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INTRODUCTION: Acute stroke leads to the activation of myeloid cells. These cells express adhesion molecules and transmigrate to the brain, thereby aggravating injury. Chronically after stroke, repair processes, including angiogenesis, are activated and enhance post-stroke recovery. Activated myeloid cells express CD13, which facilitates their migration into the site of injury. However, angiogenic blood vessels which play a role in recovery also express CD13. Overall, the specific contribution of CD13 to acute and chronic stroke outcomes is unknown. METHODS: CD13 expression was estimated in both mice and humans after the ischemic stroke. Young (8-12 weeks) male wild-type and global CD13 knockout (KO) mice were used for this study. Mice underwent 60 min of middle cerebral artery occlusion (MCAO) followed by reperfusion. For acute studies, the mice were euthanized at either 24- or 72 h post-stroke. For chronic studies, the Y-maze, Barnes maze, and the open field were performed on day 7 and day 28 post-stroke. Mice were euthanized at day 30 post-stroke and the brains were collected for assessment of inflammation, white matter injury, tissue loss, and angiogenesis. Flow cytometry was performed on days 3 and 7 post-stroke to quantify infiltrated monocytes and neutrophils and CXCL12/CXCR4 signaling. RESULTS: Brain CD13 expression and infiltrated CD13+ monocytes and neutrophils increased acutely after the stroke. The brain CD13+lectin+ blood vessels increased on day 15 after the stroke. Similarly, an increase in the percentage area CD13 was observed in human stroke patients at the subacute time after stroke. Deletion of CD13 resulted in reduced infarct volume and improved neurological recovery after acute stroke. However, CD13KO mice had significantly worse memory deficits, amplified gliosis, and white matter damage compared to wild-type animals at chronic time points. CD13-deficient mice had an increased percentage of CXCL12+cells but a reduced percentage of CXCR4+cells and decreased angiogenesis at day 30 post-stroke. CONCLUSIONS: CD13 is involved in the trans-migration of monocytes and neutrophils after stroke, and acutely, led to decreased infarct size and improved behavioral outcomes. However, loss of CD13 led to reductions in post-stroke angiogenesis by reducing CXCL12/CXCR4 signaling.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Masculino , Animais , Camundongos , Acidente Vascular Cerebral/metabolismo , Encéfalo/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , AVC Isquêmico/metabolismo , Camundongos Knockout , Movimento Celular , Camundongos Endogâmicos C57BL , Isquemia Encefálica/metabolismoRESUMO
BACKGROUND: More than twenty years after its discovery, the role of the importin beta superfamily member Ran GTP-binding protein (RanBP) 17 is still ill defined. Previously, we observed notable RanBP17 RNA expression levels in head and neck squamous cell carcinoma (HNSCC) cell lines with disruptive TP53 mutations. METHODS: We deployed HNSCC cell lines as well as cell lines from other tumor entities such as HCT116, MDA-MB-231 and H460, which were derived from colon, breast and lung cancers respectively. RNAi was used to evaluate the effect of RanBP17 on cell proliferation. FACS analysis was used for cell sorting according to their respective cell cycle phase and for BrdU assays. Immunocytochemistry was deployed for colocalization studies of RanBP17 with Nucleolin and SC35 (nuclear speckles) domains. TCGA analysis was performed for prognostic assessment and correlation analysis of RanBP17 in HNSCC patients. RESULTS: RNAi knockdown of RanBP17, significantly reduced cell proliferation in HNSCC cell lines. This effect was also seen in the HNSCC unrelated cell lines HCT116 and MDA-MB-231. Similarly, inhibiting cell proliferation with cisplatin reduced RanBP17 in keratinocytes but lead to induction in tumor cell lines. A similar observation was made in tumor cell lines after treatment with the EGFR kinase inhibitor AG1478. In addition to previous reports, showing colocalization of RanBP17 with SC35 domains, we observed colocalization of RanBP17 to nuclear bodies that are distinct from nucleoli and SC35 domains. Interestingly, for HPV positive but not HPV negative HNSCC, TCGA data base analysis revealed a strong positive correlation of RanBP17 RNA with patient survival and CDKN2A. CONCLUSIONS: Our data point to a role of RanBP17 in proliferation of HNSCC and other epithelial cells. Furthermore, RanBP17 could potentially serve as a novel prognostic marker for HNSCC patients. However, we noted a major discrepancy between RanBP17 RNA and protein expression levels with the used antibodies. These observations could be explained by the presence of additional RanBP17 splice isoforms and more so of non-coding circular RanBP17 RNA species. These aspects need to be addressed in more detail by future studies.