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1.
Lung India ; 39(3):292-300, 2022.
Article in English | ProQuest Central | ID: covidwho-1810865

ABSTRACT

A 63-year-old man presented with fever and breathlessness during the coronavirus disease 2019 (COVID-19) pandemic. He was diagnosed to have severe COVID-19 pneumonia. He was treated with oxygen, noninvasive ventilation, and glucocorticoids. He improved over 5 weeks and was shifted out of the intensive care unit. Subsequently, he experienced worsening during hospitalization with refractory hypoxemia and shock and finally succumbed to his illness. An autopsy was performed. Herein, we have presented a clinical discussion on the possible causes of the patient's fatal outcome followed by the autopsy findings.

2.
Cancer Research ; 82(4 SUPPL), 2022.
Article in English | EMBASE | ID: covidwho-1779485

ABSTRACT

Correct interpretation of tumor progression data, including the influence of host biology, in mouse models of breast cancer requires models and conditions that faithfully recapitulate human disease and human host status. Our previous attempts to investigate the effects of social isolation have proven inconclusive due to premature mortality in tumor-bearing animals. Those studies were completed in standard temperature (ST), which commonly is 70-72°F (21-22°C) for in vivo murine research based on laboratory animal care and use guidelines. Previous work from the Repasky lab (Kokulus, 2013), which we have validated (Gaymon, 2020), demonstrates that ST housing results in chronic cold stress and immune suppression mediated by an increase in norepinrephrine (NE) levels, leading to increased tumor aggressiveness. Based on these findings, we investigated the effects of social isolation on BALB/cJ-4T1-luc and C57BL/6J/E0771 tumor progression and metastasis in thermoneutral housing conditions (84-85°F). Mice were first acclimatized to thermoneutral temperature and/or isolation for two weeks in cages that were unilaterally draped to provide physical and visual isolation. In BALB/cJ mice, 4T1-luc tumors were significantly larger in isolated mice compared to group-housed (GH) mice at day 18 (p<.0001). Statistically larger tumors were observed in isolated mice compared to GH mice through day 24 and final tumor masses were Salso significantly different (p=.004). Spleen masses were not statistically different. In C57BL/6J mice, E0771 tumors were significantly larger in isolates at Day 25 (p=.002). Final tumor masses were statistically (p=.002) different while no difference in spleen sizes were observed. Data on metastasis will be presented at the meeting. We hypothesized that social isolation may perturb immune function and next investigated the growth of 4T1-luc xenograft tumors in NSG mice. 4T1-luc/NSG tumor progression and metastasis data will also be presented at the meeting. We conclude that syngeneic breast tumor growth in immunocompetent BALB/cJ and C57BL/6J mice demonstrates that social isolation is a bona fide stress with sufficient influence to exacerbate breast cancer growth. These data are potentially clinically important due the known relationship of social support to survivorship outcomes in patients and the high-risk of depression and isolation in patients following breast cancer diagnosis. The data may provide additional insight into possible effects of COVID-19 isolation on breast cancer progression.

3.
Journal of Comparative Pathology ; 191:18, 2022.
Article in English | EMBASE | ID: covidwho-1768291

ABSTRACT

Introduction: Recent studies have shown that bats are the reservoir hosts of several novel viruses, increasing the interest in bats as potential vectors of zoonotic pathogens. Several studies investigated the presence of infectious agents in bats, but their impact on the individual host and their importance on bat mortality is largely unknown. The aim of this study was to describe the microbiological and histopathological findings in 77 deceased bats belonging to nine European species (families Vespertilionidae and Molossidae). Materials and Methods: Bat carcasses were collected in the Piedmont region (Italy) by the Unconventional Rehabilitation Centre (CANC), Torino University, and submitted to necropsy. Species, age and sex of each bat were recorded. Virological (orthoreovirus, coronavirus, flavivirus, rhabdovirus, poxvirus, kobuvirus) and histopathological examinations were performed on the main organs (liver, spleen, kidney, gut, lung, heart and brain). Results: Traumatic injuries (fractures, haemorrhages, skin lesions;43%) and predation injuries (8.4%) represented the two main causes of death. Regardless of species, age and sex, the pathological examination revealed inflammatory/degenerative lesions mainly involving liver (non-suppurative hepatitis and vacuolar degeneration;20.8%) and lung (bronchopneumonia;29.9%). Coronavirus, flavivirus, rhabdovirus and kobuvirus were not detected. Poxviruses were detected in three lungs, two with pneumonia, and 14.3% of animals were positive for reoviruses. Conclusions: This study demonstrates the importance of inflammatory lesions in bat mortality, and shows that bats can harbour infectious agents. However, there is no evidence that Italian bats may represent a severe risk for human health.

