Severe Life-threatening Condition Research Articles

The Relationship Between Tumor Budding and Patient's Survival in Breast Cancer.

Breast cancer is a severe life-threatening condition in which many women are involved yearly. One factor that has recently been noticed and investigated as a diagnostic predictor of this type of cancer is the number of tumor buds and the relation of this factor with a patient's survival rate. This study includes 150 female patients over 18 years old with a mean age of 53.99 ± 12.56 years old with breast cancer, which was diagnosed at various medical centers, including Rouhani Hospital itself, and referred to Rouhani Hospital Medical Center, Babol, Iran. The number of intratumoral and peritumoral buds in patients' microscopic slides were archived and evaluated along with tumor microenvironment on hematoxylin and eosin (H&E) slides and compared to other clinicopathological findings. This article precisely investigated the relationship between the number of intratumoral and peritumoral buds with patients' 5-year survival rate. Also, the relationship between age, tumor stage, grade, size, the number of lymph nodes involved, and the presence of metastasis with the number of intratumoral and peritumoral buds was studied. The result showed a significant statistical association between the number of intratumoral and peritumoral buds with tumor size, tumor stage, presence of metastasis, the number of lymph nodes involved, and 5-year survival rate. On the other hand, there is not a significant statistical association between the number of intratumoral and peritumoral buds with age and tumor grade. Our investigation revealed a significant statistical relationship between the number of tumor buds and patients' survival rate. So, this factor should be considered significant to help those patients increase their survival ratio.

Evaluation of the Safety and Efficacy for Oral Mucositis Prevention of MIT-001 in Auto HSCT

Background: Oral mucositis (OM) is one of the most prevalent complications leading to severe pain, difficulty eating, prolonged hospitalization, and life-threatening septic condition in patients receiving chemotherapy containing conditioning regimen prior to autologous hematopoietic stem cell transplantation (auto-HSCT). MIT-001 is a novel small molecule functioning as a mitochondria-targeted radical trapping agent (RTA) that effectively inhibits cellular ferroptosis/necrosis and cytokine production via blockade of reactive oxygen species (ROS) generation and calcium accumulation in the mitochondria. The current clinical study was designed to evaluate the safety, efficacy by prevention of OM and pharmacokinetics of MIT-001 in patients with lymphoma or multiple myeloma (MM) undergoing chemotherapy prior to auto-HSCT. Methods: This phase IIa study consists of two parts: part 1 is an open label dose-escalating study dosing from 5 mg, 10 mg and up to 20 mg of MIT-001 to determine the recommended Part 2 Dose (RP2D) via evaluating the efficacy of OM, safety and pharmacokinetic characteristics of MIT-001, whereas Part 2 is a placebo-controlled, double-blinded, and randomized study to find the optimal dose of MIT-001 regarding the efficacy of OM and safety for the next IIb/III clinical trials. In Part 1, the total screening period was 28 days: conditioning chemotherapy/MIT-001 treatment for four to nine days followed by auto-HSCT and recovery for 14 days and discharge at 28 days following HSCT. MIT-001 was administered intravenously for 30 minutes once daily before conditioning chemotherapy for four to nine days, depending on the conditioning regimens including high-dose melphalan and BMT (intravenous busulfan, melphalan, thiotepa) for auto-HSCT. Pharmacokinetic blood samples of MIT-001 was collected at 5 time points including before administration to 24 hours after the start of the first and last administration of MIT-001. WHO criteria and NCI-CTCAE (v5.0) for OM grading were used for the severity of OM, which was evaluated daily during hospitalization and twice a week or once a week after discharge by investigator's choice. Pain related to OM was collected from patients using the Oral Mucositis Daily Questionnaire. Results: In part 1, total of sixteen patients were enrolled in which 5 patients were assigned in 5 mg and 20 mg group each, and six patients were assigned in the 10 mg group. Twelve lymphoma patients and four MM patients were pre-conditioned by BMT and Melphalan regimen, respectively. Severe OM (grade 3) were observed in two lymphoma patients treated with 10 mg and 20 mg MIT-001 (FAS: 13.3%, 2/16). Two patients with grade 3 OM had experienced radiation therapy of head and neck area within 1 year. Severe OM (> grade 3) did not occur in the four MM patients, while grade 2 was observed in two patients. None of the patients received total parental nutrition feeding due to OM. The median duration of grade 3 OM was 6 days (range, 3 to 9) and mean onset was 6 days (SD±1) after conditioning initiation. The duration and incidence of OM were not significantly different among the 3 groups. Mean area-under-the-curve (AUC) score for patient-reported soreness of the mouth and throat was not proportional to the dose of MIT-001. Time to engraftment was observed at a median time of 13 days (range, 11~ 26 days) determined by the neutrophil and platelet recovery time following auto-HSCT, which was within the normal range of period of auto-HSCT when compared to historical control. With the statistical analysis using the Kruskal-Wallis test, MIT-001 showed good PK profile with dose-proportionality in the range of 5 mg up to 20 mg. Two doses of 5 mg and 20 mg were determined as RP2D under steering committee. Serious adverse drug reactions were not reported. Part 2 is currently ongoing to evaluate efficacy of OM and safety of MIT-001 in forty-five patients with lymphoma and MM, where fifteen patients were allocated in 5 mg, 20 mg, and placebo group. Conclusions: The phase IIa part 1 results strongly suggest the therapeutic potential of MIT-001 to prevent severe OM in the patients with lymphoma and MM undergoing melphalan-containing conditioning followed by auto-HSCT.

