Increase In Capillary Permeability Research Articles

Revisiting the fluid requirement during the critical phase of dengue: Does it actually follow a bell-shaped curve? 

Plasma leakage due to a transient increase in capillary permeability is the hallmark of dengue haemorrhagic fever. There is no specific antiviral agent for dengue. Therefore, the mainstay of management during the plasma leakage phase is the judicious use of intravenous fluid to ensure adequate organ perfusion and to prevent fluid overload. The current practice guidelines for dengue are empirical. They are mostly based on expert opinions. The rates and amounts of fluid to be administered during the critical phase of the disease have not been studied in randomised controlled trials. It is hypothesised that the rate of fluid leakage during the critical phase follows a bell-shaped curve. Based on this concept, both WHO and Sri Lankan guidelines recommend starting fluid at a lower rate, increasing the rate until the midpoint of the CP, and gradually reducing the infusion rate thereafter. However, the authors believe that the more fluid you give during the critical phase, the more will leak out into the third space. Thus increasing the complications of fluid overload without improving the effective plasma volume. Therefore, administering fluids at an escalating rate may be superfluous and could result in fluid overload.

Abstract A098: Quantitative MRI metrics capture pancreatic cancer and stroma responses to novel KRAS inhibitor

Abstract Introduction Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer with limited treatment options. Oncogene KRAS mutations found in majority of PDA patients with KRAS(G12D) mutation being the most common. A new KRAS(G12D) specific inhibitor, MRTX1133 has been shown to induce rapid tumor regression in PDA models while the effect on stroma is only revealed by postmortem analyses of tumor specimens, making it hard to assess the dynamics of stroma remodeling. Furthermore, in clinical testing of KRAS(G12C) inhibitor, only ~50% of patients responded to the treatment despite the presence of correct genetic mutation in biopsy specimens, therefore, early and accurate assessment of the drug-target engagement is important in clinical setting. Our study was designed to test the hypothesis that multimetric MRI captures early responses to KRAS(G12D) inhibitor beyond the change of tumor size in a PDA model. Especially, changes in apparent diffusion coefficient (ADC) from diffusion weighted (DW) MRI, Ktrans from dynamic contrast enhanced (DCE) MRI, and magnetization transfer ratio (MTR). Methods A genetically engineered model of PDA bearing KRAS(G12D) and Trp53 mutation referred to as KPC was used. Male and female mice were enrolled to receive MRTX1133 at 30mg/kg BID or PBS via i.p injection. Murine PDA cells bearing KRAS(G12C) mutation were inoculated in the flank of C57BL/6 mice to grow subcutaneous tumors. In vivo DW- and DCE-MRI were obtained on a 9.4T Bruker system employing pulse sequences insensitive to respiratory motion. Results In KPC mice, striking increase of tumor ADC were detected as early as 48h after treatment initiation and was confirmed by statistical analyses at 48h and day7 accompanied by decrease of tumor size, in contrast to a trend of increased tumor size and decreased ADC in PBS-treated mice. H&E section revealed gross necrosis and extensive cell death. A clear increase of Ktrans suggesting an increase of capillary permeability and/or perfusion was detected at 48h, persisting to day7; while CD31 did not change significantly, capillary lumen area appeared enlarged at 48h, consistent with reduced interstitial fluid pressure resulted from clearance of stromal hyaluronic acid. A remarkable reduction of MTR at 48h clearly captured the stromal effect of MRTX1133 whereas no change observed in PBS-treated mice. Consistently, Sirius red (SR) staining for collagen revealed a high degree of heterogeneity where regions of depletion versus dense SR staining coexist. Lack of tumor regression and ADC change in KRAS(G12C) tumors confirmed the specificity of MRTX1133 to G12D however, a reduction of MTR was revealed, suggesting stromal impact as off-target effect of MRTX1133. Conclusion To our knowledge, this represents the first MRI study of the new KRAS inhibitor. The multimetric MRI approach is novel and significant because it captured MRTX1133-induced cancer cell death and stroma change over time. With further validation, these translatable imaging metrics can provide biological mechanism underneath tumor size change in the clinical setting. Citation Format: Mamta Gupta, Hoon Choi, Emma E. Furth, Miguel Joaquim, Stephen Pickup, Cynthia Clendenin, Margo Orlen, Thomas Karasic, Hee Kwon Song, Yong Fan, Peter O’Dwyer, Robert H. Vonderheide, Mark Rosen, Ben Z. Stanger, Rong Zhou. Quantitative MRI metrics capture pancreatic cancer and stroma responses to novel KRAS inhibitor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A098.