4.
Genetics in Medicine ; 24(3):S176-S177, 2022.
Article in English | EMBASE | ID: covidwho-1768094

ABSTRACT

Introduction: Acid sphingomyelinase deficiency (ASMD), also historically known as Niemann-Pick disease A (OMIM #257200) and B (OMIM#607616), is a rare and debilitating lysosomal storage disease caused by pathogenic variants in SMPD1 gene. Deficient activity of the lysosomal enzyme acid sphingomyelinase (ASM) leads to sphingomyelin accumulation in various organs. Visceral manifestations of ASMD include interstitial lung disease and pulmonary dysfunction, splenomegaly, hepatomegaly, dyslipidemia, thrombocytopenia, and anemia and are present across ASMD phenotypes (ASMD type A, B and A/B). In more severe cases of ASMD (ASMD type A), there are also central nervous system manifestations. No disease-specific treatment is currently approved for patients with ASMD. Olipudase alfa, an intravenous-recombinant-human ASM, is in late-stage development (Sanofi Genzyme) for the non-central-nervous-system manifestations of ASMD in children and adults. Two open-label trials, a phase 1b trial in 5 adults (NCT01722526) and a phase 1/2 trial in 20 children with chronic ASMD (ASCEND-Peds, NCT02292654) demonstrated improvement of pulmonary function, reduction of liver and spleen volume, reversal of dyslipidemia, decreased disease biomarkers, and in children, improved growth. A phase 2/3 placebo-controlled trial, the ASCEND study (NCT02004691) in 36 adults with ASMD who had splenomegaly and pulmonary dysfunction, has completed its primary analysis. Olipudase-alfa-treated patients compared to placebo-treated patients (1:1 randomization) had statistically significant increases in percent-predicted diffusing capacity of carbon monoxide (DLCO) and statistically significant decreases in spleen and liver volume after 1 year of placebo or olipudase alfa. Thirty-five of 36 patients continued in an open-label trial extension including 17 of the 18 patients who initially received placebo in the first year and all 18 patients who received olipudase alfa. Here we report Year 2 results of the ASCEND trial for the former placebo group after 1 year of olipudase alfa treatment and for the initial olipudase alfa group after 2 years of olipudase alfa treatment. Methods: All patients underwent gradual dose-escalation to 3.0 mg/kg every 2 weeks for approximately 14 weeks when starting olipudase alfa. Efficacy outcomes include percent-predicted DLCO, spleen volume, liver volume, lung high-resolution computerized tomography (HRCT) scores for ground glass appearance, histopathologic clearance of sphingomyelin in the liver, platelet count, plasma lyso-sphingomyelin, liver function, and lipid profile. Change from baseline results are presented as least-square mean (analysis of covariance [ANCOVA]) percent change ± standard error of the mean (SEM), except for ground glass appearance, which is the least-square mean ANCOVA absolute change from baseline, and percent liver tissue area occupied by sphingomyelin and plasma lyso-sphingomyelin, which are presented as mean changes ± standard deviation (SD). Absolute values at Baseline, Year 1, and Year 2 are presented as mean ± SD (Table). Results: Overall, 33 of 35 patients completed Year 2 of ASCEND;one former placebo patient withdrew due to COVID-19 travel restrictions, and one continuing olipudase alfa patient withdrew consent. COVID-19 travel restrictions also resulted in at least one missed assessment in six patients. In Year 2, improvements for patients in the former placebo group paralleled the olipudase alfa group in the primary analysis while clinical improvement continued for patients who received 2 years of olipudase alfa (Table). For patients in the former placebo group, percent-predicted DLCO increased by 28.0 ±6.2% (n=10);spleen volume decreased by 36.0 ±3.0% (n=11);liver volume decreased by 30.7 ±2.5% (n=11), and platelet count increased by 21.7 ±6.4% (n=15). In patients with 2 years of olipudase alfa treatment, percent-predicted DLCO increased by 22.2 ±3.4% (n=17) at Year 1 and 28.5±6.2% at Year 2 (n=10);spleen volume decreased by 39.5 ±2.4% (n=17) at Year 1 and 47.0 ±2.7% (n=14) at Year 2 liver volume decreased by 27.8 ±2.5% (n=17) at Year 1 and 33.4 ±2.2% (n=14) at Year 2, and platelet count increased by 16.6 ±4.0% at Year 1 (n=18) and 24.9 ±6.9% (n=13) at Year 2. HRCT ground glass appearance score decreased 0.30 ±0.5 (n=14) at Year 2 for patients in the former placebo group and decreased by 0.45 ±0.13 (n=18) at Year 1 and 0.48 ±0.07 (n=16) at Year 2 for patients continuing to receive olipudase alfa. Liver sphingomyelin clearance at Year 2 was 93.3 ±5.0% (n=10) for patients in the former placebo group and 92.7 ±5.8% at Year 1 (n=13) and 98.4 ±2.0% at Year 2 (n=10) for patients continuing to receive olipudase alfa. Plasma lyso-sphingomyelin decreased by 79.4 ±11.3% (n=14) for patients in the former placebo group and by 78.0 ±11.1% (n=18) at Year 1 and 64.4 ±28.5% (n=15) at Year 2 for patients continuing to receive olipudase alfa;several patients had transient increases due to missed infusions. Alanine aminotransferase decreased by 45.2 ±34.4% (n=15) for patients in the former placebo group, and by 36.5 ±8.4% (n=18) in Year 1 and 32.0 ±10.2% (n=12) in Year 2 for patients continuing to receive olipudase alfa. For patients in the former placebo group, high-density lipoprotein cholesterol (HDL-C) increased by 59.7 ±9.7% (n=14) and low-density lipoprotein cholesterol (LDL-C) decreased by 27.5 ±6.8% (n=13) in Year 2. For patients continuing to receive olipudase alfa, HDL-C increased by 40.0 ±6.8% (n=18) in Year 1 and 64.4 ±10.5% (n=12) in Year 2 and LDL-C decreased by 25.8 ±4.8% (n=18) in Year 1 and 23.0 ±7.1% (n=12) in Year 2. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles in patient with previously documented cardiomyopathy). No patient discontinued due to an adverse event. Conclusion: During Year 2 of ASCEND, patients crossing over from placebo to olipudase alfa had the same magnitude and time course of clinical improvement seen in patients receiving olipudase alfa for 1 year, while continuing olipudase-alfa patients had sustained or further improvements. Olipudase alfa reduced sphingomyelin storage in the liver and lyso-sphingomyelin in plasma. Clinically, olipudase alfa improved pulmonary function, reduced splenomegaly and hepatomegaly, and improved liver function and dyslipidemia for up to 2 years. These results are consistent with the published 30- and 42-month data for adults reported in the long-term extension of the open-label Phase 1b study. Treatment with olipudase alfa reduces manifestations of chronic ASMD in adults and has sustained efficacy. [Formula presented]