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias de Cabeça e Pescoço/genética , Humanos , Inibidores de Proteínas Quinases/farmacologia , RNA , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , beta Carioferinas/genética , Proteína ran de Ligação ao GTP/genética , Proteína ran de Ligação ao GTP/metabolismo , Proteína ran de Ligação ao GTP/farmacologiaRESUMO
PURPOSE: Virtual anatomy education was the only way that supported the learning process of the students during the forced lockdown time of COVID-19 pandemic. The intention of the current study was to apprehend the expected challenges experienced by the medical and dental students during their cyber anatomy classes. METHODS: This study was carried on 300 1st and 2nd year medical and dental students who joined their respective college in January 2020, and consented to participate in the study. A multiple choice questionnaire regarding their stance about these online classes was formed and student's feedback was taken. RESULTS: Most (80%) of the students longed for their traditional anatomy learning i.e., dissection courses, didactic lectures, interaction and motivation from their mentors and peer. The students blamed the learning without live dissections, models and microscopic slides for their lack of confidence. More than 80% students blamed inappropriate gadgets, absence of high-band internet connections, as possible barriers in their digital learning. Lack of self-motivation was considered by 66% students. CONCLUSIONS: This situation of anatomy education while lockdown was not intentional and should not be taken as the silver bullet solution for a subject like anatomy. Although students had to face a lot of challenges but this shift to online mode went swiftly at the time of health crisis. This digital learning may extend for an indefinite period, the students' feedback will be helpful in bringing appropriate and timely modifications in digital anatomy education.
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Anatomia , COVID-19 , Educação de Graduação em Medicina , Estudantes de Medicina , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias/prevenção & controle , Estudantes de Odontologia , Paquistão , Controle de Doenças Transmissíveis , Anatomia/educaçãoRESUMO
OBJECTIVE: To assess the reliability and concurrent validity of Cognitive Distortions Scale-Urdu based on Beck's Cognitive Model of psychopathology on patients diagnosed with mental disorders. METHODS: The correlational study was conducted from June 15, 2019, to January 30, 2020, in Lahore, Pakistan, and comprised psychiatric patients of either gender aged 18-65 years from six government hospitals, including Mayo Hospital, Services Hospital, Punjab Institute of Mental Health, Sir Ganga Ram Hospital, Gulab Devi Hospital and the Combined Military Hospital. The participants completed the demographic information form and the Cognitive Distortions Scale-Urdu. The latter was re-administered after a gap of two weeks to determine its internal consistency and test-retest reliability. Feinstein Paranoia, Subjective Wellbeing and Siddiqui Shah Depression Scales were administered along with the Cognitive Distortions Scale-Urdu to determine its concurrent validity. Statistical analysis was done using SPSS 24. RESULTS: Of the 106 patients, 56(52.8%) were recruited for reliability analysis with an overall mean age of 32.31±10.62 years, and 50(47.2%) for concurrent validity analysis with an overall mean age of 31.30±10.52 years. Correlation analysis indicated good internal consistency (α=0.87), test retest reliability (r=0.86) and moderately high concurrent validity of the scale (range: 0.44-0.89). CONCLUSIONS: The Cognitive Distortions Scale-Urdu was found to have sound psychometric properties and was suitable for researchers to obtain quantitative estimates of the frequency and intensity of cognitive distortions in clinical samples.