Availability and use of resources for emergency fracture care of pelvic trauma associated with haemorrhagic shock in Latin America: A cross-sectional study

Determining the true availability of resources and understanding the level of training of surgeons involved in the treatment of patients with pelvic fractures and haemorrhagic shock is critical. In the herein study, the availability of technical, technological, and human resources for the care of this injury in Latin America region was analysed, and the preferences of orthopaedic trauma surgeons when performing interventions for the diagnosis and treatment of patients with pelvic trauma and associated haemorrhagic shock was described. A cross sectional web-based survey containing questions on knowledge, attitudes, and practices with respect to imaging resources, emergency pelvic stabilization methods, and interventions used for bleeding control was sent to 948 Latin America orthopaedic trauma surgeons treating pelvic fractures in the emergency department. Differences between regional clusters, level of training, type of hospital, and pelvic surgery volume were assessed. 368 responses were obtained, with 37.5% of respondents reporting formal training in pelvic surgery and 36.0% having available protocol for managing these patients. The most frequently used interventions were the supra-acetabular pelvic external fixator and pelvic packing. Limited hospital and imaging resources are available for the care of patients with pelvic trauma and associated haemorrhagic shock throughout Latin America. In addition, the training of orthopaedic trauma surgeons dealing with this type of injury and the volume of pelvic surgeries per year is heterogeneous. It should be urgently considered to develop management protocols adapted to Latin America according to the availability of resources, as well as to promote training in this severe life-threatening traumatic condition.

THU188 Clinical Conundrum: Salt Wasting Congenital Adrenal Hyperplasia With Paradoxical High Cortisol

Abstract Disclosure: C. Pillai: None. Background: Salt wasting congenital adrenal hyperplasia (CAH) is a severe life-threatening condition and thus a cannot miss diagnosis. In salt wasting CAH, cortisol is generally very low. An ACTH stimulation test is often used to diagnose adrenal insufficiency and initiate life-saving hydrocortisone therapy. Clinical Case: I present a case of a male infant who was found to have salt-wasting CAH crisis despite a paradoxically high serum cortisol. He had an abnormal newborn screen for CAH. He was sent to the ER for reportedly high 17-hydroxyprogesterone (17-OHP). Endocrine was consulted and a serum 17-OHP, ACTH and cortisol level was requested. He was an incredibly difficult patient to collect blood work and after multiple attempts only a serum cortisol was collected. He was admitted for an ACTH stimulation test to rule out salt wasting CAH. His physical exam was unremarkable with male external genitalia with descended prepubertal testes. His cortisol from the ER resulted at 36.5 mcg/dL without any steroid administration in the morning. Family refused to do any additional blood work in the morning. Even anesthesiology was not able to collect the requested labs. The ACTH stimulation test was canceled, and he was discharged with close follow-up in 1 week. The state newborn screen department called and reported his initial 17-OHP was undetectably high. He was seen the same day and his BMP showed clear signs of salt wasting. His serum sodium was 131 mmol/L and potassium was 7.2 mmol/L. He was admitted for a salt wasting crisis and responded well to hydrocortisone and fludrocortisone. Serum sodium and potassium normalized. Blood draw issues continued and only BMP were collected during the hospitalization. 17-OHP after several days of therapy was 3270 ng/dl. 17-OHP, sodium and potassium have normalized on therapy. Genetic testing is pending. Conclusions: By reporting this case, I draw attention to the possibility that high levels of cortisol do not definitely rule out salt-wasting CAH. Reference Ranges: NA 132 - 145 mmol/L K 3.0 - 6.0 mmol/L Cortisol: 1.7 - 14.0 ug/dL 17 OHP:INTERPRETIVE INFORMATION for 17-Hydroxyprogesterone in premature and normal male infants: Premature (26 to 28 weeks) 124 to 841 ng/dL Premature (29 to 35 weeks) 26 to 568 ng/dL Full term Day 3 7 to 77 ng/dL 4 days to 2 months Less than 200 ng/dL. Presentation: Thursday, June 15, 2023