5.
Turkish Journal of Biochemistry ; 46(SUPPL 2):21, 2021.
Article in English | EMBASE | ID: covidwho-1766753

ABSTRACT

SARS-CoV-2 still remains to be the cause of the Covid-19 pandemic, with more than 200 million infections and over 4.5 million deaths worldwide. With the onset of this pandemic, vaccine development efforts began on an unprecedented scale in the world, and it was seen that some vaccines received global application permissions in a very short period of time. For now, it has been proven that current COVID-19 vaccines are highly effective in protecting against serious illness and death. However, there remains much to learn about the immune response of vaccines and the duration of protection, and how we can further optimize vaccines against new variants. As of today, some inactivated vaccines (eg. Sinovac, Sinopharm, BharatBiotech), mRNA vaccines (eg.Pfizer&Bionthec, Moderna), Non-Replicating Viral Vector ones (eg. Oxford, Astra- Zeneca, Sputnik V) and recombinant protein vaccines (eg.Novovax) have been approved for immediate use, but determining the longterm effectiveness of vaccination with existing vaccines and moving towards adolescent and pediatric applications, as well as the reports on some serious side effects seen especially with mRNA and vector vaccines, remain important issues. In addition, the difficulties of poor countries' access to vaccines, and serious vaccine insecurity or rejection in almost all countries constitute major obstacles against the termination of the pandemic. The extension of the time required for the formation of herd immunity leads to the emergence of new variants. The rapid spread of these variants leading to a significant decrease in the effectiveness of the existing vaccines brings about a need for the modification of the current vaccines. During this period, we developed a different vaccine candidate and two vaccine formulations that can be easily adapted to emerging variants. In our study, a fragment protein (P1;MW: 33 kDa) containing the Receptor-Binding Domain (RBD) in the spike S1 region, a fragment protein in the S2 region (P2;MW: 17.6) and nucleocapsid protein (N;MW: 46 kDa) were expressed in Escherichia coli, and subsequently the recombinant proteins were purified. It was determined that each of these three protein antigens reacted strongly with recovered Covid-19 patient sera. The combination of these three proteins was adsorbed with one adjuvant or two adjuvants led to the development of two formulations. In mouse immunization studies, these vaccine candidates elicited very high titers of anti-P1 IgG and IgG2a, anti-P2 IgG and IgG2a, and anti-N IgG and IgG2a. In the live virus neutralization assays, high virus neutralizing antibody levels were observed, and by obtaining specific interferon-gamma (INF-gamma) from immunized mouse splenocytes, we proved that a good cellular immunity was achieved too. These findings, overall, validated high immunogenicity of the P1 and P2 proteins of the S region and the N protein to order to develop an effective vaccine candidate against SARS CoV-2 infection. In addition, a variant recombinant protein was designed by our group and prepared in the same way. This protein that contains the most important point mutations of the known variants is being intended to be incorporated into our candidate vaccine. Our studies are being conducted in this direction and we aim at starting Phase I trials as soon as possible. In conclusion, such alterations/adaptations in vaccine formulations are highly important to optimize current vaccines. In order to reduce the worldwide effects of SARS-CoV-2 variants, it is necessary to develop new generation COVID-19 vaccines besides an urgent elimination of the vaccine inequality all over the world.

6.
Journal of Medicine (Bangladesh) ; 23(1):82-83, 2022.
Article in English | EMBASE | ID: covidwho-1760203
7.
Radiol Case Rep ; 17(5): 1741-1744, 2022 May.
Article in English | MEDLINE | ID: covidwho-1757767

ABSTRACT

Splenic rupture is most commonly encountered after blunt abdominal trauma. Spontaneous atraumatic splenic rupture is a rare but dramatic occurrence that is most commonly attributed to infection or neoplasia. We report the case of a 27-year-old female patient without pathological history. Admitted to the emergency department for the sudden onset of left hypochondrial pain associated with vomiting, rapidly progressing to hypovolemic shock. She had reported an influenza-like illness a week earlier for which her COVID-19 PCR was negative. Emergency abdominal ultrasound and CT-scan revealed a ruptured spleen and widespread hemorrhagic fluid in the abdomen. Exploration revealed multiple ruptures in the spleen capsule. The patient underwent splenectomy with good clinical evolution. Despite the rarity of this condition, physicians should consider the diagnosis of spontaneous non traumatic splenic rupture when encountering healthy patients presenting with nonspecific left hypochondrial abdominal pain and hypovolemia. Mortality is essentially related to the delay in diagnosis and treatment and to the severity of the underlying pathology. Treatment often consists of splenectomy.