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Transtornos Mentais , Adulto , Cognição , Humanos , Saúde Mental , Psicometria , Reprodutibilidade dos Testes , Adulto JovemRESUMO
BACKGROUND: Ultraviolet radiations (UV) absorbed by the skin can drive photochemical reactions which range from sunburn to skin cancer. The repeated exposure to Infrared radiations (IR) induces the heat into the skin, which causes dehydration and erythema as an immediate effect. This heat activates the metalloproteinase enzyme that reduces the number of procollagen and collagen fibers in the dermal skin, which results premature skin aging. This work aims to design a protective measure in order to avoid these damages. METHOD: The proposed protective measure is a wristwatch with an alert alarm which can sense UV and IR radiations. Whenever UV/IR radiation levels exceed beyond the defined limits, alarm will be activated that warns the user to apply protective measures. These radiations are detected by SI1145 digital UV Index/IR/visible light sensor and assigned, using Arduino, to an appropriate UV index and IR radiation levels. RESULTS: The IR and UV readings were recorded several times and at four different hours through the day. The readings showed its highest value at 10 am and 2 pm, which are considered the highest sun intensity. The other readings were at 6 am and 5 pm and considered the least dangerous hours. CONCLUSION: The data collected from the sensor are used to program the alarm. To combine all components, a PCB and a prototype were designed and printed. The UV/IR wristwatch is applicable to alert the user from the continuous and accumulated harmful effects of the radiations and enable them to seek protective measures.
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Desenho de Equipamento , Dermatopatias/prevenção & controle , Raios Ultravioleta/efeitos adversos , Dispositivos Eletrônicos Vestíveis , Algoritmos , Desenho de Equipamento/métodos , Humanos , Dosímetros de Radiação , Radiometria/instrumentação , Dermatopatias/etiologia , Pigmentação da Pele , Fatores de TempoRESUMO
The microbial resistance to current antibiotics is increasing day by day, which in turn accelerating the development of new effective drugs. Several studies have proved the high antimicrobial potential of the interaction of several organic ligands with a variety of metal ions. In the present study, a conventional method has been adopted in the synthesis of twelve new heteroleptic complexes of cobalt (II), nickel (II), copper (II) and zinc (II) using three aldimines, namely, (HL1 ((E)-2-((4-chloro-2-hydroxybenzylidene)amino)-3,4-dimethyl-5-phenylcyclopent-2-en-1-one), HL2 ((Z)-3-((4-chlorobenzylidene)amino)-4-hydroxy-5-nitrobenzenesulfonic acid) HL3 (2,2'-((1,2-phenylenebis(azaneylylidene))bis(methaneylylidene))diphenol)) as primary ligands, while phenyl glycine was the secondary ligand. The synthesized compounds were characterized by UV-vis, IR and multinuclear (1H and 13C) NMR spectroscopy, elemental analysis, and electrical conductance. The IR study revealed the coordination of the aldimine derivatives with the -OH and N atom of imine moiety. In contrary to this, the phenyl glycine coordinated to the metal ions via oxygen of carboxylate and nitrogen of the amino group. The spectroscopic analysis unveiled the tetrahedral geometry of the synthesized metal (II) complexes, except for ligand HL3 which exhibited octahedral geometry. The synthesized compounds generally showed antibacterial activity for all microbes, except Ni (II) complexes lacking sensitivity. Furthermore, to access the bioavailability, the synthesized complexes were screened for their solubilization in the micellar media of sodium lauryl sulphate. The metal complex-surfactant interaction was revealed by UV-vis spectroscopy and electrical conductivity measurements.