Management of Acutely Decompensated Pulmonary Hypertension.

Pulmonary arterial hypertension is a severe life-threatening condition associated with increased pulmonary vascular resistance and resulting right heart dysfunction. Admission to intensive care unit with acutely decompensated right heart failure is a significant negative prognostic event with a high risk of multisystem organ dysfunction and death. Presentations are heterogenous and may combine signs of both diastolic and systolic dysfunction complicating management. Renal dysfunction is often present, but other organ systems can be involved resulting in findings such as acute hepatic dysfunction or bowel wall congestion and ischemia. The goals of therapy are to rapidly reverse ventriculo-arterial decoupling and reduce right ventricular afterload to prevent progression to refractory or irreversible right heart failure. Triggering events must be investigated for and addressed urgently if identified. Volume status management is critical and both noninvasive and invasive testing can aid in prognostication and guide management, including the use of inotropes and vasopressors. In cases of refractory right heart dysfunction, consideration of urgent lung transplantation and mechanical circulatory support is necessary. These patients should be managed at expert centers in an intensive care setting with a multidisciplinary team of practitioners experienced in the management of right heart dysfunction given the high short- and long-term mortality resulting from acute decompensated right heart failure.

Pathophysiology of the coagulation system in general heat injury (scientific and literary review)

General unintentional overheating of the body (heat stroke) is a severe life-threatening condition that causes thousands of deaths worldwide every year due to climate changes. Coagulation disorders associated with general heat injury are a determining factor in the course and prognosis of the pathological condition. Coagulopathy is a pathophysiological process that is activated as a result of a systemic inflammatory reaction the basis of which is a destabilized external primary protection of the body against hyperthermia and negative changes in the vascular endothelium. Based on the data of foreign authors and their own clinical experience, the authors were able to highlight certain features and patterns of the development of coagulopathies in thermal trauma.

Neonatal abstinence syndrome: paediatric case report

Neonatal abstinence syndrome (NAS) is a severe life-threatening condition, characterised as a spectrum of clinical manifestations observed in neonates where maternal opioid use, both prescribed and illicit, has taken place during pregnancy. This article was written after experience of the condition identified a learning outcome, a potential change in practice, and the differences between out-of-hospital and in-hospital managements of NAS. In addition, this article will aim to identify the complications of NAS, the severity of the condition, and the varying methods of treatment.

A case of acquired thrombotic thrombocytopenic purpura (TTP) mimicking transient ischemic attack (TIA)

TTP is a rare multisystem disease among children due to dysfunction of ADAMTS 13 enzyme in plasma causing defective vWF cleavage, thus giving rise to platelet aggregation, micro thrombi formation, platelet consumption, capillary blockage and finally organ dysfunction leading to a severe life-threatening condition with mortality around 90% if untreated. It can be congenital (5%) or acquired (95%) and Plasmapheresis works wonder for both the subtypes.: Here we have described a case of acquired TTP masquerading TIA in an 8-year-old girl child who had attacks of sudden onset aphasia and upper limb weakness lasting for few hours with spontaneous recovery. On detailed examination we found pallor and few petechial spots on face and upper limbs with a peripheral blood picture suggestive of thrombocytopenia with microangiopathic hemolytic anemia but a normal renal function. We sent blood for ADAMTS 13 activity which reported a critically low level of ADAMTS 13 enzymatic activity with presence of inhibitors and absent genetic mutation. Immediate Plasmapheresis was started along with oral prednisolone therapy for a span of one month which resulted both clinical and hematological recovery. Platelet count acted as a good indicator of clinical remission. A high degree of clinical suspicion is required to make a prompt diagnosis of this life threatening disease (TTP) since this carries a very high mortality rate and can mimic a more common disease HUS.