8.
Leukemia and Lymphoma ; 62(SUPPL 1):S34, 2021.
Article in English | EMBASE | ID: covidwho-1747045

ABSTRACT

Introduction: CLL is characterized by deficient immunity which clinically manifests as an increased predisposition toward malignancies and infectious complications. T-cells from patients with CLL exhibit a skewed repertoire with a predominance of Tregs as well as impaired immune synapse formation and cytotoxic function. Unlike chemotherapy, novel targeted agents may have beneficial immunomodulatory effects, which may be particularly relevant in the COVID-19 era. Small ubiquitin-like modifier (SUMO) family proteins regulate a variety of cellular processes, including nuclear trafficking, gene transcription, and cell cycle progression, via post-translational modification of target proteins. Sumoylation regulates NFjB signaling, IFN response, and NFAT activation, processes indispensable in immune cell activation. Despite this, the role of sumoylation in T cell biology in the context of cancer is not known. TAK-981 is a small molecule inhibitor of the SUMO-activating enzyme (SAE) that forms a covalent adduct with an activated SUMO protein, thereby preventing its transfer to the SUMO-conjugating enzyme (Ubc9). Here, we investigated the immunomodulatory effects of TAK-981 in CLL. Methods: T cells from patients with CLL were purified using Dynabeads. Activation, proliferation, and apoptosis of CD3+ T cells were studied following T-cell receptor engagement (TCR;aCD3/CD28) with/without 0-1 lM TAK-981. Cytokines were measured after in vitro stimulation. For polarization assays, FACS-sorted naïve CD4+ T cells were cultured for 7 days in control or differentiation media. For gene expression profiling (GEP;Clariom S), RNA was harvested after 3 and 24 h of TCR engagement from FACS-sorted naïve CD4+ T cells. For in vivo immunization experiments, CD4+KJ1-26+ cells were inoculated IV into BALB/cJ mice. Mice received 100 mg IV ovalbumin ± R848 followed by TAK-981 7.5 mg/kg or vehicle control IV twice weekly for 10 days before spleen collection. Both recipient and transplanted splenocytes were analyzed. For analysis of tumor-infiltrating lymphocytes (TILs), BALB/c mice were injected with 1×106 A20 lymphoma cells and treated as above. TAK-981 was provided by Millennium Pharmaceuticals, Inc. (Cambridge, MA, USA). Results: T cells from patients with CLL demonstrated high baseline protein sumoylation that slightly increased following TCR engagement. Treatment with TAK-981 significantly downregulated SUMO1 and SUMO2/3-modified protein levels, yet did not disrupt early TCR signaling as evidenced by sustained ZAP70, p65/NFjB, and NFAT activation detected by immunoblotting, immunocytochemistry, and GEP. Treatment with TAK-981 resulted in dose-dependent upregulation of the early activation marker CD69 in CD4+ T cells following 72 and 96 h of TCR stimulation vs. control. Meanwhile, the expression of CD25, HLA-DR, and CD40L was delayed in the presence of TAK-981. Interestingly, CD38, an IFN response target, was induced 2-fold in TAK-981-treated cells after 24 h and persisted at high levels at subsequent timepoints. T cell proliferation was reduced in the presence of high (1 lM) but not low/intermediate concentrations of TAK-981, accompanied by reduced S phase entry and decreased synthesis of IL- 2. However, T cells did not undergo apoptosis under those conditions. Targeting SAE in either control or Th1/Treg polarizing conditions facilitated an increase in IFNc and loss of FoxP3 expression (accompanied by decreased IL-2/STAT5), suggesting a shift toward Th1 and away from Treg phenotype, respectively. GEP (Reactome, GSEA) confirmed a dramatically upregulated IFN response in TAK-981-treated CD4+ naïve T cells. Furthermore, targeting SAE enhanced degranulation (CD107a), IFNc, and perforin secretion in cytotoxic CD8+ T cells and potentiated T cell cytotoxicity in allogeneic assays with lymphoma cells (OCI-LY3, U2932) as targets. Consistent with our in vitro data, OVA-stimulated transplanted transgenic KJ1-26+ splenocytes, as well as total CD4+ T cells from recipient mice treated with TAK-981 in vivo exhibited a significant reduction in express on of FoxP3 and an increased production of IFNc. In the A20 syngeneic model, treatment with TAK-981 similarly downregulated FoxP3 expression in CD4+ TILs and induced IFNc secretion in CD8+ TILs. Conclusion: Using a combination of in vitro and in vivo experiments, we demonstrate that pharmacologic targeting of sumoylation with TAK-981 does not impair proximal TCR signaling in T cells obtained from patients with CLL, but leads to rebalancing toward healthy immune T cell subsets via induction of IFN response and downmodulation of Tregs. These data provide a strong rationale for continued investigation of TAK-981 in CLL and lymphoid malignancies.

9.
Iranian Red Crescent Medical Journal ; 23(12), 2021.
Article in English | CAB Abstracts | ID: covidwho-1727389

ABSTRACT

Introduction: Atraumatic Splenic Rupture (ASR) is a rare but life-threatening clinicopathological phenomenon with limited information on patient features, occurrence, or etiology. ASR is an uncommon and lethal complication that is observed in infectious (mainly mononucleosis) and hematological diseases (mainly malignant homeopathies) in more than half of cases. Mortality is approximately around 20%, and some deaths occur before the diagnosis is confirmed, while others occur after surgery due to delayed management and poor patient status. Case Presentation: A 48-year-old man with no history of the underlying disease presented to the Emergency Department with abdominal pain. He was admitted with leukocytosis 145..103/l, hemoglobin 6.4 g/dl, platelets 15..103/l, erythrocyte sedimentation rate 89 mm/h, and D-Dimer 1043 ng/FEU ml. Sputum test through PCR ruled out severe acute respiratory syndrome coronavirus 2 infections. Due to peripheral blood smear and bone marrow aspiration/biopsy, acute myeloid leukemia was diagnosed for the patient. On the third day of hospitalization, the patient's abdominal pain intensifies. Ultrasound revealed medium free fluid inside the abdomen and pelvis. The patient was transferred to the operating room to undergo an emergency laparotomy. There was a large hematoma in the spleen with a rupture in its posterior surface. Splenectomy was performed, and the histopathological study of the spleen showed leukemic involvement, capsular ruptures, and subcapsular hematomas.

