Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 24
Filtrar
1.
Mayo Clin Proc ; 99(5): 795-811, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38702128

RESUMO

Inflammatory disease of the pericardium represents a relatively common presentation, especially among the young. For the most part, inflammatory pericardial disease can be expeditiously and effectively managed without significant sequelae. However, some individuals present with severe and recurrent illness, representing significant therapeutic challenges. During the past decade, there have been great strides made in developing an evidence-based approach to management of inflammatory pericardial disease, the result of which has been the development of (1) a systematic, protocoled approach to initial care; (2) targeted therapeutics; and (3) specialized, collaborative, and integrated care pathways. Herein we present a review of the current state of the art as it pertains to the diagnostic evaluation and therapeutic considerations in inflammatory pericardial disease with a focus on acute and complicated pericarditis.


Assuntos
Pericardite , Humanos , Pericardite/diagnóstico , Pericardite/terapia , Pericardite/etiologia , Doença Aguda
2.
J Am Heart Assoc ; 13(9): e032520, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38686858

RESUMO

BACKGROUND: Symptomatic limitations in apical hypertrophic cardiomyopathy may occur because of diastolic dysfunction with resultant elevated left ventricular filling pressures, cardiac output limitation to exercise, pulmonary hypertension (PH), valvular abnormalities, and/or arrhythmias. In this study, the authors aimed to describe invasive cardiac hemodynamics in a cohort of patients with apical hypertrophic cardiomyopathy. METHODS AND RESULTS: Patients presenting to a comprehensive hypertrophic cardiomyopathy center with apical hypertrophic cardiomyopathy were identified (n=542) and those who underwent invasive hemodynamic catheterization (n=47) were included in the study. Of these, 10 were excluded due to postmyectomy status or incomplete hemodynamic data. The mean age was 56±18 years, 16 (43%) were women, and ejection fraction was preserved (≥50%) in 32 (91%) patients. The most common indication for catheterization was dyspnea (48%) followed by suspected PH (13%), and preheart transplant evaluation (10%). Elevated left ventricular filling pressures at rest or exercise were present in 32 (86%) patients. PH was present in 30 (81%) patients, with 6 (20%) also having right-sided heart failure. Cardiac index was available in 25 (86%) patients with elevated resting filling pressures. Of these, 19 (76%) had reduced cardiac index and all 6 with right-sided heart failure had reduced cardiac index. Resting hemodynamics were normal in 8 of 37 (22%) patients, with 5 during exercise; 3 of 5 (60%) patients had exercise-induced elevation in left ventricular filling pressures. CONCLUSIONS: In patients with apical hypertrophic cardiomyopathy undergoing invasive hemodynamic cardiac catheterization, 86% had elevated left ventricular filling pressures at rest or with exercise, 81% had PH, and 20% of those with PH had concomitant right-sided heart failure.


Assuntos
Miocardiopatia Hipertrófica Apical , Cateterismo Cardíaco , Hemodinâmica , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miocardiopatia Hipertrófica Apical/complicações , Miocardiopatia Hipertrófica Apical/fisiopatologia , Hemodinâmica/fisiologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/diagnóstico , Estudos Retrospectivos , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia
3.
MAGMA ; 36(1): 107-118, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36053432

RESUMO

OBJECTIVE: It is well known that the use of shift reagents (SRs) in nuclear magnetic resonance (NMR) studies is substantially limited by an intact blood-brain barrier (BBB). The current study aims to develop a method enabling chemical shift imaging in the living rat brain under physiological conditions using an SR, Tm[DOTP]5-. MATERIALS AND METHODS: Hyperosmotic mannitol bolus injection followed by 60 min infusion of a Tm[DOTP]5- containing solution was administered via a catheter inserted into an internal carotid artery. We monitored the homeostasis of physiological parameters, and we measured the thulium content in brain tissue post mortem using total reflection fluorescence spectroscopy (T-XRF). The alterations of the 23Na resonance spectrum were followed in a 9.4T small animal scanner. RESULTS: Based on the T-XRF measurements, the thulium concentration was estimated at 2.3 ± 1.8 mM in the brain interstitial space. Spectroscopic imaging showed a split of the 23Na resonance peak which became visible 20 min after starting the infusion. Chemical shift imaging revealed a significant decrease of the initial intensity level to 0.915 ± 0.058 at the end of infusion. CONCLUSION: Our novel protocol showed bulk accumulation of Tm[DOTP]5- thus enabling separation of the extra-/intracellular 23Na signal components in the living rat brain while maintaining physiological homeostasis.