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Anti-Infecciosos/química , Complexos de Coordenação/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Cobalto/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cobre/química , Condutividade Elétrica , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Ligantes , Testes de Sensibilidade Microbiana , Níquel/química , Dodecilsulfato de Sódio/química , Solubilidade , Espectrofotometria Infravermelho , Zinco/químicaRESUMO
This study investigates the driving factors behind frugal innovation in Small and Medium-sized Enterprises (SMEs). It specifically examines sustainable leadership as an independent variable, considering its impact on frugal innovation, with sources of knowledge mediating this relationship and information credibility moderating the effects. Employing a Partial Least Squares Structural Equation Modeling (PLS-SEM) approach, data were gathered from 325 employees of SMEs in Pakistan. This methodology was chosen for its ability to handle complex relationships between multiple variables simultaneously, offering robust insights into the interplay among sustainable leadership, sources of knowledge, information credibility, and frugal innovation. The results reveal significant associations between sustainable leadership, sources of knowledge, information credibility, and frugal innovation. Sustainable leadership demonstrates a substantial influence on both sources of knowledge and frugal innovation. Furthermore, sources of knowledge play a vital role in mediating the relationship between sustainable leadership and frugal innovation. Information credibility emerges as a significant moderator, affecting the pathways between sustainable leadership, sources of knowledge, and frugal innovation. The findings underscore the importance of sustainable leadership and credible information sources in driving frugal innovation within SMEs. They highlight the intricate interdependencies among these variables and emphasize the pivotal role of information credibility in shaping these dynamics. These results carry significant implications for SMEs in Pakistan, shedding light on the mechanisms through which sustainable leadership and reliable knowledge sources can stimulate frugal innovation in emerging economies.
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The cottontail rabbit papillomavirus (CRPV)-associated VX2 carcinoma of the New Zealand White rabbit serves as a model system for human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCCs). The aim of this study was to evaluate the tumor-inhibiting effect of RNAi-mediated knockdown of the CRPV oncogenes, E6 and E7, using siRNA-loaded lipopolyplexes (LPPs). VX2-carcinoma-derived cells were cultured for up to 150 passages. In addition, CRPV E6 and E7 oncogenes were transiently expressed in COS-7 cells. Efficiency and safety of LPPs were evaluated in both VX2 cells and the COS-7 cell line. Both of these in vitro CRPV systems were validated and characterized by fluorescence microscopy, Western blot, and RT-qPCR. Efficient knockdown of CRPV E6 and E7 was achieved in VX2 cells and COS-7 cells pretransfected with CRPV E6 and E7 expression vectors. Knockdown of CRPV oncogenes in VX2 cells resulted in reduced viability, migration, and proliferation and led to a G0/G1 block in the cell cycle. CRPV E6 and E7 siRNA-loaded LPPs could represent promising therapeutic agents serving as a paradigm for the treatment of papillomavirus-positive cancers and could be of value for the treatment of CRPV-associated diseases in the rabbit such as papillomas and cancers of the skin.
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Ruptured cerebral aneurysms can cause significant morbidity and mortality. Endoluminal devices to treat aneurysms such as the Pipeline™ Flex Embolization Device with Shield Technology (PFES) (Medtronic, Dublin, Ireland) integrate phosphorylcholine on the surface of the device in order to reduce platelet adherence that causes periprocedural thromboembolic events and subsequent long-term intrastent stenosis. In addition to the Shield Technology, patients are commonly placed on dual antiplatelet therapy (DAPT) for six months to reduce thromboembolic events and subsequent long-term intrastent stenosis. There is a strong positive correlation between the length of DAPT use and bleeding. Here, we present a case of a 66-year-old female with a right supraclinoid internal carotid artery (ICA) aneurysm treated with a PFES who was placed on dual antiplatelet therapy for the first 31 days postoperative and subsequently maintained on aspirin (ASA) 81 mg monotherapy. At two months, a follow-up diagnostic cerebral angiogram showed complete occlusion of the aneurysm with a patent stent. Our case sets the stage for further research into the optimal length of dual antiplatelet therapy required in PFES to prevent short and long-term thromboembolic events. This report indicates that it may be safe for patients with PFES to intermittently halt the use of DAPT to manage bleeding complications or perform surgery.