10.
Critical Care Medicine ; 50(1 SUPPL):350, 2022.
Article in English | EMBASE | ID: covidwho-1691866

ABSTRACT

INTRODUCTION: We report a case of MIS-C, confirmed on autopsy, in a toddler with hypoplastic left heart syndrome (HLHS). DESCRIPTION: The patient was a 15 month-old male with HLHS (aortic and mitral atresia) with a superior cavopulmonary anastomosis, and complete heart block with a pacemaker, admitted for respiratory distress. He had known exposure to multiple COVID+ family members, a positive SARS-COV-2 RT-PCR, fevers, elevated inflammatory markers, skin and mucosal changes, and multi-system organ dysfunction, evolving into severe, irreversible multiple organ failure. He met laboratory and clinical criteria for MIS-C. He was treated with high-dose Methylprednisolone, IVIG, Anakinra, and convalescent plasma, but continued to clinically deteriorate. Upon death, the family elected for autopsy. Significant autopsy findings included: acute ischemia of the papillary muscles;peripheral lung infarcts and hemophagocytosis in the bone marrow. The hemophagocytosis in the bone marrow has been noted on several of the small number of autopsies performed on children with fatal MIS-C. DISCUSSION: The patient met WHO and CDC criteria for MIS-C during his hospital stay. Both criteria require fever, elevated inflammatory markers without alternative cause, evidence of prior COVID-19 infection/exposure, and multi-organ involvement. While the pathophysiology of MIS-C remains unknown, the syndrome clinically and immunologically overlaps with other hyperferritinemic syndromes, such as hemophagocytic lymphohistiocytosis and macrophage activating syndrome, where immune-mediated multi-organ injury results from a dysregulated innate immune response-related cytokine storm. The finding of marrow hemophagocytosis on this patient's autopsy adds to the small body of literature on autopsies of children with fatal MIS-C, which also note hemophagocytosis in the marrow and/or spleen. The immune profile and pathology of patients with MIS-C suggests that Macrophages have a significant role in MIS-C. This case thus adds additional credence to this important role of Macrophages, which in turn can further direct studies into its management, to prevent similar deaths.

11.
International Journal of Pharmacy and Pharmaceutical Sciences ; 14(2):21-30, 2022.
Article in English | EMBASE | ID: covidwho-1689625

ABSTRACT

Objective: To see the effects of Raj Nirwan Bati (RNB) on the hematobiochemical parameters, coagulation tests, and histopathological changes in the lungs, liver, kidneys and spleen and also to evaluate the immunomodulatory activity of RNBin Wistar rats. Methods: A total of 24 adult albino Wistar rats (of bodyweight 200-250 g) of either sex were divided into 3 groups. In the normal control group (n=8), no drug was administered and in the rest of the groups (A and B), RNB@ 26 mg/kg body weight./day and 260 mg/kg body weight/day respectively were administered orally for a period of 14 d. The blood samples were collected from the jugular vein at zero d (before drug administration) and after the 14th d of drug administration in both groups (A and B). The organ samples (lungs, liver, kidneys, and spleen) were collected after euthanizing the rats using Ketamine anesthesia overdose intraperitoneally (IP) after the 14th d of drug administration. White Blood Cells (WBC), Red Blood Cells (RBC), Hemoglobin (Hb), Hematocrit (HCT), Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin(MCH), Mean Corpuscular Hemoglobin Concentration(MCHC), number of platelets, Differential Leucocyte Count(DLC) i.e. the percentage of neutrophils, lymphocytes, eosinophils, monocytes and basophils, neutrophil adhesion percentage, Prothrombin test (PT), Activated Partial Thromboplastin Time (APTT), fibrinogen, D-dimer, Lactate Dehydrogenase (LDH), urea, creatinine, Aspartate Amino Transferase (AST), Alanine amino Transferase (ALT), Alkaline Phosphatase (ALP), C-Reactive Protein (CRP) were evaluated and histological examination of organs were done. Results: After statistical analysis, it was found that the decrease in TLC, RBC, Hb, HCT, and LDH in Wistar rats after RNB intervention in Group A as compared to that of before RNB intervention, was found to be statistically significant (P=0.001, P=0.002, P=0.001, P=0.039, and P=0.008). On the other hand, an increase was observed in MCV, Urea, Creatinine and ALT values in the Wistar rats after RNB intervention in Group ‘A’ as compared to that of before RNB intervention and this increase in values was statistically significant (P=0.007, P=0.001, P<0.001 and P=0.038). After RNB intervention in Group B, the increase in MCH, fibrinogen concentration, and monocytes percentage, was found to be statistically significant (P=0.004, P=0.033, and P=0.001) as well as the decrease in PT and APTT was statistically significant (P=0.007and P=0.002). After comparing the Mean Hematobiochemical and coagulation test parameters in the rats of Group A and Group B, after RNB intervention, it was observed that the concentration of Urea, Creatinine, APTT, and D-dimer were less in Group B as compared to that of Group A and this difference was statistically significant(P<0.001, P<0.001, P<0.001 and P=0.022). Histologically the findings in the lungs of group B were more distortion of lung architecture, most of the alveoli become collapse and make emphysematous changes, more diffuse inflammatory infiltrate within interalveolar septa and around bronchioles as compared to Group A. In the liver of group B rats, the histological findings were mild to moderate distortion of lobular architecture, healthy hepatocytes with more activation of kupffer cells as well as larger and more aggregates of inflammatory cells as compared to group A. Histological findings of kidneys in group A and group B rats were similar to that of control group rats. Conclusion: The results suggest that the RNB is having an immunomodulatory effect. It might be helpful in the restoration of coagulation factors and can help treat the COVID patients. No harmful effects on the lungs, liver, kidney, and spleen were seen. These findings may act as baseline data for planning further clinical trials in human study subjects to evaluate the effects on various comorbidities.