Assuntos
Imageamento por Ressonância Magnética , Túlio , Ratos , Animais , Espectroscopia de Ressonância Magnética/métodos , Sódio , Encéfalo/diagnóstico por imagem
4.
Cureus ; 14(11): e31154, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36483902

RESUMO

Paraneoplastic syndromes (PNS) are uncommon, distinct clinical complications of a primary tumor. Paraneoplastic cerebellar degeneration (PCD) is a PNS that is described as an autoimmune response targeting Purkinje cells in the cerebellum. Ovarian cancer (OC) is one of the most prevalent causes of cancer-related deaths in women. Anti-Yo is the most common onconeural antibody produced in the PCD immune response and is most typically found in ovarian and breast cancer patients. While the current literature highlights the predisposing genetic factors, diagnostic workflows, and treatment options, the pathophysiology of PCD, among other considerations, remains largely unestablished. This review aimed to systematically observe procedural solutions to facilitate an early diagnosis and improve the prognosis of patients with OC-associated PCD. To that end, we examined literature published from 01/01/2015-11/10/2022 indexed in PubMed by using the keywords "paraneoplastic, cerebellar degeneration" combined with "ovarian cancer." Inclusion criteria were met if PCD and OC diagnoses were made and if studies provided adequate patient information. After screening and assessing records for eligibility using the inclusion and exclusion criteria, 18 articles involving 102 patients were included. The typical patient observed in this sample was diagnosed with International Federation of Gynecology and Obstetrics (FIGO) Stage III, high-grade serous carcinoma. The diagnostic workup typically included a clinical evaluation for dysarthria (50%), ataxia (60%), and gait abnormalities (50%), along with multiple imaging modalities and serological findings (90%). Genetic screening for human leukocyte antigen (HLA) haplotype susceptibility for PCD and immune tolerance modulators regulation may also be recommended prior to starting treatment. Findings support the use of corticosteroids (35%) and intravenous immunoglobulin (IVIg) (40%) as viable treatment options for managing PCD in conjunction with systemic therapy for the primary malignancy. A diagnosis of PCD should be considered if a patient has had a malignancy in the past five years with the presence of explicit cerebellar symptoms. This clinical diagnosis can be further supplemented by serologic and radiologic findings. Recognizing PCD symptoms and scheduling genetic and proteomic testing may help with early diagnosis and better prognosis.

5.
Global Spine J ; : 21925682221121099, 2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36148681

RESUMO

STUDY DESIGN: Retrospective review. OBJECTIVES: This study aimed to assess and compare the clinical course and complications between surgical decompression and decompression with fusion in lumbar spine patients aged ≥80 years. METHODS: A retrospective review of electronic medical records at a single institution was conducted between September 2005 and December 2021. Logistic regression was used to identify potential risk factors for the occurrence of complications. RESULTS: Over a 16-year period, 327 patients were allocated to the decompression only group and 89 patients were allocated to the decompression and instrumented fusion group. The study had a mean follow-up duration of 36.7 ± 12.4 months. When assessing the CCI, patients of the instrumentation group had fewer comorbidities (8.9 ± .5 points vs 6.2 ± 1.5 points; P < .001), significantly longer surgical duration (290 ± 106 minutes vs 145 ±50.2 minutes; P < .001), significantly higher volume of intraoperative blood loss (791 ± 319.3 ml vs 336.1 ± 150.8 ml; P < .001), more frequent intraoperative blood transfusion (7 ± 2.1% vs 16± 18.0%; P < .001), and extended stays in the intensive care unit and hospitalization rates. Logistic regression analysis revealed that surgical duration and extent of surgery were unique risk factors for the occurrence of complications. CONCLUSIONS: Lumbar decompression and additional fusion in octogenarians are considerable treatment techniques; albeit associated with increased complication risks. Prolonged operative time and extent of surgery are critical confounding factors associated with higher rates of postoperative complications. Surgery should only be performed after careful outweighing of potential benefits and risks.

