic erythematous maculopapular skin rash (resembling EM) which appeared on the face and subsequently spread to the trunk, arms, legs, palms, and soles. There was no mucosal involvement. At the onset of rash, the patient reported headaches, associated with photosensitivity and intermittent fevers. Workup for viral meningitis yielded negative results. Laboratory investigation revealed mild anemia, elevated inflammatory markers, a positive ANA with speckled pattern, a positive anti-Ro/SSA, anti-La/SSB antibodies, and a positive rheumatoid factor (RF). Lupus anticoagulant antibody was positive along with a low-positive anticardiolipin IgM antibody and a negative beta-2 glycoprotein antibody. Anti-dsDNA, anti-Smith, anti-Jo-1, anti-centromere, and anti-Scl-70 antibodies were negative. Hepatitis serologies, herpes simplex virus 1 and 2, mycoplasma, Epstein-Barr virus, HIV, and parvovirus B19 were negative. Left arm skin biopsy demonstrated vacuolar interface dermatitis and positive colloidal iron stain suggestive of dermal mucin deposition, favoring the diagnosis of cutaneous collagen vascular disease. Cutaneous lesions improved with administration of oral prednisolone. CONCLUSION: Rowell's syndrome should be considered in patients who present with cutaneous LE and lesions resembling EM. Further serological markers should be pursued in the absence of obvious EM-precipitating factors.

Long-Term Effect of Environmental Enrichment on Reproductive Performance of Swiss Webster Mice and Their Female Offspring.

The aim of this study was to evaluate the effect of an environmental enrichment (EE) plan on the reproductive performance of Swiss Webster mice and their female offspring used as recipients for embryo transfer. A total of 54 breeder mice and 60 F1 females, used as foster mothers, were allocated in two experimental groups to receive or not receive EE for physical well-being. Reproductive outcomes of the Swiss trios such as birth rate and pup number, litter size, pups' weight at weaning, interlitter interval and time to first litter were analyzed. Environmental enrichment significantly increased pups weight from breeding trios compared to the control group (14.4 ± 0.1 vs. 13.8g ± 0.1, EE vs. control, respectively; p < 0.01). Other parameters did not differ between both groups. Reproductive parameters of female offspring used as recipients for embryo transfer did not differ among groups subjected or not to EE. These data demonstrate that the EE protocol applied in Swiss Webster breeder mice positively enhanced pups weight, and did not interfere with other reproductive outcomes. In conclusion, this study supports the implementation of EE plans usually applied for animal welfare in mouse facilities with slight improvement in reproductive performance.

Acute myocardial infarction on Nongated chest computed tomography.

Contrast-enhanced chest computed tomography (CT) is not considered part of the evaluation of myocardial infarction. However, acute myocardial infarction has been detected on contrast-enhanced chest CT as areas of decreased myocardial enhancement in patients evaluated for other indications, such as pulmonary embolism and aortic dissection. We present a case of acute myocardial infarction on a nongated chest CT in a 67-year-old male who presented with atypical chest pain and initial nondiagnostic electrocardiogram. This case highlights that acute myocardial infarction may be detectable on contrast-enhanced CT. When evaluating contrast-enhanced chest CT's for other etiologies of chest pain, radiologists should look for potential myocardial perfusion abnormalities that can provide clues to the presence of myocardial infarction.

A Case of Sudden Death: Subarachnoid Hemorrhage, Pheochromocytoma, Berry Aneurysm.

Subarachnoid hemorrhage is a medical emergency. Berry aneurysm rupture is the second most common cause following trauma. Diagnosis is often challenging. Neurogenic heart syndrome often complicates subarachnoid hemorrhage. A concomitant pheochromocytoma can be deadly causing sudden cardiac arrhythmia. Here, we describe a case of subarachnoid hemorrhage with concomitant incidental pheochromocytoma in a relatively young female who died suddenly, diagnosed during autopsy. A 57-year-old Hispanic woman with past medical history of asthma, prediabetes, and uncontrolled hypertension collapsed unexpectedly. She initially had ventricular tachycardia, followed by pulseless electrical activity and finally asystole without response to resuscitation. In the emergency department she was on epinephrine, calcium, naloxone, and tPA with suspected thrombotic stroke. Despite measures, she was pronounced dead. Autopsy revealed subarachnoid hemorrhage due to a ruptured berry aneurysm. Additionally, pheochromocytoma was detected in the right adrenal gland. Subarachnoid hemorrhage has a grave prognosis by itself. This case describes the uncommon detection of pheochromocytoma in the setting of subarachnoid hemorrhage.

HPLC-PDA-MS and NMR characterization of C-glycosyl flavones in a hydroalcoholic extract of Citrus aurantifolia leaves with antiplatelet activity.

A hydroalcoholic extract of lime ( Citrus aurantifolia) leaves has been developed in Cuba to be used as a nutritional supplement and phytomedicine in the form of tincture (TLL). A HPLC-PDA-ESI/MS/MS method has been used for the comprehensive analysis of C-glycosyl flavones in TLL. Six C-glycosyl flavones were characterized and, to confirm the proposed structures and to elucidate the nature of the sugar units, a preparative procedure was applied, and isolated compounds were characterized by NMR. Apigenin-6,8-di-C-beta-D-glucopyranoside (vicenin II) (1), diosmetin-6,8-di- C-beta- d-glucopyranoside (2), apigenin-8-C-beta-D-glucopyranoside (vitexin) (3), apigenin-8-C-[alpha-L-arabinopyranosyl-(1-->6)]-O-beta-D-glucopyranoside (4), apigenin-6-C-[alpha-l-arabinopyranosyl-(1-->6)]-O-beta-D-glucopyranoside (5). and apigenin-6-C-beta-D-glucopyranoside (isovitexin) (6) were identified in TLL and quantified by HPLC-PDA. Compounds 4 and 5 were two new arabinosyl derivatives of vitexin and isovitexin. Inhibitor effect of TLL on platelet aggregation induced by physiological agonists of platelets was evaluated in human plasma. TLL inhibited significantly ADP and epinephrine-induced platelet aggregation in a concentration-dependent manner (IC 50=0.40 and 0.32 mg/mL, respectively).