12.
Molecular Genetics and Metabolism ; 135(2):S126-S127, 2022.
Article in English | EMBASE | ID: covidwho-1677224

ABSTRACT

Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal disease characterized by pulmonary dysfunction, hepatosplenomegaly, and dyslipidemia. Olipudase alfa, intravenous-recombinant-human ASM, is in late-stage development (Sanofi Genzyme) for non-central-nervous-system manifestations of ASMD. We report 2-year outcomes for 33/36 ASMD adults with splenomegaly (mean baseline spleen volume: 11.3 multiples of normal [MN]) and respiratory impairment (mean baseline percent-predicted-diffusing capacity for carbon monoxide [DLCO]: 49.3%) who participated in the 1-year double-blind placebo-controlled primary-analysis period [PAP] of the ASCEND trial of olipudase alfa (NCT02004691) and completed a second year in the open-label extension. Patients underwent gradual dose-escalation to 3.0 mg/kg/2-weeks. During the PAP, olipudase-alfa-treated compared to placebo-treated patients (1:1 randomization) had statistically significant increases in DLCO and decreases in spleen and liver volume. One placebo patient withdrew during year-1. In year-2, improvements in former placebo patients paralleled the olipudase-alfa group in the PAP (all values: ANCOVA LS-mean percent change from trial baseline ± SEM): DLCO increased 28.0 ± 6.2% (n = 10);spleen volume decreased 36.0 ± 3.0% (n = 11);liver volume decreased 30.7 ± 2.5% (n = 11). Olipudase-alfa patients who received 2 years of treatment continued improving: DLCO increased 28.5 ± 6.2%, n = 10 (year-1 increase: 22.2 ± 3.4%, n = 17);spleen volume decreased 47.0 ± 2.7%, n = 14 (year-1 decrease: 39.5 ± 2.4%, n = 17), liver volume decreased 33.4 ± 2.2%, n = 14 (year-1 decrease: 27.8 ± 2.5, n = 17). Improvements in dyslipidemia, liver function, liver sphingomyelin clearance, and plasma lyso-sphingomyelin in former placebo patients paralleled those seen in olipudase-alfa patients in the PAP;continuing olipudase-alfa patients maintained these benefits in year-2. Overall, 99% of treatment-emergent adverse events were mild/moderate, with one treatment-related serious adverse event. During year-2, six patients missed ≥1 assessments and one patient discontinued due to COVID-19 travel restrictions;one additional patient discontinued (withdrawal of consent). In summary, during year-2 of ASCEND, crossover-placebo patients improved to a similar extent as olipudase-alfa patients in year-1 and patients continuing on olipudase alfa showed sustained or further improvements.

13.
JMA J ; 5(1): 157-160, 2022 Jan 17.
Article in English | MEDLINE | ID: covidwho-1668046

ABSTRACT

A 68-year-old woman with a history of schizophrenia developed coronavirus disease (COVID)-19 and was transferred to our hospital. Despite treatment, she died of respiratory failure 16 days after the onset. At the time of autopsy, polymerase chain reaction (PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA using swabs from the nasopharynx and the lung was positive; however, the cerebrospinal fluid was negative. An autopsy showed diffuse alveolar damage and recent multiple cerebral infarcts. Acute splenitis was observed with thrombi adhering to the vascular endothelium in areas of severe neutrophilic infiltration. Immunohistochemistry using an antibody against the SARS-CoV-2 nucleocapsid showed immunoreactivity along the hyaline membrane of the lung; however, the antibody showed no immunoreactivity in the medulla, the thalamus, the frontal lobe, and the pituitary. Future pathologic studies should clarify the mechanisms involved in a variety of clinical and pathological changes related to COVID-19.

14.
Aging Dis ; 13(1): 24-28, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1667758

ABSTRACT

There has been a surge of mucormycosis cases in India in the wake of the second wave of COVID-19 with more than 40000 cases reported. Mucormycosis in patients of COVID-19 in India is at variance to other countries where Aspergillus, Pneumocystis, and Candida have been reported to be the major secondary fungal pathogens. We discuss the probable causes of the mucormycosis epidemic in India. Whereas dysglycaemia and inappropriate steroid use have been widely suggested as tentative reasons, we explore other biological, iatrogenic, and environmental factors. The likelihood of a two-hit pathogenesis remains strong. We propose that COVID-19 itself provides the predisposition to invasive mucormycosis (first hit), through upregulation of GRP78 and downregulation of spleen tyrosine kinase involved in anti-fungal defense, as also through inhibition of CD8+ T-cell mediated immunity. The other iatrogenic and environmental factors may provide the second hit which may have resulted in the surge.

15.
American Journal of the Medical Sciences ; 362(4):418-423, 2021.
Article in English | Web of Science | ID: covidwho-1663268

ABSTRACT

Coronavirus disease 2019 (COVID-19) has been associated with an increased risk of venous and arterial thrombotic disease. Although pulmonary embolism has been the most common thrombotic complication, there have been recent reports of COVID-19-associated large-vessel ischemic stroke, acute upper- and lower-limb ischemia, as well as infarctions of the abdominal viscera, including renal, splenic, and small bowel infarctions. Here, we describe a case of splenic infarction (SI) associated with aortic thrombosis, which evolved despite the prophylactic use of low-molecular-weight heparin (LMWH), in a 60-year-old female patient with COVID-19. The patient was treated clinically with a therapeutic dose of LMWH, followed by warfarin, and eventually presented a favorable outcome. We also present a review of the literature regarding SI in patients with COVID-19.