#236 : Alleviating Effects of EGCG on Ovarian Hyperstimulation Syndrome and the Potential Modulating Mechanism

Background and Aims: Ovarian hyperstimulation syndrome (OHSS) is one of the most severe complications of COH during IVF treatment. Increased capillary permeability is a hallmark of the pathophysiology of OHSS, vascular endothelial growth factor (VEGF) is an important mediator in OHSS, and studies have established a correlation between serum VEGF levels and the severity of the OHSS. (-)-epigallocatechin-3-gallate (EGCG), the most prevalent and biologically active polyphenolic catechin in green tea, has been reported to produce a number of beneficial effects on humans. Numerous studies have shown that in many pathological processes, EGCG could inhibit VEGF and its receptor expression and have an angiogenesis effect. Herein, EGCG might have a therapeutic effect on OHSS. Methods: We investigated the role of EGCG in OHSS both in vitro and in vivo. Primary human granulosa-lutein (hGL) cells and a human granulosa-like tumor (KGN) cell line were cultured and treated for 24 hours with various concentrations of EGCG. In SD rats, an animal OHSS model was established by injecting pregnant mare serum gonadotropin (PMSG) and randomly assigning them to receive vehicle only or EGCG for three days. For comparison, all experiments were repeated 3-8 times. The effect of EGCG on KGN and hGL cells was determined by MTT assay. The body weight of rats was measured every day, and the ovary size and weight were measured after removal. Evans-blue was used to determine permeability. ELISA was used to measure serum estrogen and VEGF levels in rats. RNA and protein expressions of VEGF, VEGFR-2, TGF-[Formula: see text]1, and T[Formula: see text]R II were detected by qPCR and Western-blotting and immunostaining in vitro and in vivo experiments. Results: Our research found that giving rats EGCG prevented the development of OHSS, as evidenced by histological examination, ovarian weight, and morphology. When compared to the OHSS group, the EGCG treatment group had significantly lower ovary weight (147.9 vs 206.5 mg) (Fig. 1). Furthermore, when compared to OHSS rats, EGCG-treated rats have lower ovarian VEGF expression as measured by IHC and RT-qPCR. VEGF and E2 protein levels in the serum of the EGCG treatment group are significantly lower. EGCG exerted inhibitory effects on cell growth only in high dose (50 uM) and longtime (48 h) treatment in KGN and hGL cells. In KGN cells and hGL cells, EGCG significantly reduces the expression of VEGF and TGF-[Formula: see text] at the RNA and protein levels. Furthermore, EGCG inhibits TGF-[Formula: see text]1-induced VEGF production and secretion in KGN cells by suppressing TGF-[Formula: see text] expression and its traditional Smad signaling pathway. EGCG also downregulates VEGF expression through the 67-kDa laminin receptor-mediated PKA-CREB pathway (Fig. 2). Conclusions: EGCG inhibited VEGF via the TGF-[Formula: see text]1 classical-SMAD pathway and the 67LR-mediated CREB pathway, reducing ovarian inflammation and slowing the progression of OHSS in a rat model.

Correlation between hematocrit and inferior vena cava collapsibility in adult patients with dengue fever: A prospective, observational study at a tertiary care setup in Eastern India

Background: Dengue fever (DF) is a vector-borne arboviral infection prevalent in tropical and sub-tropical countries. Early recognition of severity of the disease with appropriate fluid management is a challenge to the clinicians. Increase in capillary permeability is the pathophysiological hallmark of the disease which parallels with increase in hematocrit. This study aimed to evaluate the inferior vena cava (IVC) collapsibility and its relation to hematocrit. Methods: A prospective, observational study was conducted in the inpatient department of tropical medicine over a period of 1 year in a tertiary care set up in Eastern India. Clinical data and hematocrit of adult dengue cases were documented and their IVC collapsibility determined by bedside ultrasonography (USG) was recorded. Association was assessed between IVC collapsibility and hematocrit. Results were statistically analyzed. Results: Seventy dengue cases were included - 59 cases of DF with warning signs and 11 cases of dengue hemorrhagic fever (DHF). 85.7% of study population presented at febrile phase of their illness. Bedside USG was correlated with hematocrit on day 2 of admission. IVC was collapsible in 79.7% cases of DF and 90.9% cases of DHF. Of the 47 DF cases with collapsible IVC, 95.7% had high hematocrit, while all DHF cases with collapsible IVC had high hematocrit. A significant association between IVC collapsibility and hematocrit was noted (P = 0.000). Conclusion: The assessment of intravascular volume status by bedside USG-IVC collapsibility is a helpful noninvasive and better tool than hematocrit for determining fluid resuscitation in DF.

Identification of bioactive components on antihemorrhoidal activity of Cistus laurifolius L. using RP-HPLC and LC-QTOF-MS