6.
Cureus ; 14(6): e25557, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35785003

RESUMO

Pulmonary tuberculosis (TB) is highly prevalent in Pakistan, and immunosuppressed individuals (including those on long-term corticosteroid therapy) are at an especially high risk of infection. Owing to the limited number of effective antituberculous drugs, treating resistant cases or patients who develop unfavorable side effects from the first-line agents becomes a daunting task. We discuss a patient with congenital adrenal hyperplasia (CAH) suffering from pulmonary TB who developed drug-induced hepatitis after being started on recommended first-line anti-TB drugs.

7.
World J Gastroenterol ; 26(35): 5343-5353, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32994692

RESUMO

BACKGROUND: Little is known about inflammatory bowel disease (IBD) burden and its impact on bone mineral density (BMD) among adult patients in Saudi Arabia. To the best of our knowledge, our study is the only study to give an update about this health problem in adult Saudi patients with IBD. IBD is a great risk factor for reduced BMD due to its associated chronic inflammation, malabsorption, weight loss and medication side effects. Consequently, screening for reduced BMD among patients with IBD is of utmost importance to curb and control anticipated morbidity and mortality among those patients. AIM: To assess the relationship between IBD and BMD in a sample of adult Saudi patients with IBD. METHODS: Ninety adult patients with IBD - 62 Crohn's disease (CD) and 28 ulcerative colitis (UC) - were recruited from King Fahad Specialist Hospital gastroenterology clinics in Buraidah, Al-Qassim. All enrolled patients were interviewed for their demographic information and for IBD- and BMD-related clinical data. All patients had the necessary laboratory markers and dual-energy x-ray absorptiometry scans to evaluate their BMD status. Patients were divided into two groups (CD and UC) to explore their clinical characteristics and possible risk factors for reduced BMD. RESULTS: The CD group was significantly more prone to osteopenia and osteoporosis compared to the UC group; 44% of the CD patients had normal BMD, 19% had osteopenia, and 37% had osteoporosis, while 78% of the UC patients had normal BMD, 7% had osteopenia, and 25% had osteoporosis (P value < 0.05). In the CD group, the lowest t-score showed a statistically significant correlation with body mass index (BMI) (r = 0.45, P < 0.001), lumbar z-score (r = 0.77, P < 0.05) and femur z-score (r = 0.85, P < 0.05). In the UC group, the lowest t-score showed only statistically significant correlation with the lumbar z-score (r = 0.82, P < 0.05) and femur z-score (r = 0.80, P < 0.05). The ROC-curve showed that low BMI could predict the lowest t-score in the CD group with the best cut-off value at ≤ 23.43 (m/kg2); area under the curve was 0.73 (95%CI: 0.59-0.84), with a sensitivity of 77%, and a specificity of 63%. CONCLUSION: Saudi patients with IBD still have an increased risk of reduced BMD, more in CD patients. Low BMI is a significant risk factor for reduced BMD in CD patients.


Assuntos
Doenças Ósseas Metabólicas , Colite Ulcerativa , Doenças Inflamatórias Intestinais , Osteoporose , Absorciometria de Fóton , Adulto , Densidade Óssea , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/epidemiologia , Doenças Ósseas Metabólicas/etiologia , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico por imagem , Colite Ulcerativa/epidemiologia , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/epidemiologia , Osteoporose/diagnóstico por imagem , Osteoporose/epidemiologia , Osteoporose/etiologia , Arábia Saudita/epidemiologia
8.
Cureus ; 11(8): e5510, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31687286