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Anesthesia drug overdose hazards and lack of gold standards in anesthesia monitoring lead to an urgent need for accurate anesthesia drug detection. To investigate the PPG waveform features affected by anesthesia drugs and develop a machine-learning classifier with high anesthesia drug sensitivity. This study used 64 anesthesia and non-anesthesia patient data (32 cases each), extracted from Queensland and MIMIC-II databases, respectively. The key waveform features (total area, rising time, width 75%, 50%, and 25%) were extracted from 16,310 signal recordings (5-s duration). Discriminant analysis, support vector machine (SVM), and K-nearest neighbor (KNN) were evaluated by splitting the dataset into halve training (11 patients, 8570 segments) and halve testing dataset (11 patients, 7740 segments). Significant differences exist between PPG waveform features of anesthesia and non-anesthesia groups (p < 0.05) except total area feature (p > 0.05). The KNN classifier achieved 91.7% (AUC = 0.95) anesthesia detection accuracy with the highest sensitivity (0.88) and specificity (0.90) as compared to other classifiers. Kohen's kappa also shows almost perfect agreement (0.79) with the KNN classifier. The KNN classifier trained with significant PPG features has the potential to be used as a reliable, non-invasive, and low-cost method for the detection of anesthesia drugs for depth analysis during surgical operations and postoperative monitoring.
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Algoritmos , Fotopletismografia , Humanos , Aprendizado de Máquina , Monitorização Fisiológica/métodos , Fotopletismografia/métodos , Máquina de Vetores de SuporteRESUMO
The artery of Percheron (AOP) is a rare anatomic variant, characterized by a single thalamoperforating artery arising from the P1 segment of the posterior cerebral artery that bifurcates to supply bilateral thalami with variable vascular supply to the midbrain. The occlusion of this artery is responsible for bilateral thalamic stroke with or without midbrain involvement. Since December 2019, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a worldwide pandemic. Acute ischemic stroke is a rare but known manifestation of COVID-19. There have only been a few reports of bilateral deep cerebral involvement in COVID-19 infection. In the absence of risk factors for such events, we suspect COVID-19 may have a contributory role. In this case report, we present a case of AOP infarction presenting as transient loss of consciousness, intermittent anisocoria, dysarthria, and right-sided weakness in the setting of COVID-19 infection. Given the degree of variation in clinical presentation for AOP infarcts and lack of evidence of ischemia on initial imaging studies, many patients may miss the time window for tissue plasminogen activator (tPA) administration. This case highlights the importance of timely neurological evaluation in patients presenting with COVID-19 and neurological complaints. Increased community awareness of neurological manifestations of AOP infarctions is of utmost importance as early detection and intervention improve clinical outcomes.
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Epidermolysis bullosa (EB) includes a group of rare gesnodermatoses that result in blistering and erosions of the skin and mucous membranes. Genetically, pathogenic variants in around 20 genes are known to alter the structural and functional integrity of intraepidermal adhesion and dermo-epidermal anchorage, leading to four different types of EB. Here we report the underlying genetic causes of EB phenotypes segregating in seven large consanguineous families, recruited from different regions of Pakistan. Whole exome sequencing, followed by segregation analysis of candidate variants through Sanger sequencing, identified eight pathogenic variants, including three novel (ITGB4: c.1285G>T, and c.3373G>A; PLEC: c.1828A>G) and five previously reported variants (COL7A1: c.6209G>A, and c.1573C>T; FERMT1: c.676insC; LAMA3: c.151insG; LAMB3: c.1705C>T). All identified variants were either absent or had very low frequencies in the control databases. Our in-silico analyses and 3-dimensional (3D) molecular modeling support the deleterious impact of these variants on the encoded proteins. Intriguingly, we report the first case of a recessively inherited form of rare EBS-Ogna associated with a homozygous variant in the PLEC gene. Our study highlights the clinical and genetic diversity of EB in the Pakistani population and expands the mutation spectrum of EB; it could also be useful for prenatal diagnosis and genetic counseling of the affected families.