Ethnopharmacological relevanceCistus laurifolius is widely used in folk medicine in Anatolia for the treatment of many ailments. The leaves of the plant are used in the form of tea in the treatment of hemorrhoids in the Western Black Sea Region and Central Anatolia. Aims of the studyIt was aimed at evaluating the anti-hemorrhoidal effects of C. laurifolus leaves in croton oil-induced hemorrhoid model in rats. Materials and methodsThe methanolic and aqueous extracts of C. laurifolius were tested for in vivo anti-hemorrhoidal efficacy using an experimental hemorrhoid model, followed by histological and biochemical analysis. Hemorrhoid was created by using croton oil on the anal region of the rats. TNF-α and VEGF mRNA expression levels were assessed using real-time PCR detections. The extract was also tested for anti-inflammatory properties, which are based on the suppression of an increase in capillary permeability caused by acetic acid. LC-QTOF-MS and RP-HPLC were used for the phytochemical analysis. ResultsIn comparison to the control, histological and biochemical assessment showed that the methanolic extract of C. laurifolius is particularly effective against hemorrhoids. The same extract group's TNF-α mRNA expression was found to be the lowest. Additionally, the methanolic extract showed a strong inhibitory effect on the increase in capillary permeability resulted on by acetic acid. Three phenolic compounds were discovered in the extracts by phytochemical analyses, while more than eighteen compounds were found by LC-QTOF-MS analysis. Five of these compounds are phenolic acid derivatives, and flavonoids constitute the majority of the group. ConclusionThis is the first evidence from the research that C. laurifolius possesses strong anti-inflammatory and anti-hemorrhoidal properties.

Idiopathic systemic capillary leak syndrome: a case report

BackgroundIdiopathic systemic capillary leak syndrome (ISCLS) is a rare disease characterized by recurrent episodes of acute life-threatening attacks of shock, hemoconcentration, and hypoalbuminemia. Increase in capillary permeability results in reversible plasma movement into the interstitial spaces followed by appearance of related symptoms or complications, including renal failure. This condition can be potentially life-threatening; however, it is easily misdiagnosed.Case presentationA 47-year-old man with no previous medical history presented to the emergency department after experiencing general weakness and abdominal pain. He developed hypovolemic shock within 3 h of presentation and initial laboratory tests showed hemoconcentration, hypoalbuminemia and acute kidney injury. Following vigorous fluid therapy and supportive care, the patient recovered, but a similar episode recurred after 4 months without any specific trigger. Based on the combined clinical manifestations and laboratory findings of both the attacks, he was diagnosed with ISCLS. Symptomatic relief was achieved via oxygen supplementation and massive volume replacement using normal saline and the patient was prescribed bambuterol 10 mg and theophylline 400 mg once-a-day. He was discharged from the hospital on day 5 of hospitalization. Thereafter, the patient has been followed for 5 years without any symptoms or recurrence of ISCLS even in the situation of COVID-19 infection.ConclusionsISCLS is an extremely infrequent and commonly misdiagnosed disease. However, early diagnosis, treatment and prophylaxis through accumulated clinical data can prevent ISCLS recurrence and the development of related fatal complications. Therefore, clinicians need to be well aware of the variety of clinical characteristics and treatment options of this disease.

The Role Extracorporeal Membrane Oxygenation in Acute Respiratory Distress Syndrome

Treatment of oxygen therapy should be based on appropriate indication and dose of administration. British Thoracic Society (BTS) recommends oxygen therapy were administered with a 94–98% saturation target in most acute patients and for patients with hypercapnic respiratory failure, BTS recommends 88-92 saturation target or spesific saturation target. Acute respiratory distress syndrome (ARDS) is characterized by acute, diffuse, inflammatory lung injury leading to increased capillary permeability in the alveolus with clinical manifestations of hypoxemia and bilateral opafication. The use of extracorporeal membrane oxygenation (ECMO) along with mechanical ventilator can be useful for ARDS patients and can improve survival.

JS09.6.A Low incidence of radiation-induced brain lesions and stable QoL following proton irradiation for CNS and Skull Base tumors- results from the prospective MedAustron register REGI-MA-002015

Abstract Background Irradiation of intracranial tumors may induce endothelial damage in the surrounding normal brain tissues, resulting in an increase of capillary permeability. These changes can be depicted on magnetic resonance imaging (MRI) as a new contrast medium uptake - not associated with tumor. Radiation-induced brain lesions (RIBL) occur after photon as well as proton irradiation. This study evaluated the incidence of RIBL after proton irradiation and their impact on Quality of Life (QoL). Material and Methods 421 patients treated between 01/2017 and 06/2021 were included. All patients participated in a prospective registry study (ClinicalTrials.gov Identifier: NCT03049072). Follow-up evaluations including MRIs were at 3,6,12 months after treatment completion and annually thereafter. QoL parameters were assessed by EORTC-CTC30 and BN20 questionnaires. Results 48.9% (n=206) patients received therapy for intracranial non-CNS tumors (meningioma, pituitary adenoma, and other), 26.8% (n=113) for head and neck cancer with skull base involvement, 14.5% (n=61) for primary CNS tumors and 9.7% (n=41) for skull base tumor. Median follow-up was 24 months (range 6-54 ), 352 (86%) patients had proton therapy as primary treatment, 59 (14%) had salvage treatment with proton re-irradiation (ReRT). Median prescribed dose was 58.5 Gy (RBE) (range 40-78 Gy (RBE)), median D1% of brain tissue was 54.3 Gy (RBE) (range 30-76 Gy RBE). Local control and overall survival were 91% and 95% at 2 years. The cumulative RIBL incidence was 15.0% (n=63), with significantly lower occurrence in the primary RT group vs. the ReRT group (12.9% vs. 27.1%; p<0.001). According to Grade, the distribution was 10.5% (n=44) Grade I (asymptomatic, MRT finding only), Grade II RIBL, 13 (3.1%) (moderate symptoms) (grade 2) and 1,4% (n=6) developed Grade 3 toxicity. Actuarial 2-year RIBL incidence was 18.2% (95%CI: 14.1-23.2) for the all Grades and the entire, 15.7% (95%CI: 11.6-21) following primary radiation and 34.2% (95%CI: 21.9-50.9) after ReRT. All RIBL developed outside the residual tumor, but inside the Planning Target Volume (PTV), median D1% was 60.3Gy (RBE) (range 46.1- 122.3 Gy(RBE)), median time to development was 11.8 months (range 2.7-37 months) in the total cohort, for primary RT 14.2mo (4.3mo -37.1mo) and 6.0mo (2.7mo -19.3mo) following ReRT. At the time of analysis 26 of the 63 RIBL had resolved (41.3%). General QoL was not compromised. In a matched-pair analysis of 54/50 patients with/without RIBL, only at the 12 month a significant difference in the global health score in favour of non-RIBL patients was observed. At 24 months the score for RIBL patients improved without difference between the groups. Conclusion Overall incidence of RIBL after proton radiotherapy is very low - even for skull base tumors requiring high total doses and it had no significant negative impact on long term QoL.