RESUMO

Introduction Acne is one of the most common skin conditions worldwide. Self-medication for acne is a fairly common practice among medical students. The objective of our study was to identify the prevalence of self-medication and to assess its knowledge, attitude, and practices among medical students. Materials and methods This descriptive cross-sectional study was conducted at Rawalpindi Medical University, Rawalpindi, Pakistan, from January 2019 to June 2019. Data were collected by using the convenient sampling technique. Students were asked to fill a semi-structured questionnaire. Students of all the medical years studying in our university were included in the study. Data were entered and analyzed using the Statistical Package for Social Sciences (SPSS) version 23.0 (IBM Corp., Armonk, US). Results Out of 349 students, 244 (69.9%) suffered from acne and self-medication was practiced by 123 (50.4%) acne sufferers. The practice of self-medication was significantly higher in students having acne lesions on the face (52.2%). The most common source of information was reported to be acquaintances (55.8%). Most of the students had knowledge of the dosage of drugs (46.3%) and precautions for their use (41.5%). Sixty-three percent of the students were of the opinion that self-medication is part of self-care. Most of the students read the expiration date on the drug label (88.6%). Conclusion Acne is a highly prevalent condition among medical students and the practice of self-medication among acne sufferers is high. The practice of self-medication and visits to dermatologists were both significantly more common in the students with lesions on the face. The knowledge of students regarding self-medication of acne was not adequate.

9.
Cureus ; 11(8): e5482, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31656711

RESUMO

Introduction Cardiovascular diseases are an important cause of mortality in Pakistan. Developing nations like Pakistan with poor literacy rates and the majority of the population living in rural areas seem to be insufficient in their knowledge of symptoms. A study indicated that about half of the cardiac deaths occur within one hour of onset of symptoms, thus it is necessary to have adequate knowledge of symptoms to identify the sufferer and to pursue medical services as early as possible. The aim of our study was to assess the knowledge of ischemic heart disease (IHD) symptoms in the population and to investigate the relationship of age, gender, socio-economic status, education, and occupation with knowledge. Materials and Methods This was a descriptive cross-sectional study carried out in the Holy Family Hospital, Rawalpindi, Pakistan over a period of four months from May 2018 to August 2018. The study population comprised of people visiting the hospital. Individuals aged 18 and above were included while medical professionals were excluded. An interviewer-assisted semi-structured questionnaire was used as the data collection tool. After taking consent, 225 participants were asked about their demographic profile and to enlist as many symptoms of IHD as possible. Reference was made to the seven typical symptoms of IHD as recognized by the World Health Organization (WHO). Statistical Package for Social Sciences (SPSS), v23.0 (IBM SPSS Statistics, Armonk, NY) was used for the analysis. Independent samples t-test and one-way ANOVA test were applied; p ≤ 0.05 was considered significant.  Results Out of the seven symptoms endorsed by WHO, chest pain was most frequently identified (42%), followed by pain in the arm (23%), diaphoresis (19%), weakness and fainting (16%), dyspnea (15%), paleness (8%), and sickness and vomiting (5%). Mean score, out of seven symptoms, was 1.28 ± 1.19. Among the total participants, 34% could not enlist any symptom. Participants with higher education, skilled workers, and those having relatives who suffered from IHD showed significantly higher knowledge about IHD symptoms. Conclusions The study showed a paucity of knowledge about IHD symptoms among the participants. Hence it provides grounds for future awareness campaigns to educate the masses.