Risk Factors of Hypocalcemic Patients at Surgical Intensive Care Unit of Zagazig University Hospitals

Background: Hypocalcemia may be present as an asymptomatic laboratory finding or as a severe life-threatening condition. Objective: The study aimed to estimate incidence rate of hypocalcemia and to identify risk factors associated with hypocalcemia in patients of Surgical Intensive Care Unit of Zagazig University Hospitals. Patients and methods: This study involved 310 patients who enrolled to Surgical Intensive Care Unit, Zagazig University Hospitals over a period of six months. Total serum calcium concentration and ionized calcium concentration were measured. Results: The distribution of the studied cases according to admission diagnosis, 40% of the studied cases were admitted to ICU due to sepsis and septic shock, 16% polytrauma, 10% respiratory failure, 10% post-operative monitoring, 6% with ICH, 6% with uncontrolled HTN, 4% with ischemic stroke, 2% pancreatitis, 2% dehydration and electrolyte imbalance, 2% DKA and one case due to organophosphorus poisoning and 1% rhabdomyolysis. There was statistically significant negative correlation between GCS score and Ca total and ionized at 3rd day. However, a statistically significant positive correlation was detected between Ph and Ca total at 3rd day.Only sepsis, septic shock, hypertensive crisis, aminoglycosides, respiratory failure and APACHE score were significant risk factors for hypocalcemia. Conclusion: Hypocalcemia is more common in cases with sepsis and septic shock, hypertensive crisis, respiratory failure and cases with electrolyte disturbance.

RECURRENT DIFFUSE ALVEOLAR HEMORRHAGE IN SYSTEMIC SCLEROSIS AS COMPLICATION OF COVID-19

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Diffuse alveolar hemorrhage (DAH) is a rare but severe life-threatening condition characterized by widespread bleeding of the pulmonary vasculature into the alveolar space. DAH have a myriad of underlying etiologies. Rheumatic diseases have shown association with DAH. The Coronavirus disease 2019 (COVID-19) pandemic has increased the complexity associated with diagnosing DAH. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infects the endothelium using the angiotensin-converting enzyme 2 receptor causing a lymphocytic endotheliitis. The increased inflammatory state secondary to COVID-19 has been associated with development of vasculitis syndromes. Although systemic sclerosis (SSc) has been linked to recurrent DAH, there is scarce evidence associating COVID-19 and SSc with DAH. CASE PRESENTATION: A 61-year-old female with a past medical history of SSc, interstitial lung disease (ILD) and DAH presented with worsening shortness of breath of 2 days duration. She was found to have acute hypoxic respiratory failure. Computed tomography (CT) of thorax showed diffuse bilateral ground-glass opacities. SARS-Cov-2 polymerase chain reaction was positive. She was started on broad spectrum antibiotics, dexamethasone and received two units of COVID-19 convalescent plasma. Due to respiratory distress, she was intubated. A decline in her hemoglobin prompted a diagnostic bronchoscopy that showed increasing frank blood in the bronchoalveolar lavage. Antinuclear antibody with centromere pattern and rheumatoid factor were positive with low complement C3 and C4. Steroids were switched to high-dose IV methylprednisolone. Three cycles of plasmapheresis were given with no clinical improvement. DISCUSSION: COVID-19 pandemic has changed the traditional approach to dyspnea. This change in the paradigm, as a result of limited resources and increased occupational risk, may hinder the diagnosis of complex disorders like SSc-ILD and DAH. It's of paramount importance to test rapidly for SARS-CoV-2 infection. ILD is a common complication of SSc. The high-resolution CT similarities between the 2 diseases make it difficult to distinguish COVID-19-ILD superinfection from worsening of SSc-ILD. Bronchoscopy and surgical lung biopsy should always be weighed against their possible complications, occupational exposure and prognosis. CONCLUSIONS: COVID-19 may overlap and complicate the diagnosis of SSc-ILD. COVID-19 associated acute respiratory distress syndrome is attributed to cytokines release (cytokine storm). This likely worsens the underlying inflammatory process in SSc-ILD and could explain the development of DAH. Although there is limited evidence to guide specific treatment, steroid therapy has proven to have mortality benefit in severe COVID-19. The role of steroids, plasmapheresis, immunomodulators and antifibrotic therapy in COVID-19 with SSc-ILD complicated with DAH is unknown. REFERENCE #1: Colby TV, Fukuoka J, Ewaskow SP, Helmers R, Leslie KO. Pathologic approach to pulmonary hemorrhage. Annals of Diagnostic Pathology. 2001;5(5):309-19. REFERENCE #2: Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. The Lancet. 2020;395(10234):1417-8. REFERENCE #3: Wong AW, Fidler L, Marcoux V, Johannson KA, Assayag D, Fisher JH, et al. Practical Considerations for the Diagnosis and Treatment of Fibrotic Interstitial Lung Disease During the Coronavirus Disease 2019 Pandemic. Chest. 2020;158(3):1069-78. DISCLOSURES: No relevant relationships by Vedesh Babu, source=Web Response No relevant relationships by Alejandra Garcia Fernandez, source=Web Response No relevant relationships by ahmad hamdan, source=Web Response No relevant relationships by Carlos Matute Martinez, source=Web Response