Hantavirus.

Hantaviruses are tri-segmented lipid-enveloped RNA viruses belonging to the Bunyaviridae family. Human infection corresponds to a zoonosis associated with two different clinical syndromes: hemorrhagic fever with renal syndrome that occurs in Asia and Europe and hantavirus cardiopulmonary syndrome (HCPS) that occurs in the North America, Central America and South America. The major pathogenic mechanisms in HCPS include (1) direct microvascular endothelial injury leading to increased capillary permeability and the development of noncardiogenic pulmonary edema and acute respiratory distress syndrome, and (2) exaggerated host immune response leading to secondary organ damage. The incubation period for this disease is quite long (6-39 days, median: 18 days); however, rapid progression to respiratory failure and shock can occur highlighting the importance of high index of clinical suspicion. Management revolves around high-quality supportive care. Various management and preventative strategies are currently being explored and warrant further examination to improve the overall outlook following infection with hantavirus.

Would carvacrol be a supporting treatment option effective in minimizing the deleterious effects of COVID-19?

The pathophysiological process of the disease, Covid-19, is mediated by innate immunity, with the presence of macrophages responsible for secreting type 1 and 6 interleukins (IL), tumor necrosis factor (TNF) leading to dilation of endothelial cells with a consequent increase in capillary permeability. The treatment of this disease has been much discussed, but the variability in the clinical picture, the difficulties for diagnosis and treatment, especially of those patients who have the most severe clinical condition of the disease. Immunization is an effective tool for controlling the spread and overload of health services, but its effectiveness involves high investments in the acquisition of inputs, development of vaccines, and logistics of storage and distribution. These factors can be obstacles for countries with lower economic, technological, and infrastructure indexes. Reflecting on these difficulties, we raised the possibility of adjuvant therapies with imminent research feasibility, as is the case with the use of carvacrol, a monoterpenic phenol whose has biological properties that serve as a barrier to processes mediated by free radicals, such as irritation and inflammation, due to its antioxidant action. Many authors highlighted the activity of carvacrol as a potent suppressor of COX-2 expression minimizing the acute inflammatory process, decreasing the release of some pro-inflammatory mediators such as IL-1β, TNF-α, PGE2. Anyway, the benefits of carvacrol are numerous and the therapeutic possibilities too. With this description, the question arises: would carvacrol be a supporting treatment option, effective in minimizing the deleterious effects of Covid-19? There is still a lot to discover and research.