10.
Cureus ; 11(6): e4965, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31453037

RESUMO

Background Respiratory infections are associated with high morbidity and mortality, especially in critically ill patients. The excessive use of broad-spectrum antibiotics has led to the development of drug resistance, thus resulting in the emergence of pathogens which are difficult to treat. The aim of this study was to identify common pathogens in tracheal secretions and to study the patterns of their sensitivity and resistance to various antibiotics. Materials and methods This descriptive cross-sectional study was conducted in the Department of Pathology and Microbiology, Holy Family Hospital, Rawalpindi, Pakistan, from August 2017 to December 2017, using the convenient sampling technique. Tracheal secretions from patients in the intensive care unit (ICU), tested in the Pathology and Microbiology Department of Holy Family Hospital, were included in the study. The culture was done on blood and MacConkey agar and the sensitivity pattern was performed on Muller Hinton agar. Data were analyzed using SPSS v.23.0. Results Out of the bacteria isolated from positive growth cultures, Acinetobacter (45; 53.6%) was the most common isolate followed by Klebsiella (11; 13.1%). Acinetobacter was most sensitive to tigecycline (94.7%), and gram-negative bacteria such as Acinetobacter, Klebsiella, and Pseudomonas showed resistance to higher generation cephalosporins. Conclusion Acinetobacter was the most common gram-negative bacilli isolated. Tigecycline was found to be effective against Acinetobacter.

11.
Neoplasia ; 20(7): 643-656, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29793116

RESUMO

BACKGROUND: Widespread infiltration of tumor cells into surrounding brain parenchyma is a hallmark of malignant gliomas, but little data exist on the overall invasion pattern of tumor cells throughout the brain. METHODS: We have studied the invasive phenotype of malignant gliomas in two invasive mouse models and patients. Tumor invasion patterns were characterized in a patient-derived xenograft mouse model using brain-wide histological analysis and magnetic resonance (MR) imaging. Findings were histologically validated in a cdkn2a-/- PDGF-ß lentivirus-induced mouse glioblastoma model. Clinical verification of the results was obtained by analysis of MR images of malignant gliomas. RESULTS: Histological analysis using human-specific cellular markers revealed invasive tumors with a non-radial invasion pattern. Tumors cells accumulated in structures located far from the transplant site, such as the optic white matter and pons, whereas certain adjacent regions were spared. As such, the hippocampus was remarkably free of infiltrating tumor cells despite the extensive invasion of surrounding regions. Similarly, MR images of xenografted mouse brains displayed tumors with bihemispheric pathology, while the hippocampi appeared relatively normal. In patients, most malignant temporal lobe gliomas were located lateral to the collateral sulcus. Despite widespread pathological fluid-attenuated inversion recovery signal in the temporal lobe, 74% of the "lateral tumors" did not show signs of involvement of the amygdalo-hippocampal complex. CONCLUSIONS: Our data provide clear evidence for a compartmental pattern of invasive growth in malignant gliomas. The observed invasion patterns suggest the presence of preferred migratory paths, as well as intra-parenchymal boundaries that may be difficult for glioma cells to traverse supporting the notion of compartmental growth. In both mice and human patients, the hippocampus appears to be a brain region that is less prone to tumor invasion.


Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Hipocampo/patologia , Animais , Animais Geneticamente Modificados , Neoplasias Encefálicas/diagnóstico por imagem , Modelos Animais de Doenças , Glioma/diagnóstico por imagem , Xenoenxertos , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Camundongos , Microscopia de Fluorescência , Invasividade Neoplásica
12.
Front Microbiol ; 8: 1509, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28883809

RESUMO

Haemonchus contortus is one of the most important parasites of ruminants with worldwide distribution that can bring huge economic losses to the breeding industry of cattle, sheep, and goats. In recent 20 years, studies on H. contortus in China mainly focused on the epidemiology, population genetics, anthelmintic resistance, structural and functional studies of important genes regulating the development of this parasite, interaction between parasite molecules and host cells and vaccine development against haemonchosis, and achieved good progress. However, there is no systematic review about the studies by Chinese researchers on H. contortus in China. The purpose of this review is to bring together the findings from the studies on H. contortus in China in order to obtain the knowledge gained from the recent studies in China and provide foundation for identifying future research directions to establish novel diagnostic methods, discover new drug targets and vaccine candidates for use in preventing and controlling H. contortus in China.