16.
Archives of Pediatric Infectious Diseases ; 10(1), 2022.
Article in English | EMBASE | ID: covidwho-1635674

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has imposed a significant burden worldwide, manifesting as a severe disease and causing mortality even in children. Severe COVID-19 disease is characterized by cytokine storm with progression to secondary hemophagocytic lymphohistiocytosis (sHLH). We describe an 18-month-old boy in Iran, previously healthy, diagnosed with COVID-19-induced sHLH. Three weeks after close contact with COVID-19 confirmed cases, he was admitted with high fever, lethargy, mild respiratory distress, skin rash, and conjunctivitis with swollen eyelids and lips. Laboratory data revealed elevated levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and liver enzymes, and mild thrombocytopenia. His clinical condition rapidly deteriorated, with septic shock, hepatosplenomegaly, and respiratory failure. Laboratory tests showed cytopenia, coagulopathy, hy-perferritinemia, and hypertriglyceridemia, which met the criteria for sHLH diagnosis. Chest computed tomography (CT) revealed bilateral infiltrations that suggested acute respiratory distress syndrome (ARDS) of COVID-19 that was confirmed by a positive real-time polymerase chain reaction (RT-PCR) test. Therefore, the child was treated with intravenous immunoglobulin (IVIG), glucocorti-coid, hydroxychloroquine, lopinavir/ritonavir, and interferonβ-1a. This therapeutic strategy enabled complete recovery from fever, regaining consciousness, weaning from respiratory support, and resolving shock. Serial chest radiographs showed diminishing infiltrations. Sequential physical examinations revealed an overall significant reduction in spleen and liver span. Laboratory data showed rapid improvement from cytopenia and coagulopathy, normalization of liver enzyme levels, and reduction in hyperinflam-mation markers. Although ARDS is the most common cause of death from COVID-19, other complications such as sHLH may be lethal;thus, early diagnosis and appropriate treatment are necessary for saving patients’ lives.

17.
Gastroenterology ; 160(6):S-188, 2021.
Article in English | EMBASE | ID: covidwho-1596485

ABSTRACT

Background: Patients with SARS-CoV-2 who initially present with gastrointestinal (GI) symp-toms, with or without respiratory symptoms, have a milder clinical course than those who do not have GI complaints. Risk factors for severe COVID-19 disease include increased adiposity and sarcopenia, but whether these risk factors are similarly associated with worse outcomes among patients with GI symptoms has not been established. Methods: This was a retrospective study of hospitalized patients with COVID-19 who underwent abdominal CT scan for clinical indications within 30 days of positive SARS-COV-2 test. Abdominal body composition measures including skeletal muscle index (SMI), intramuscular adipose tissue index (IMATI), visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI), and visceral-to-subcutaneous adipose tissue ratio (VAT/SAT Ratio) were measured on a single axial CT slice at the L3 vertebral level. Hepatic steatosis was measured by absolute liver attenuation and by liver/spleen attenuation ratio. Clinical characteristics and outcomes were collected from the electronic medical record. GI symptoms were classified at time of first positive SARS-CoV-2 test. The association between body composition measurements and the primary outcome of death or discharge to hospice within 30 days after positive SARS-CoV-2 test was tested. Results: Of 190 patients with COVID-19 who had abdominal CT scans, 117 (62%) had GI symptoms including nausea, vomiting, diarrhea, or abdominal pain. Among those without GI symptoms at presentation, the most common reasons for abdominal CT scan were as part of a multi-organ evaluation of fever/sepsis, evaluation of GI symptoms that developed later during the hospital course, and evaluation for retroperitoneal hemorrhage. There were no differences in baseline patient characteristics comparing those with or without GI symptoms (Table 1). Patients with GI symptoms were less likely to be admitted to the ICU than patients without GI symptoms (16% versus 37% respectively;p <0.01) but had similar 30-day mortality (15% versus 18% respectively;p=0.66). Among patients with GI symptoms, those who died or were discharged to hospice had significantly increased IMATI (unadjusted p=0.025) and no differences in other measures (Table 2). On the other hand, among patients without GI symptoms, those who died or were discharged to hospice within 30 days had increased IMATI (p=0.049), reduced SMI (p=0.010), and increased VAT/SAT Ratio that was not statistically significant (p=0.419). Conclusions: Among patients with COVID-19, the relationship between measures of adiposity/sarcopenia and death differs in patients with and without GI symptoms.(Table Presented)Table 1. Clinical Characteristics among 190 patients hospitalized for COVID-19 based on presence of GI symptoms.(Table Presented)Table 2. Body composition measurements among 117 patients with GI symptoms and 73 patients with no GI symptoms based on death/hospice at 30 days.

18.
Cells ; 10(12)2021 12 08.
Article in English | MEDLINE | ID: covidwho-1598446

ABSTRACT

Organ-specific proteins (OSPs) possess great medical potential both in clinics and in biomedical research. Applications of them-such as alanine transaminase, aspartate transaminase, and troponins-in clinics have raised certain concerns of their organ specificity. The dynamics and diversity of protein expression in heterogeneous human populations are well known, yet their effects on OSPs are less addressed. Here, we used mice as a model and implemented a breadth study to examine the panorgan proteome for potential variations in organ specificity in different genetic backgrounds. Using reasonable resources, we generated panorgan proteomes of four in-bred mouse strains. The results revealed a large diversity that was more profound among OSPs than among proteomes overall. We defined a robustness score to quantify such variation and derived three sets of OSPs with different stringencies. In the meantime, we found that the enriched biological functions of OSPs are also organ-specific and are sensitive and useful to assess the quality of OSPs. We hope our breadth study can open doors to explore the molecular diversity and dynamics of organ specificity at the protein level.