BUPRENORPHINE-NALOXONE-INDUCED NONCARDIOGENIC PULMONARY EDEMA

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Buprenorphine-naloxone is used to treat chronic pain and opioid use disorder. Each medication in this combination has been associated with noncardiogenic pulmonary edema. Here we report the case of a 56-year-old woman treated for chronic pain with buprenorphine-naloxone, and a history of multiple hospitalizations for pulmonary edema. Her buprenorphine-naloxone was held on admission and her symptoms improved gradually with supportive care. CASE PRESENTATION: A 56-year-old woman with past history significant for congestive heart failure, chronic obstructive pulmonary disease, and chronic pain treated with buprenorphine-naloxone presented to the emergency department via ambulance for altered mental status and worsening dyspnea for 3 days. Upon arrival to the ED she was tachypneic with a SpO2 of 50% on room air and required non-invasive ventilation. Physical exam revealed diminished breath sounds bilaterally and no peripheral edema. Laboratory data was significant for an elevated D-dimer and BNP. Covid-19 screening was negative. Chest x-ray showed diffuse hazy opacities. CTA chest was negative for pulmonary embolism, but did show extensive parenchymal opacities and diffuse ground glass densities bilaterally. Steroids and antibiotics were initiated, and buprenorphine-naloxone was discontinued.She described several similar prior hospitalizations, but denied ever receiving a diagnosis. Echocardiogram showed a normal ejection fraction and grade II diastolic dysfunction. Infectious and vasculitis etiologies were ruled out. The patient declined bronchoscopy. Records from prior hospitalizations revealed non-diagnostic bronchoalveolar lavage and wedge biopsies. Environmental exposure was ruled out via a peer reviewed questionnaire and negative allergen testing. With no clear etiology, the patient's hypoxia improved. We propose that the patient's presentation was secondary to noncardiogenic pulmonary edema induced by buprenorphine-naloxone. DISCUSSION: Non-cardiogenic pulmonary edema is an acute process resulting in hypoxia secondary to an increase in capillary permeability. Major causes include ARDS, pulmonary embolism, TRALI, and opioid overdose, but many other etiologies have been implicated. Buprenorphine, like other opioids, is a known cause of pulmonary edema (1). Naloxone induced pulmonary edema, while rare, has also been described (2). A review of the literature was not able to find buprenorphine-naloxone combination as a cause of non-cardiogenic pulmonary edema. We believe this patient's pulmonary edema may have been secondary to this medication's opioid effects, naloxone effects, or possibly an allergic reaction. Given the wide use of this medication physicians should be made aware of this possible complication. CONCLUSIONS: Non-cardiogenic pulmonary edema is a potential complication of buprenorphine-naloxone. REFERENCE #1: Thammakumpee G, Sumpatanukule P. Noncardiogenic Pulmonary Edema Induced by Sublingual Buprenorphine. Chest. 1994;106(1):306-308. REFERENCE #2: Bansal S, Khan R, Tietjen P. Naloxone-Induced Pulmonary Edema [abstract]. Chest. 2007;132(4):692A. DISCLOSURES: No relevant relationships by Muhammad Aboudan, source=Web Response No relevant relationships by Brandon Govan, source=Web Response No relevant relationships by Abi Waqas, source=Web Response

Pathogenesis and Treatment of Refractory Oedema in Nephrotic Syndrome

Oedema is a hallmark feature of nephrotic syndrome (NS) and can cause significant patient morbidity. The pathogenesis of oedema formation is complex and results from abnormalities in sodium retention, inter-play of neurohormonal factors, and changes in capillary filtration barrier. Salt retention is often primary (‘overfill’ theory) because of increased sodium-potassium adenosine triphosphatase activity in the collecting duct cells, increased direct epithelial sodium channel activation (ENaC) by urinary proteases (independent of aldosterone), and an overall increased effective arterial blood volume. However, a subset of patients with NS, especially children, demonstrate decreased effective arterial blood volume (‘underfill’ theory) and secondary sodium retention as the primary mechanism of oedema formation. Increased capillary permeability and vascular inflammation contributes as well. Loop diuretics with or without salt-poor albumin are the mainstay of therapy in adults, although no large clinical trials exist to guide diuretic choice or dosage. Combination diuretic therapy is recommended to achieve multi-site nephron blockade and overcome diuretic resistance, which is a frequent challenge. Use of direct ENaC inhibitors (amiloride) in combination with loop diuretics may be especially beneficial given the primary role of ENaC in sodium retention. Aquaretics such as vasopressin receptor antagonists may have a role in treatment as well. Well-designed clinical trials are essential to guide therapy of refractory oedema in NS. In this review, the authors discuss the pathogenesis of oedema formation in patients with NS and propose a treatment algorithm for management of resistant oedema based on the limited available evidence.

Mechanisms Governing Anaphylaxis: Inflammatory Cells, Mediators, Endothelial Gap Junctions and Beyond.

Anaphylaxis is a severe, acute, life-threatening multisystem allergic reaction resulting from the release of a plethora of mediators from mast cells culminating in serious respiratory, cardiovascular and mucocutaneous manifestations that can be fatal. Medications, foods, latex, exercise, hormones (progesterone), and clonal mast cell disorders may be responsible. More recently, novel syndromes such as delayed reactions to red meat and hereditary alpha tryptasemia have been described. Anaphylaxis manifests as sudden onset urticaria, pruritus, flushing, erythema, angioedema (lips, tongue, airways, periphery), myocardial dysfunction (hypovolemia, distributive or mixed shock and arrhythmias), rhinitis, wheezing and stridor. Vomiting, diarrhea, scrotal edema, uterine cramps, vaginal bleeding, urinary incontinence, dizziness, seizures, confusion, and syncope may occur. The traditional (or classical) pathway is mediated via T cells, Th2 cytokines (such as IL-4 and 5), B cell production of IgE and subsequent crosslinking of the high affinity IgE receptor (FcεRI) on mast cells and basophils by IgE-antigen complexes, culminating in mast cell and basophil degranulation. Degranulation results in the release of preformed mediators (histamine, heparin, tryptase, chymase, carboxypeptidase, cathepsin G and tumor necrosis factor alpha (TNF-α), and of de novo synthesized ones such as lipid mediators (cysteinyl leukotrienes), platelet activating factor (PAF), cytokines and growth factors such as vascular endothelial growth factor (VEGF). Of these, histamine, tryptase, cathepsin G, TNF-α, LTC4, PAF and VEGF can increase vascular permeability. Recent data suggest that mast cell-derived histamine and PAF can activate nitric oxide production from endothelium and set into motion a signaling cascade that leads to dilatation of blood vessels and dysfunction of the endothelial barrier. The latter, characterized by the opening of adherens junctions, leads to increased capillary permeability and fluid extravasation. These changes contribute to airway edema, hypovolemia, and distributive shock, with potentially fatal consequences. In this review, besides mechanisms (endotypes) underlying IgE-mediated anaphylaxis, we also provide a brief overview of IgG-, complement-, contact system-, cytokine- and mast cell-mediated reactions that can result in phenotypes resembling IgE-mediated anaphylaxis. Such classifications can lead the way to precision medicine approaches to the management of this complex disease.