13.
Exp Cell Res ; 349(2): 199-213, 2016 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-27515001

RESUMO

The biology of glioblastoma invasion and its mechanisms are poorly understood. We demonstrate using time-lapse microscopy that grafting of glioblastoma (GBM) tumorspheres into rodent brain slices results in experimental ex vivo tumors with invasive properties that recapitulate the invasion observed after orthotopic transplantation into the rodent brain. The migratory movements and mitotic patterns were clearly modified by signals extrinsic to the invading cells. The cells migrated away from the tumorspheres, and removal of the spheres reduced the directed invasive movement. The cell cultures contained different populations of invasive cells that had distinct morphology and invasive behavior patterns. Grafts of the most invasive GBM culture contained 91±8% cells with an invasive phenotype, characterized by small soma with a distinct leading process. Conversely, the majority of cells in less invasive GBM grafts were phenotypically heterogeneous: only 6.3±4.1% of the cells had the invasive phenotype. Grafts of highly and moderately invasive cultures had different proportions of cells that advanced into the brain slice parenchyma during the observation period: 89.2±2.2% and 23.1±6.8%, respectively. In grafts with moderately invasive properties, most of the cells (76.8±6.8%) invading the surrounding brain tissue returned to the tumor bulk or stopped centrifugal migration. Our data suggest that the invasion of individual GBM tumors can be conditioned by the prevalence of a cell fraction with particular invasive morphology and by signaling between the tumor core and invasive cells. These findings can be important for the development of new therapeutic strategies that target the invasive GBM cells.


Assuntos
Neoplasias Encefálicas/patologia , Movimento Celular/fisiologia , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Invasividade Neoplásica/patologia , Transdução de Sinais/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Humanos , Invasividade Neoplásica/genética , Fenótipo , Transdução de Sinais/genética , Fatores de Tempo
14.
Oncotarget ; 6(28): 26192-215, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26295306

RESUMO

Glioblastoma (GBM) is both the most common and the most lethal primary brain tumor. It is thought that GBM stem cells (GSCs) are critically important in resistance to therapy. Therefore, there is a strong rationale to target these cells in order to develop new molecular therapies.To identify molecular targets in GSCs, we compared gene expression in GSCs to that in neural stem cells (NSCs) from the adult human brain, using microarrays. Bioinformatic filtering identified 20 genes (PBK/TOPK, CENPA, KIF15, DEPDC1, CDC6, DLG7/DLGAP5/HURP, KIF18A, EZH2, HMMR/RHAMM/CD168, NOL4, MPP6, MDM1, RAPGEF4, RHBDD1, FNDC3B, FILIP1L, MCC, ATXN7L4/ATXN7L1, P2RY5/LPAR6 and FAM118A) that were consistently expressed in GSC cultures and consistently not expressed in NSC cultures. The expression of these genes was confirmed in clinical samples (TCGA and REMBRANDT). The first nine genes were highly co-expressed in all GBM subtypes and were part of the same protein-protein interaction network. Furthermore, their combined up-regulation correlated negatively with patient survival in the mesenchymal GBM subtype. Using targeted proteomics and the COGNOSCENTE database we linked these genes to GBM signalling pathways.Nine genes: PBK, CENPA, KIF15, DEPDC1, CDC6, DLG7, KIF18A, EZH2 and HMMR should be further explored as targets for treatment of GBM.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Biologia Computacional , Perfilação da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neurais/metabolismo , Proteômica , Animais , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genótipo , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Glioblastoma/patologia , Xenoenxertos , Humanos , Camundongos , Terapia de Alvo Molecular , Transplante de Neoplasias , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Prognóstico , Mapas de Interação de Proteínas , Proteômica/métodos , Transdução de Sinais , Análise de Sobrevida , Fatores de Tempo , Células Tumorais Cultivadas
15.
Mol Cancer ; 14: 160, 2015 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-26292663