Generation and characterisation of a semi-synthetic siderophore-immunogen conjugate and a derivative recombinant triacetylfusarinine C–specific monoclonal antibody with fungal diagnostic application

Invasive pulmonary aspergillosis (IPA) is a severe life-threatening condition. Diagnosis of fungal disease in general, and especially that caused by Aspergillus fumigatus is problematic. A. fumigatus secretes siderophores to acquire iron during infection, which are also essential for virulence. We describe the chemoacetylation of ferrated fusarinine C to diacetylated fusarinine C (DAFC), followed by protein conjugation, which facilitated triacetylfusarinine C (TAFC)-specific monoclonal antibody production with specific recognition of the ferrated form of TAFC. A single monoclonal antibody sequence was ultimately elucidated by a combinatorial strategy involving protein LC-MS/MS, cDNA sequencing and RNAseq. The resultant murine IgG2a monoclonal antibody was secreted in, and purified from, mammalian cell culture (5 mg) and demonstrated to be highly specific for TAFC detection by competitive ELISA (detection limit: 15 nM) and in a lateral flow test system (detection limit: 3 ng), using gold nanoparticle conjugated- DAFC-bovine serum albumin for competition. Overall, this work reveals for the first time a recombinant TAFC-specific monoclonal antibody with diagnostic potential for IPA diagnosis in traditional and emerging patient groups (e.g., COVID-19) and presents a useful strategy for murine Ig sequence determination, and expression in HEK293 cells, to overcome unexpected limitations associated with aberrant or deficient murine monoclonal antibody production.

Human Wharton's jelly-derived mesenchymal stem cells alleviate concanavalin A-induced fulminant hepatitis by repressing NF-\u03baB signaling and glycolysis

BackgroundFulminant hepatitis is a severe life-threatening clinical condition with rapid progressive loss of liver function. It is characterized by massive activation and infiltration of immune cells into the liver and disturbance of inflammatory cytokine production. Mesenchymal stem cells (MSCs) showed potent immunomodulatory properties. Transplantation of MSCs is suggested as a promising therapeutic approach for a host of inflammatory conditions.MethodsIn the current study, a well-established concanavalin A (Con A)-induced fulminant hepatitis mouse model was used to investigate the effects of transplanting human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on fulminant hepatitis.ResultsWe showed that hWJ-MSCs effectively alleviate fulminant hepatitis in mouse models, primarily through inhibiting T cell immunity. RNA sequencing of liver tissues and human T cells co-cultured with hWJ-MSCs showed that NF-κB signaling and glycolysis are two main pathways mediating the protective role of hWJ-MSCs on both Con A-induced hepatitis in vivo and T cell activation in vitro.ConclusionIn summary, our data confirmed the potent therapeutic role of MSCs-derived from Wharton's jelly of human umbilical cord on Con A-induced fulminant hepatitis, and uncovered new mechanisms that glycolysis metabolic shift mediates suppression of T cell immunity by hWJ-MSCs.

Pre Eclampsia: Its contribution to Pregnancy Related Acute Kidney Injury. A tertiary care nephrology unit experience

Preeclampsia, eclampsia and hemolysis, elevated liver enzymes and thrombocytopenia (HELLP) are among many other conditions of pregnancy related AKI (PR-AKI). Present study aims to report case series of patients with PR-AKI developing in association with preeclampsia, their course of illness and outcome.
 Patients and Methods: Subjects for the study reported here comprise a cohort of 227 women coming to this institution with diagnosis of preeclampsia and AKI. Results: From January 1990 to December 2014, there were 1,441 women with PR-AKI brought to this institution among these 227 (15.75%) fulfilled the criteria of preeclampsia. On presentation 93.4% were oligo-anuric, thrombocytopenia was found in 48%, deranged INR in 18.9% and raised liver enzymes in 33.5%. On arrival 22% were in sepsis, mechanical ventilator support required in 11%. Impaired Glasgow coma scale noticed in 22%. Intra uterine death of fetus was reported in 75%. Antepartum hemorrhage in 38% and post partum hemorrhage in 32%. Renal replacement therapy in form of hemodialysis was conducted in 94.7%. Complete recovery seen in 25%, partial recovery in 31%, CKD developed in 4.4%, ESRF in 27.3% and 12 % died during acute phase of illness. Sepsis, multi-organ failure and requirement of mechanical ventilatory support on arrival were significant predictors of mortality with p value <0.001.
 Conclusion: Preeclampsia and its progress to eclampsia can be a severe life-threatening condition especially when patients present with sepsis and multi organ failure. A significant number of women developed irreversible AKI and progessed to CKD.

Extensive skull base osteomyelitis, devastating complication of otitis externa: A case report and review of the literature

Skull base osteomyelitis (SBO), also referred to as malignant otitis externa (MOE) in its typical form, is usually a complication of otitis externa and severe uncommon and life-threatening condition requiring early diagnosis and long-term treatment in order to avoid its neurologic sequelae. We report the case of 69 years old female with a history of uncontrolled type 2 diabetes, who presented refractory and chronic right-sided purulent otorrhea with temporal headaches for 6 months, treated with no improvement by multiple attempts of ambulatory empiric therapy. After the appearance of grade III facial palsy and painful swelling in the right periorbital and zygomatic areas, the patient consulted in our department where a CT scan showed massive cortical and trabecular destruction of the right petrous bone and the mastoid extended to the lateral orbital wall, the zygomatic arch and the greater sphenoid wing realising extensive osteomyelitis of the skull base and the lateral face. The treatment was started immediately based on intravenous broad-spectrum antibiotics. Despite aggressive long-term treatment, the patient passed away, underlying the increased SBO morbidity and mortality secondary to delayed diagnosis.

Reverse phase-liquid chromatography assisted protocol for simultaneous determination of lamivudine and tenofovir disoproxil fumarate in combined medication used to control HIV infection: an investigative approach

BackgroundHuman immunodeficiency virus (HIV) causes severe life-threatening condition, i.e., AIDS. HIV destabilises an individual’s ability to prevent infection. Therefore, the combine medication lamivudine (LVD) and tenofovir disoproxil fumarate (TDF) are prescribed to suppress the amount of HIV infection in individual’s body; thus, the individual’s immune system could function properly. Consequently, the objective of present research work was to investigate robust and sensitive liquid chromatography avenue for simultaneous determination of lamivudine and tenofovir disoproxil fumarate in pure material and combined dosage form.ResultsThe reversed-phase chromatographic separation has been performed through Hypersil BDS C18 column using solvent system composed of 10 mM potassium dihydrogen phosphate (pH 4.0): acetonitrile (60:40% v/v). The determination was executed at 30 oC at 1 mL/min rate for flow of solvent system through column. The eluents of column were monitored at 265 nm using Photodiode Array detector has revealed admirable retention times, i.e., 4.67 and 8.78 min for both drugs, respectively. The calibration curve demonstrated excellent linearity in the range of 10–50 μg/mL for lamivudine and tenofovir disoproxil fumarate with better determination coefficients was more than (r2 0.999).ConclusionThe estimable method was effectively validated with respect to accuracy, precision, sensitive (limit of detection and limit of quantitation), robustness, ruggedness, and for selectivity and specificity. The value less than 2 for percentage relative standard deviation for accuracy, precision, robustness, and ruggedness satisfying the acceptance criteria as per procedure of International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use.