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Epidermólise Bolhosa/genética , Variação Genética/genética , Moléculas de Adesão Celular/genética , Colágeno Tipo VII/genética , Epidermólise Bolhosa/classificação , Epidermólise Bolhosa/fisiopatologia , Família , Feminino , Homozigoto , Humanos , Integrina beta4/genética , Laminina/genética , Masculino , Proteínas de Membrana/genética , Mutação , Proteínas de Neoplasias/genética , Paquistão , Linhagem , Fenótipo , Plectina/genética , Sequenciamento do Exoma/métodos , CalininaRESUMO
The current study offers an efficient design of novel nanoparticle microspheres (MCs) using a hydrothermal approach. The Co0.5Ni0.5GaxFe2-xO4 (0.0 ≤ x ≤ 1.0) MCs were prepared by engineering the elements, such as cobalt (Co), nickel (Ni), iron (Fe), and gallium (Ga). There was a significant variation in MCs' physical structure and surface morphology, which was evaluated using energy dispersive X-ray analysis (EDX), X-ray diffractometer (XRD), high-resolution transmission electron microscopy (HR-TEM), and scanning electron microscope (SEM). The anti-proliferative activity of MCs was examined by MTT assay and DAPI staining using human colorectal carcinoma cells (HCT-116), human cervical cancer cells (HeLa), and a non-cancerous cell line-human embryonic kidney cells (HEK-293). Post 72 h treatment, MCs caused a dose dependent inhibition of growth and proliferation of HCT-116 and HeLa cells. Conversely, no cytotoxic effect was observed on HEK-293 cells. The anti-fungal action was assessed by the colony forming units (CFU) technique and SEM, resulting in the survival rate of Candida albicans as 20%, with severe morphogenesis, on treatment with MCs x = 1.0. These findings suggest that newly engineered microspheres have the potential for pharmaceutical importance, in terms of infectious diseases and anti-cancer therapy.
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Photodynamic therapy (PDT) is a minimally invasive therapeutic approach used in the treatment of various medical conditions and cancerous diseases, involving light, a photosensitizing substance, and oxygen. Curcumin, a naturally occurring compound, carries antitumor activities and potentially could be exploited as a photosensitizer in PDT. Only little is known about liposomal-encapsulated curcumin that could help in increasing the efficacy, stability, and bioavailability of this compound. This study investigates the in vitro effects of curcumin-loaded liposomes in combination with PDT. Three papilloma virus-associated cell lines were treated with curcumin-loaded liposomes corresponding to a curcumin concentration of 0-100 µmol/L for 4 h followed by illumination at 457 nm (blue) for 45, 136, and 227 s at a fluence of 220.2 W/m2 (100 mA) corresponding to 1, 3 and 5 J·cm-2. After 24 h, the biological outcome of the treatment was assessed with the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), SYTO9/PI (propidium iodide), Annexin V-FITC (fluorescein isothiocyanate)/PI, clonogenic survival, and scratch (wound closure) assays. Photoactivation of curcumin-loaded liposomes led to a significant reduction in colony formation and migratory abilities, as well as to an increase in tumor cell death. The results point to the combination of curcumin-loaded liposomes with PDT as a potentially useful tool for the treatment of papillomavirus-associated malignancies.
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COVID-19 pandemic caused by SARS-CoV-2, continues to manifest with severe acute respiratory syndrome among the adults, however, it offers a convincing indication of less severity and fatality in pediatric age group (0-18 years). The current trend suggests that children may get infected but are less symptomatic with less fatality, which is concordant to earlier epidemic outbreaks of SARS-CoV and MERS-CoV, in 2002 and 2012, respectively. According to the available data, children appear to be at lower risk for COVID-19, as adults constitute for maximum number of the confirmed cases (308,592) and deaths (13,069) as on 22nd March (https://www.worldometers.info/coronavirus). However, rapid publications and information of the adult patients with COVID-19 is in progress and published, on the contrary, almost no comprehensive data or discussion about the COVID-19 in children is available. Therefore, in this review, we outline the epidemiology, clinical symptoms, diagnosis, treatment, prevention, possible immune response and role of thymus in children to combat the COVID-19 outbreak.