Subject(s)
Organ Specificity/genetics , Proteins/genetics , Proteome/genetics , Proteomics , Animals , Genetic Variation/genetics , Humans , Mice
19.
Blood ; 138:3132, 2021.
Article in English | EMBASE | ID: covidwho-1582320

ABSTRACT

Background: As of early August 2021, more than 190 million people have developed coronavirus disease (COVID-19), a pandemic that has killed approximately 4 million people. Caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 exhibited a highly variable clinical course, ranging from a high proportion of asymptomatic and mild infections to severe and fatal disease. However, the immunological determinants underlying the heterogeneity of COVID-19 remain to be fully elucidated. Methods: To systemically analyze the immunopathogenesis of COVID-19, a multicompartment mathematical model based on both immunological principles and COVID-19-related work performed by the scientific community was built to illustrate the dynamics of host immunity after SARS-CoV-2 infection. We used ordinary differential equations (ODEs) to simulate the time-dependent functions of immunologic variations in the four compartments, which were draining lymph nodes, peripheral blood, lung and distant lymph nodes and spleen. Our model consisted of equations for 109 immunologic variations, which contained 223 parameters. K was used to characterize the adequacy of the SARS-CoV-2-specific naïve T/B cell pool;K I represented the hill coefficient of antigen-presenting cell (APC) differentiation. Further, we used method of pseudo landscape to visualize the effect of APC capacity and the SARS-CoV-2-specific naïve T/B cell pool on clinical outcomes. Results: Based on both immunologic knowledge and extensive COVID-19-related work performed by the scientific community, we constructed a knowledge-driven mathematical model that incorporated SARS-CoV-2 infection, bacterial infection, leukocyte chemotaxis, innate immunity and adaptive immunity. The model simulated and predicted the different trajectories of the viral load, bacterial load, immune cells, cytokines and infected epithelial cells in patients with different severities. A higher viral load and longer virus-shedding period were observed in patients with higher severity, along with an increase in SARS-CoV-2-infected lung epithelial cells. The trajectories of both peripheral blood IL-6 and lymphocytes predicted COVID-19 outcomes. Based on the distribution, trafficking and differentiation of immune cells after SARS-CoV-2 infection, we proposed that early-stage lymphopenia is related to lymphocyte chemotaxis. The delayed initiation of both innate and adaptive immunity resulted in elevated SARS-CoV-2 shedding and was a pivotal cause of COVID-19 severity. Spatiotemporally, viral shedding and postviral bacterial infection evoked stronger innate immunity. Viral shedding could be restrained by the rapid initiation of APC, antibody-secreting cell (ASC) and cytotoxic T cell (CTL). Moreover, our model predicted that the insufficient SARS-CoV-2-specific naïve T/B cell pools and inactive APC caused a series of chain reactions, including viral shedding, bacterial infection, sepsis and cytokine storms. Finally, pseudopotential analysis revealed that a high state characterized by severe bacterial infections and cytokine storms was a stable attractor for patients with insufficient SARS-CoV-2-specific naïve T/B cells and inactive APC (Figure 1). Conclusion: Overall, our analysis provided a comprehensive view of the dynamics of host immunity after SARS-CoV-2 infection and highlighted that the antigen-specific naïve T/B cell pool and APC ability may essentially determine COVID-19 heterogeneity from an immunological standpoint. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

20.
Blood ; 138:3080, 2021.
Article in English | EMBASE | ID: covidwho-1582264

ABSTRACT

Thalassemia is an inherited blood disorder characterized by defective hemoglobin production, ineffective erythropoiesis and chronic hemolytic anemia. Patients with both transfusion-dependent thalassemia (TDT) and non-transfusion dependent thalassemia (NTDT) have risk factors associated with severe SARS-CoV-2 infection including iron overload, endocrinopathies, massive splenomegaly or previous splenectomy and coagulopathy (Motta et al, Am J Hematol, 95: E198-E199., 2020). Although vaccination is encouraged for these patients, data on the efficacy and safety of anti Sars-CoV-2 vaccines are limited (Karimi, M, et al, Br J Haematol, 190: e137-e140, 2020;Mandana Zafari, et al, Hemoglobin, 45:1, 1-4, 2021) due to exclusion of these patients from clinical trials. In a single center, prospective, cohort study we compared 67 patients affected by TDT to 61 healthy controls (HC), matched for age and sex. Study population and HC received two doses of BNT162b2 anti-SARS-Cov-2 mRNA vaccine on days 1 and 21, between April 1st and May 15 th, 2021. Serological tests were performed by a commercially available immunoassay for the quantitative determination of anti-spike IgG antibodies to SARS-CoV-2. The results were reported as Arbitrary Units (AU)/mL, with a cut-off for defining response as 50 or greater AU/ml. Patients and HC samples were collected four weeks after the second dose of vaccine. Median age of patients was 43 years (range 19-77), 39% of them were male and 61% were female. Median age of HC was 39 years (range 19-86), 43% of them were male and 57% were female. All controls achieved a response (50 or greater AU/mL) to vaccination, whereas 66/67 (98,5%) patients responded. Antibody titers were significantly higher (p=0.0005) in the HC group (mean 9863 ± 7784;median 7712, range 1206-51664) compared to patients (mean 7945 ± 12326;median 4025, range 19-89202) (Figure 1). When analyzing the patients' factors, age, sex, transfusion interval, serum ferritin level, and spleen size did not impact on the response to vaccination. With a median follow-up of 12 weeks, no relevant side effects were recorded after vaccination and no case of COVID19 occurred among vaccinated TDT patients. In conclusion, BNT162b2 anti-SARS-Cov-2 mRNA vaccine demonstrated efficacy and safety in our cohort of TDT patients. Response rate was similar to that of HC. Nevertheless, antibody titers in TDT patients were significantly lower than in HC. Further observations are ongoing to assess duration of response, efficacy and possible factors influencing this finding. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

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