Аnaphylactic shock. Сlinical guidelines

Anaphylactic shock is a severe life-threatening condition caused by medicines, food, hymenoptera, animal poisons, etc. Therefore, anaphylactic shock (anaphylaxis) can develop both in medical institution and outside it, and physicians of any specialties should be ready to treat this condition. In this regard, clinical guidelines for anaphylactic shock have been developed. These recommendations were approved by the Russian Association of Allergy and Clinical Immunology (Protocol No. 743/12 dated December 30, 2020) and the Federation of Anesthesiologists and Resuscitators (Protocol No. 1 dated January 13, 2021), approved at a meeting of the Scientific and Practical Council of the Ministry of Health of the Russian Federation (Protocol No. 743/12 dated December 10, 2020). Guidelines covered a number of nosologies corresponding to codes of the International Statistical Classification of Diseases and Related Health Problems: T 78.0; T 78.2; T 80.5; T 88.6. The clinical guidelines systematize modern data on etiology, epidemiology, classification, clinical picture, diagnosis, treatment, and prevention of anaphylactic shock. In addition, an algorithm for managing a patient with anaphylactic shock has been developed. Clinical guidelines for anaphylactic shock are intended for practitioners of all specialties, students, and teachers of medical universities, residents, and graduate students.

Phenobarbital, midazolam, bumetanide, and neonatal seizures: The devil is in the details.

Kaila, Löscher, and colleagues report that phenobarbital (PHB) and midazolam (MDZ) attenuate neonatal seizures following birth asphyxia, but the former only when applied before asphyxia and the latter before or after the triggering insult. In contrast, the NKCC1 chloride importer antagonist bumetanide (BUM) had no effect whether applied alone or with PHB. The observations are compelling and in accord with earlier studies. However, there are several general issues that deserve discussion. What is the clinical relevance of these data and the validity of animal models of encephalopathic seizures? Why is it that although they act on similar targets, these agents have different efficacy? Are both PHB and MDZ actions restricted to γ-aminobutyric acidergic (GABAergic) mechanisms? Why is BUM inefficient in attenuating seizures but capable of reducing the severity of other brain disorders? We suggest that the relative failure of antiepileptic drugs (AEDs) to treat this severe life-threatening condition is in part explicable by the recurrent seizures that shift the polarity of GABA, thereby counteracting their effects on their target. AEDs might be efficient after a few seizures but not recurrent ones. In addition, PHB and MDZ actions are not limited to GABA signals. BUM efficiently attenuates autism symptomatology notably in patients with tuberous sclerosis but does not reduce the recurrent seizures, illustrating the uniqueness of epilepsies. Therefore, the efficacy of AEDs to treat babies with encephalopathic seizures will depend on the history and severity of the seizures prior to their administration, challenging a universal common underlying mechanism.

TMAO promotes apoptosis and oxidative stress of pancreatic acinar cells by mediating IRE1α-XBP-1 pathway.

Background:Acute pancreatitis caused by hyperlipidemia is a severe life-threatening condition. Therefore, it is urgent to develop new therapeutic methods to treat this disease.Methods:Cell viability was determined by the Cell Counting Kit-8 (CCK-8) assay. Western blotting (WB) was used to detect the expression levels of apoptotic and endoribonuclease inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP-1) pathway-associated proteins. The induction of cell apoptosis was determined using flow cytometry. The expression levels of the oxidative stress indicators were measured by an enzyme-linked immunosorbent assay.Results:WB analysis and the CCK-8 assay demonstrated that trimethylamine-N-oxide (TMAO) decreased cell viability and facilitated apoptosis of MPC-83 cells in a dose-dependent manner. Furthermore, the induction of oxidative stress was assessed by evaluating the levels of specific markers, including hydrogen peroxide, reactive oxygen species, nitric oxide, and superoxide dismutase. The levels of the aforementioned markers were increased in the TMAO-treated group. Subsequently, the IRE1α/XBP-1 pathway-associated proteins were analyzed by WB analysis and the data demonstrated that the regulatory effects of TMAO on MPC-83 cells were meditated by the IRE1α/XBP-1 signaling pathway. Subsequently, rescue experiments were performed to further assess the effects of TMAO.Conclusion:The present study provides evidence on the application of TMAO as a potential diagnostic and therapeutic strategy for the therapeutic intervention of hyperlipidemic acute pancreatitis.

Thrombotic Lesion of the Pulmonary Vessels in Patients with Pulmonary Embolism

After suffering pulmonary embolism (PE), doctors are confronted with various consequences of the disease, from asymptomatic residual pulmonary thrombosis to the formation of chronic thromboembolic pulmonary hypertension (CTEPH). There is also a subgroup of patients who have undergone pulmonary embolism, who experience shortness of breath during physical exertion, absent before pulmonary embolism, or shortened dyspnea preceding PE, combined with residual thrombosis of pulmonary artery (PA) and normal average pressure in PA at rest during catheterization of the right heart (CRH). This condition is defined as chronic thromboembolic pulmonary disease or post thromboembolic syndrome. Pathogenetic aspects of this condition are not fully investigated. It is important to predict the development of postembolic syndrome and to develop algorithms for the diagnosis, treatment and rehabilitation of patients with symptoms and residual pulmonary thrombosis. In case of the development of pulmonary vasculopathy in some patients who have undergone pulmonary embolism, a severe life-threatening condition forms - CTEPH, characterized by an increase in pressure in the pulmonary artery, right heart failure due to the presence of organized blood clots that have entered the pulmonary vascular bed during PE. The volume of thrombotic masses does not always correlate with clinical symptoms, which indicates the importance of microvascular remodeling. If CTEPH is suspected, a diagnostic algorithm is required, including ventilation-perfusion scintigraphy, CT angiopulmonography and catheterization of the right heart. Treating a patient with CTEPH is a difficult task fora doctor. The timely referral of the patient to the center where they are involved in treatment, including surgery and CTEPH is extremely important. Timely performed thrombendarterectomy in some cases allows to completely cure the patient. In the case of inoperable CTEPH or residual pulmonary hypertension after thrombendarterectomy, balloon angioplasty of the PA is used as well as drug treatment with specific drugs that reduce the pressure in the PA (riociguat), endothelin receptor antagonists (bosentan, macitentan), prostanoids (inhalant illoprost) phosphodiesterase-5 inhibitor and combined therapy. In this article we considered some consequences directly related to PE: asymptomatic residual pulmonary thrombosis, chronic thromboembolic pulmonary disease, chronic thromboembolic pulmonary hypertension.

Negative pressure increases microvascular perfusion during severe hemorrhagic shock

Hemorrhagic shock (HS) is a severe life-threatening condition characterized by loss of blood volume and a lack of oxygen (O2) delivery to tissues. The objective of this study was to examine the impact of manipulating Starling forces in the microcirculation during HS to increase microvascular perfusion without restoring blood volume or increasing O2 carrying capacity. To decrease interstitial tissue pressure, we developed a non-contact system to locally apply negative pressure and manipulate the pressure balance in capillaries, while allowing for visualization of the microcirculation. Golden Syrian hamsters were instrumented with dorsal window chambers and subjected to a controlled hemorrhaged of 50% of the animal's blood volume without any fluid resuscitation. A negative pressure chamber was attached to the dorsal window chamber and a constant negative pressure was applied. Hemodynamic parameters (including microvascular diameter, blood flow, and functional capillary density [FCD]) were measured before and during the four hours following the hemorrhage, with and without applied negative pressure. Blood flow significantly increased in arterioles during negative pressure. The increase in flow through arterioles also improved microvascular perfusion as reflected by increased FCD. These results indicate that negative pressure increases flow in the microcirculation when fluid resuscitation is not available, thus restoring blood flow, oxygen delivery, and preventing the accumulation of metabolic waste. Applying negative pressure might allow for control of microvascular blood flow and oxygen delivery to specific tissue areas.