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most common primary brain malignancy and confers a dismal prognosis. GBMs harbor glioblastoma-initiating cells (GICs) that drive tumorigenesis and contribute to therapeutic resistance and tumor recurrence. Consequently, there is a strong rationale to target this cell population in order to develop new molecular therapies against GBM. Accumulating evidence indicates that Nα-terminal acetyltransferases (NATs), that are dysregulated in numerous human cancers, can serve as therapeutic targets. METHODS: Microarrays were used to study the expression of several NATs including NAT12/NAA30 in clinical samples and stem cell cultures. The expression of NAT12/NAA30 was analyzed using qPCR, immunolabeling and western blot. We conducted shRNA-mediated knockdown of NAT12/NAA30 gene in GICs and studied the effects on cell viability, sphere-formation and hypoxia sensitivity. Intracranial transplantation to SCID mice enabled us to investigate the effects of NAT12/NAA30 depletion in vivo. Using microarrays we identified genes and biochemical pathways whose expression was altered upon NAT12/NAA30 down-regulation. RESULTS: While decreased expression of the distal 3'UTR of NAT12/NAA30 was generally observed in GICs and GBMs, this gene was strongly up-regulated at the protein level in GBM and GICs. The increased protein levels were not caused by increased levels of the steady state mRNA but rather by other mechanisms. Also, shorter 3'UTR of NAT12/NAA30 correlated with poor survival in glioma patients. As well, we observed previously not described nuclear localization of this typically cytoplasmic protein. When compared to non-silencing controls, cells featuring NAT12/NAA30 knockdown exhibited reduced cell viability, sphere-forming ability, and mitochondrial hypoxia tolerance. Intracranial transplantation showed that knockdown of NAT12/NAA30 resulted in prolonged animal survival. Microarray analysis of the knockdown cultures showed reduced levels of HIF1α and altered expression of several other genes involved in the hypoxia response. Furthermore, NAT12/NAA30 knockdown correlated with expressional dysregulation of genes involved in the p53 pathway, ribosomal assembly and cell proliferation. Western blot analysis revealed reduction of HIF1α, phospho-MTOR(Ser2448) and higher levels of p53 and GFAP in these cultures. CONCLUSION: NAT12/NAA30 plays an important role in growth and survival of GICs possibly by regulating hypoxia response (HIF1α), levels of p-MTOR (Ser2448) and the p53 pathway.


Assuntos
Glioblastoma/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Acetiltransferase N-Terminal C/biossíntese , Proteínas de Neoplasias/biossíntese , Serina-Treonina Quinases TOR/genética , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glioblastoma/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Masculino , Camundongos , Acetiltransferase N-Terminal C/genética , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Prognóstico , RNA Mensageiro/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Mol Cancer ; 14: 121, 2015 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-26081429

RESUMO

BACKGROUND: Glioblastomas are invasive therapy resistant brain tumors with extremely poor prognosis. The Glioma initiating cell (GIC) population contributes to therapeutic resistance and tumor recurrence. Targeting GIC-associated gene candidates could significantly impact GBM tumorigenicity. Here, we investigate a protein kinase, PBK/TOPK as a candidate for regulating growth, survival and in vivo tumorigenicity of GICs. METHODS: PBK is highly upregulated in GICs and GBM tissues as shown by RNA and protein analyses. We knocked down PBK using shRNA vectors and inhibited the function of PBK protein with a pharmacological PBK inhibitor, HITOPK-032. We assessed viability, tumorsphere formation and apoptosis in three patient derived GIC cultures. RESULTS: Gene knockdown of PBK led to decreased viability and sphere formation and in one culture an increase in apoptosis. Treatment of cells with inhibitor HITOPK-032 (5 µM and 10 µM) almost completely abolished growth and elicited a large increase in apoptosis in all three cultures. HI-TOPK-032 treatment (5 mg/kg and 10 mg/kg bodyweight) in vivo resulted in diminished growth of experimentally induced subcutaneous GBM tumors in mice. We also carried out multi-culture assays of cell survival to investigate the relative effects on GICs compared with the normal neural stem cells (NSCs) and their differentiated counterparts. Normal NSCs seemed to withstand treatment slightly better than the GICs. CONCLUSION: Our study of identification and functional validation of PBK suggests that this candidate can be a promising molecular target for GBM treatment.