A case study on off‐label medications vs alternative medicines in Patients with mild to moderate symptoms of COVID‐19

BackgroundThe emergence of SARS‐CoV‐2/2019 novel coronavirus (COVID‐19) first appeared in the US in March 2019. There were no current guidelines or clear direction on the use of antivirals or other agents on treating Covid‐19 for this new virus, and escalating death rates in the underserved community became disturbing. The early studies consisted of studying Chloroquine (CQ) or Hydroxychloroquine (HCQ) with or without Azithromycin (AZ), Lopinavir/Ritonavir (LV/RV) and other HIV Protease Inhibitors; Remdesivir (RDV) looked promising; however, it was still in clinical trial phases. COVID‐19 causes individuals to suffer from respiratory distress, organ failure, hypotension, lactic acidosis, oliguria, and other acute blood disorders due to various pathogens and conditions. This massive infection triggers an immune response which vasoactivates chemicals, such as cytokines, dilate the blood vessels and increase capillary permeability, causing vascular fluid to shift to the interstitium. The immune system extends signaling molecules (cytokines) that recruit immune cells to the infection site as part of an inflammatory response. In a desperate attempt to save lives, Valtrex (VX) was used to treat COVID‐19 as an off‐label use to stop viral replication, stop inflammation, and promote recovery time for patients sent home with viral pneumonia due to COVID 19 that were Short of breath and who were symptomatic. VX is not without bothersome side‐effects: it must be used with caution in persons with kidney disease and in people 60 years and older. To treat the pneumonia with a combination approach, amoxicillin (AMX) with clavulanate(CLV) was used twice a day for five days. In addition, Diflucan 150 mg was used to halt the overproduction of yeast caused by using antibiotics.MethodsMEDLINE, PubMed, and print repositories on trials: for CQ HCQ with or without AZ, LV/RV, Protease Inhibitors, and RDV in COVID‐19 or SARS‐CoV‐2 infection, until May 2020. The patients were given consent for off‐label use of the treatment. The patients involved in the study were between the ages of 25 to 49. They had documented positive test results for SARS‐CoV‐2 infection. Radiologic studies were done as well as a complete blood count and a chemistry level.ResultsThere were ten people treated with VX, AMX, and Diflucan((DFN). All the participants recovered. One participant had to receive supplemental oxygen and saline nebulizer treatments at home for one due to shortness of breath a month. The comparison group used high doses of probiotics 100 billion cells and ginger shots twice a day. The people who used VX, AMX, and DFN reported recovery from the symptoms of fever, coughing, and SOB in 24‐48 hours. However, the patients that used the alternative medications reported symptom improvement around day 5 ‐7. In conclusion, there is an insufficient confirmation regarding the clinical effectiveness and safety of VX in patients with COVID‐19. Its use should be considered preliminary, requiring ethical approval and clinical trial oversight. VX can potentially be used in patients with mild to moderate symptoms of Covid‐19 that are sent home and asked to self‐quarantine who are symptomatic but requires additional study.

Production of a novel recombinant brown spider hyaluronidase in baculovirus-infected insect cells

Hyaluronidases are low expressed toxins of brown spider venoms, but, as highly active molecules, they present an important role as spreading factors. By degrading extracellular matrix components, these enzymes favor the diffusion of toxins in the affected tissue and at systemic level. Here, a novel isoform of hyaluronidase of Loxosceles intermedia Mello-Leitão (1934) venom was cloned, expressed in a baculovirus-insect cell expression system and fully active purified. This recombinant enzyme, named LiHyal2 (Loxosceles intermedia Hyaluronidase isoform 2), shares high identity with hyaluronidases of other spiders and scorpions. The catalytic and sugar binding amino acid residues are conserved in LiHyal2, human, and honeybee venom hyaluronidases and the molecular model of LiHyal2 shares major similarities with their crystal structures, including the active site. LiHyal2 was expressed as a 45 kDa protein and degraded hyaluronic acid (HA) and chondroitin sulphate as demonstrated by HA zymography and agarose gel electrophoresis. Lectin blot analysis revealed that LiHyal2 is post-translationally modified by the addition of high mannose N-linked carbohydrates. In vivo experiments showed that LiHyal2 potentialize dermonecrosis and edema induced by a recombinant phospholipase-D (PLD) of L. intermedia venom, as well as enhance the increase in capillary permeability triggered by this PLD, indicating that these toxins act synergistically during envenomation. Altogether, these results introduce a novel approach to express spider recombinant toxins, contribute to the elucidation of brown spider venom mechanisms and add to the development of a more specific treatment of envenomation victims.

The Use of Visceral Proteins as Nutrition Markers: An ASPEN Position Paper.

Serum albumin and prealbumin, well-known visceral proteins, have traditionally been considered useful biochemical laboratory values in a nutrition assessment. However, recent literature disputes this contention. The aim of this document is to clarify that these proteins characterize inflammation rather than describe nutrition status or protein-energy malnutrition. Both critical illness and chronic illness are characterized by inflammation and, as such, hepatic reprioritization of protein synthesis occurs, resulting in lower serum concentrations of albumin and prealbumin. In addition, the redistribution of serum proteins occurs because of an increase in capillary permeability. There is an association between inflammation and malnutrition, however, not between malnutrition and visceral-protein levels. These proteins correlate well with patients' risk for adverse outcomes rather than with protein-energy malnutrition. Therefore, serum albumin and prealbumin should not serve as proxy measures of total body protein or total muscle mass and should not be used as nutrition markers. This paper has been approved by the American Society for Parenteral and Enteral Nutrition Board of Directors.

From nutrition to medicine: Assessing hemorrhoid healing activity of Solanum melongena L. via in vivo experimental models and its major chemicals

Ethnopharmacological relevanceSolanum melongena L. (eggplant) is used for treatment of rheumatism, beriberi, itching, toothache, bleeding, asthma, bronchitis, cholera, neuralgia and hemorrhoids in traditional medicine (Turkish, Chinese, and Indian). Hemorrhoids from these diseases, are common illness in all over the world, which are treated with various approaches including ethnobotanicals.Aim of the study: This study aimed to evaluate the anti-hemorrhoidal activity of eggplant, an edible plant, which is commonly utilized around the world. Materials & methodsIn vivo anti-hemorrhoidal activity of the methanolic extract prepared from eggplant was evaluated by experimental hemorrhoid model, subsequently histological and biochemical analysis. Hemorrhoid, which was induced by applying croton oil to the anal area of the rats. Furthermore, the extract was screened for anti-inflammatory activity which is based on the inhibition of acetic acid-induced increase in capillary permeability. The healing potential was comparatively assessed with a reference Pilex® tablet and cream. Phytochemical analysis performed by HPLC. The amount of the major phenolic compound (chlorogenic acid) in extract was found by using HPLC method. ResultsHistological and biochemical analysis demonstrated that eggplant extract is highly effective against hemorrhoid in comparison to the controls and the commercial preparation. In addition, the methanolic extract demonstrated significant inhibitory effect on acetic acid-induced increase in capillary permeability.The phytochemical studies identified major compound as chlorogenic acid (2.86%) by liquid chromatography. ConclusionThe eggplant calyxes, not edible, are easy to reach, by products/vast from the food sources. This is the first scientific evidence revealing that the eggplant extract has significant anti-hemorrhoidal and anti-inflammatory activity.

The Usefulness of Scintigraphic Studies in the Assessment of Asymptomatic Bowel Disease in Patients with Primary Antibody Diseases.

Enteropathy may be the first presentation of immunodeficiency or it may occur during the course of the disease and in association with malabsorption in patients affected by primary antibody diseases. For these patients, immunoglobulin G (IgG) replacement therapy prevents infectious and non-infectious complications. Nonetheless some patients cannot achieve optimal IgG trough levels, even when treated with high Ig doses in absence of protein-losing syndromes. We investigated seven patients affected by common variable immunodeficiencies (CVIDs) and treated with high Ig doses (600–800 mg/kg/month) showing low IgG trough level. Patients underwent abdominal scintigraphy with human polyclonal immunoglobulin G labeled with 99mTc and with white blood cells labeled by 111 Indium-oxinate to investigate asymptomatic bowel inflammation. A concentration of labeled leukocytes in abdominal segments greater than that observed with human polyclonal immunoglobulin G was evident only in one patient. In five patients a slight concentration of both radiopharmaceuticals was reported, due to mild intestinal inflammatory response. These data might be related to mild increase of capillary permeability in the absence of inflammation leukocyte mediated. This study discloses a new cause of IgG-accelerated catabolism due to inflammatory bowel conditions without diarrhea in CVID patients.

Malignant Edema in Horse by Clostridium perfringens Type A

Background: Malignant edema is one of the terms used to designate severe necrotizing syndromes in soft tissues by Clostridium spp. which are potentially fatal in farm animals. These species are responsible for myonecrosis, belonging to the group of histotoxic clostridia, and may also culminate in toxemia with the worsening of the lesions. These clostridia and their spores require a gateway such as wounds on mucous membranes or skin, which may occur due to shear, tail cut, injuries during delivery, castration or injections by contaminated needles. This report aims to describe the clinical-pathological findings of a case of malignant edema caused by C. perfringens type A in an equine.Case: A female equine, undefined breed, used as traction animal, had a history of abdominal pain. According to the requisitioning veterinary, the tutor reused needles for medication. On palpation, a compact mass was noticed in the pelvic flexure, as well as edema on the region of head and neck with crackling areas. After surgical intervention for compactation correction, the animal did not show anesthetic recovery and was submited to euthanasia. Tissue samples were collected, fixed in 10% buffered formalin solution, routinely processed for histopathology and stained with hematoxylin and eosin and Gram stain. Samples of serous-sanguineous edema fluid and fragments of the abdominal muscles and neck were collected. The samples were kept under refrigeration and sent for microbiological culture. Necropsy showed the subcutaneous region of the pectoral was markedly gelatinous and yellowish (edema) and subcutaneous emphysema characterized by accumulation of serous-sanguineous fluid and gas bubbles. In microscopy, we verified fibrous-haemorrhagic, emphysematous, suppurative and diffuse superficial histiocytic necrotizing cellulitis and myositis. Gram-positive bacillary aggregates were observed in spleen and subcutaneous sections. Colony suggestive of Clostridium perfringens were submitted to PCR for confirmation of identity followed by genotyping. Lastly, C. perfringens type A was isolated from the muscle fragments and serosanguinolent liquid collected.Discussion: In the present study, the diagnosis of malignant edema caused by Clostridium perfringens type A in an equine was confirmed by the clinical-pathological findings added to the isolation and genotyping of the agent from fragments of injured muscle. Although C. perfringens has been reported in cases of clostridial myositis in horses in the United States, in Brazil there are only reports of sporadic cases associated with C. septicum, C. novyi and C. chauvoei in this species. In histotoxic cases by C. perfringens, alpha toxin is known to be the main virulence factor involved, causing destruction of the phospholipid membrane of erythrocytes, endothelial cells, leukocytes and muscle fibers. As consequence, there is an increase in the vascular permeability of capillaries and, with the spread of the infection, there is production of inflammatory edema with serosanguineous exudate and gas. Typically, anatomopathological findings are characterized by increased volume of the affected region associated with edema with bloody fluid and rancid odor, gas bubbles in the subcutaneous tissue, and fasciae associated or not with necrotic myositis. It is assumed that a contaminated needle injection, performed during the treatment of colic symptoms on the property has been the gateway to infection. The clinical course of clostridial infection in horses is considered acute, ranging from 24 to 48 h. In this case, was observed the animal with signs of cervical and pectoral edema still in the property, a day before euthanasia. This is the first study to confirm Clostridium perfringens as a cause of gas gangrene in horses in Brazil.

Hypotension and Bradycardia Produced by Transthoracic Application of Low-Intensity Ultrasound Therapy in Hearts of Healthy Rats - A Preclinical Study.

ObjectiveTo investigate the cardiovascular effects produced by transthoracic application of low-intensity pulsed ultrasound therapy (LIPUST).MethodsThree-month-old male Wistar rats (± 300 g, N=16) were randomly allocated in two groups, namely SHAM (control group, faked procedures) and UST (animals treated with LIPUST). These animals, under anesthesia, were instrumented (femoral artery and vein catheterization) for hemodynamic recordings (mean blood pressure [MBP], heart rate [HR]) and blood biochemical profile (lipids, creatine kinase-myocardial band [CK-MB]). Then, LIPUST (spatial average-temporal average [ISATA] 1-MHz, power 0.1 to 1.2 W/cm2, pulsed 2:8 ms, cycle at 30%, for three minutes) was applied to animals from the UST group, externally to their thorax. SHAM animals were equally manipulated, but without application of ultrasound energy. After the hemodynamic and biochemical measurements, animals were sacrificed, and their hearts were mounted in a Langendorff apparatus for coronary reactivity evaluation. Standard histology techniques were employed to analyze the hearts.ResultsLIPUST application caused statistically significant reductions in MBP (92±4 vs. 106±1 mmHg) and HR (345±14 vs. 380±17 rpm) when compared with SHAM procedures. UST rats exhibited higher CK-MB levels (318±55 vs. 198±26 U/dL) and lower plasma triglycerides levels (38±7 vs. 70±10 mg/dL) than SHAM animals. Coronary reactivity was not significantly changed by LIPUST. Cardiac histopathology showed an increase in capillary permeability in treated animals when compared with SHAM animals.ConclusionNoninvasive LIPUST induces significant metabolic and hemodynamic changes, including intensity-dependent bradycardia and hypotension, indicating a possible therapeutic effect for cardiac events.