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P-glycoprotein (P-gp) associated multidrug resistance (MDR) represents a major failure in cancer treatment. The overexpression of P-gp is responsible for ATP-dependent efflux of drugs that decrease their intracellular accumulation. An effective downregulation of MDR1 gene using small interfering RNA (siRNA) is one of the safe and effective tools to overcome the P-gp triggered MDR. Therefore, the development of an efficient and non-toxic carrier system for siRNA delivery is a fundamental challenge for effective cancer treatment. Polyamidoamine (PAMAM) dendrimer has been used for efficient delivery of siRNA (dendriplexes) to the tumor cells but the associated toxicity problems render its use in biological applications. A non-covalent lipid modification (lipodendriplexes) is supposed to offer a promising strategy to overcome the demerits linked to the naked dendriplexes system. In the current study, we deliver siRNA, designed against MDR1 gene (si-MDR1), in colorectal carcinoma cells (Caco-2), having overexpression of P-gp, to check the role of MDR1 gene in tumor progression and multidrug resistance using two dimensional (2D) and three dimensional (3D) environment. Imatinib mesylate (IM), a P-gp substrate, was used as model drug. Our results revealed that the effective knockdown by lipodendriplexes system can significantly reduce the tumor cell migration in 2D (p < 0.001) and 3D (p < 0.001) cell cultures as compared to unmodified dendriplexes and si-Control groups. It was also observed that lipodendriplexes aided downregulation of MDR1 gene effectively, re-sensitized the Caco-2 cells for IM uptake and showed a significantly (p < 0.001) higher apoptosis. Our findings imply that our lipodendriplexes system has a great potential for siRNA delivery, however, further in vivo application using a suitable targeted system can play a major role for better cancer therapeutics.
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Apoptose , Resistencia a Medicamentos Antineoplásicos , Células CACO-2 , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Inibidores de Proteínas Quinases , RNA Interferente PequenoRESUMO
BACKGROUND: The objective of this study was to describe presentation, natural history, management and long-term outcomes of patients with psychogenic purpura (PP), also known as Gardner-Diamond Syndrome. METHODS: In this retrospective study, records of patients with a diagnosis of PP seen at Mayo Clinic, Rochester from 1976 to 2016 were reviewed. Available literature regarding PP was also comparatively reviewed. RESULTS: Seventy-six patients with a diagnosis of PP were identified and 54/76 (71%) experienced a prodromal sensation. The Condensed MCMDM-1 bleeding score, excluding cutaneous manifestations, was <3 in 91% of patients. Laboratory tests of primary and secondary hemostasis were normal. Fifty-four percent of patients had an underlying psychiatric diagnosis. Management approaches included psychological counseling and psychiatry evaluation in 44 patients. Pharmacologic treatment for 30 patients included psychotropic agents, antihistamines, hormonal medications and anti-inflammatory agents. At a median follow-up of 5years (range 1-34),13/28 (46.4%) experienced recurrent ecchymoses and 6 continued to seek hematology follow-up at Mayo Clinic, Rochester. Our data was similar to the aggregate data from case reports in the literature. CONCLUSIONS: For patients with unexplained recurrent ecchymosis a diagnosis of PP should be considered. Diagnosis is one of exclusion and initial evaluation should include documenting a bleeding score and obtaining laboratory tests assessing primary and secondary hemostasis. The relatively low bleeding scores together with laboratory assessments support that PP is primarily a dermal rather than a systemic bleeding diathesis. In our cohort, addressing psychological stressors was the most effective treatment; however pharmacologic therapy can be used for refractory disease.