Assuntos
Glioblastoma/metabolismo , Glioblastoma/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Indolizinas/farmacologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Inibidores de Proteínas Quinases/farmacologia , Quinoxalinas/farmacologia , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Esferoides Celulares , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
J Child Orthop ; 9(2): 153-60, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25845647

RESUMO

STUDY DESIGN: Retrospective database, chart and medical imaging review. OBJECTIVES: To report on the outcome and evaluate possible risk factors for postoperative complications following selective spinal fusion in patients with adolescent idiopathic scoliosis (AIS). MATERIALS AND METHODS: All patients with AIS who underwent either a selective thoracic or selective thoracolumbar/lumbar spinal fusion at our institution from January 2001 to December 2011 inclusive were included in this study. The minimum postoperative follow-up period of all patients was 2 years. RESULTS: During the 11-year study period, 157 patients with AIS underwent surgery for their progressive spinal deformity. Thirty patients (19 %) had a selective spinal fusion, with 16 patients (group A) having a selective thoracic, and 14 patients (group B) having a selective thoracolumbar/lumbar spinal arthrodesis. In both groups the main postoperative complications were adding-on (25 % group A, 36 % group B) and coronal decompensation (25 % group A, 29 % group B). In group A, no statistically significant risk factors for postoperative complications were identified. In group B, global coronal balance was identified as a significant risk factor for adding-on. Patients with adding-on had significantly higher coronal balance scores (mean 3.6) than those who did not experience adding-on (mean 1.9) (p = 0.03). In addition, those with adding-on had a significantly smaller bending lumbar Cobb angle (mean 15) than those without adding-on (mean 31.6) (p = 0.015). None of the patients who underwent selective spinal fusion required revision surgery. CONCLUSION: Although the complication rate after performing a selective spinal fusion is high, the revision rate remains low and the debate whether or not to perform a selective spinal fusion will continue.

18.
Aliment Pharmacol Ther ; 37(8): 786-94, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23432394

RESUMO

BACKGROUND: While the Crohn's disease activity index (CDAI) is the gold standard for defining clinical endpoints in Crohn's disease (Crohn's) clinical trials, its ability to distinguish symptoms due to inflammation from those that are non-inflammatory has been questioned. AIM: To compare CDAI scores in patients with Crohn's and those with Irritable Bowel Syndrome (IBS). METHODS: This was a prospective, cross-sectional cohort study of 91 patients with either Crohn's (n = 44) or IBS (n = 47). Total CDAI and individual component scores were recorded and comparisons were made between Crohn's and IBS patients. RESULTS: Mean CDAI scores were higher in the IBS patients (183 vs. 157, P = 0.1). Sixty-two per cent (n = 29) of IBS patients had CDAI scores greater than 150. Mean CDAI haematocrit score (35.9 vs. 23.0, P = 0.02) and CRP level (6.8 vs. 2.0, P = 0.002) were higher in the Crohn's group. Analysis of CDAI sub-scores demonstrated that IBS patients had significantly higher pain (mean 1.7 vs. 0.8, P = 0.0007) and well-being scores (mean 1.2 vs. 0.8, P = 0.04) relative to patients with Crohn's. Specifically evaluating patients with CDAI greater than 150 (n = 51), IBS patients had higher pain sub-scores (mean 2.4 vs. 1.4, P = 0.002), whereas patients with Crohn's had higher CRP (mean 8.4 vs. 1.8, P = 0.001). CONCLUSIONS: Our study demonstrates that the CDAI does not discriminate patients with symptoms due to active Crohn's from patients with IBS. Patients with IBS can have CDAI scores in the clinically meaningful range. Objective measures, such as CDAI haematocrit score and CRP, are more specific markers of inflammation.


Assuntos
Doença de Crohn/diagnóstico , Síndrome do Intestino Irritável/diagnóstico , Perfil de Impacto da Doença , Adolescente , Adulto , Idoso , Biomarcadores/metabolismo , Estudos de Coortes , Doença de Crohn/metabolismo , Diagnóstico Diferencial , Feminino , Hematócrito , Humanos , Síndrome do Intestino Irritável/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Adulto Jovem
20.
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA