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1.
Nature ; 598(7881): 510-514, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34646013

RESUMO

Human epithelial tissues accumulate cancer-driver mutations with age1-9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10-12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11-14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.


Assuntos
Competição entre as Células , Proliferação de Células , Células Clonais/citologia , Células Clonais/metabolismo , Células Epiteliais/citologia , Neoplasias Esofágicas/patologia , Mutação , Animais , Carcinogênese/imunologia , Morte Celular , Sobrevivência Celular , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/patologia , Epitélio/imunologia , Neoplasias Esofágicas/imunologia , Feminino , Masculino , Camundongos , Fatores de Tempo
2.
Acta Virol ; 64(3): 359-374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32985215

RESUMO

Equine influenza (EI) is an important viral respiratory disease of equines caused by influenza A virus (IAV). The antigenic drift in IAVs necessitates regular updating and harmonization of vaccine strain with the circulating virus. The reverse genetics-based recombinant viruses could be easy instrument in generating vaccine against circulating virus in a quick and effective manner. Present study has been envisaged to evaluate the immunogenicity and protective efficacy of inactivated recombinant equine influenza virus (rgEIV) vaccine candidate having six segments from H1N1 virus (A/WSN/33/H1N1) and HA (hemaglutinin) and NA (neuraminidase) segments from H3N8 equine influenza virus [(A/eq/Jammu-Katra/06/08) of clade 2 of Florida sublineage] generated through reverse genetic engineering. BALB/c mice were immunized with inactivated rgEIV adjuvanted with aluminium hydroxide gel and challenged with H3N8 virus (A/eq/Jammu-Katra/06/08). The protective efficacy was evaluated through serology, cytokine profiling, clinical signs, gross and histopathological changes, immunohistochemistry and residual virus quantification. Immunizations induced robust humoral immune response as estimated through hemagglutination inhibition assay (HAI). The antibodies were isotyped and the predominant subclass was IgG1. The vaccine candidate produced mixed Th1 and Th2 responses through stimulation of IFN-γ, IL-2, IL-4 and IL-6 expression. Immunization protected mice against challenge as reflected through reduction in clinical signs and body weight loss, early recovery, mild pathological changes (gross and histopathological lesions) as evident through scoring of lesions, low residual virus in nasopharynx and lungs quantified through egg titration and quantitative reverse transcriptase PCR (qRT-PCR). The study demonstrates that inactivated recombinant EIV generated through reverse genetic approach provides equivalent protection to that observed with inactivated whole H3N8 EIV vaccine. Keywords: equine influenza; reverse genetics; vaccine; pathology; murine model.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N8 , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae , Genética Reversa , Animais , Anticorpos Antivirais , Modelos Animais de Doenças , Doenças dos Cavalos/prevenção & controle , Cavalos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H3N8/genética , Vacinas contra Influenza/genética , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle
3.
Climacteric ; 22(4): 377-382, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30652511

RESUMO

Purpose: Midlife women frequently experience stress and menopausal symptoms. Mindfulness is thought to mitigate stress by avoiding emotional reactivity and ruminative thinking. We sought to assess the association of mindfulness and stress on menopausal symptoms among midlife women. Materials and methods: In this cross-sectional study, women aged 40-65 years completed questionnaires, including the Menopause Rating Scale (MRS), the Perceived Stress Scale-4 (PSS-4), and the Mindfulness Attention Awareness Scale (MAAS). Linear regression was used to assess the impact of mindfulness and stress on menopausal symptoms with use of univariate and multivariable analyses, adjusting for patient characteristics. Results: In this cohort of 1744 midlife women, higher mindfulness (MAAS) and lower stress (PSS-4) scores correlated independently with lower menopausal symptom (MRS) scores. On multivariable analysis, a significant interaction effect was observed between the MAAS and PSS-4 on the MRS, such that with higher PSS-4 scores, the magnitude of association between the MAAS and lower MRS scores was larger. Conclusion: Among midlife women, higher mindfulness and lower stress correlated with lower menopausal symptom scores independently. Among women experiencing more stress, the magnitude of association between mindfulness and lower menopausal symptom scores was greater, largely driven by psychological subdomain scores. Mindfulness may mitigate menopausal symptoms among midlife women.


Assuntos
Menopausa , Atenção Plena , Estresse Psicológico , Adulto , Idoso , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Psicometria
4.
BMC Complement Altern Med ; 18(1): 174, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29866088

RESUMO

BACKGROUND: In the view of endemic avian influenza H9N2 infection in poultry, its zoonotic potential and emergence of antiviral resistance, two herbal plants, Ocimum sanctum and Acacia arabica, which are easily available throughout various geographical locations in India were taken up to study their antiviral activity against H9N2 virus. We evaluated antiviral efficacy of three different extracts each from leaves of O. sanctum (crude extract, terpenoid and polyphenol) and A. arabica (crude extract, flavonoid and polyphenol) against H9N2 virus using in ovo model. METHODS: The antiviral efficacy of different leaves extracts was systematically studied in three experimental protocols viz. virucidal (dose-dependent), therapeutic (time-dependent) and prophylactic (dose-dependent) activity employing in ovo model. The maximum non-toxic concentration of each herbal extracts of O. sanctum and A. arabica in the specific pathogen free embryonated chicken eggs was estimated and their antiviral efficacy was determined in terms of reduction in viral titres, measured by Haemagglutination (HA) and real time quantitative reverse transcription polymerase chain reaction (RT-qPCR) assays. RESULTS: All the extracts of O. sanctum (crude extract, terpenoid and polyphenol) and A. arabica (crude extract, flavonoid and polyphenol) showed significant virucidal activity, however, crude extract ocimum and terpenoid ocimum showed highly significant to significant (p < 0.001-0.01) decrease in virus genome copy numbers with lowest dose tested. Similarly, therapeutic effect was observed in all three extracts of O. sanctum in comparison to the virus control, nevertheless, crude extract ocimum and terpenoid ocimum maintained this effect for longer period of time (up to 72 h post-incubation). None of the leaves extracts of A. arabica had therapeutic effect at 24 and 48 h post-incubation, however, only the crude extract acacia and polyphenol acacia showed delayed therapeutic effect (72 h post-inoculation). Prophylactic potential was observed in polyphenol acacia with highly significant antiviral activity compared to virus control (p < 0.001). CONCLUSIONS: The crude extract and terpenoid isolated from the leaves of O. sanctum and polyphenol from A. arabica has shown promising antiviral properties against H9N2 virus. Future investigations are necessary to formulate combinations of these compounds for the broader antiviral activity against H9N2 viruses and evaluate them in chickens.


Assuntos
Acacia/química , Antivirais , Vírus da Influenza A Subtipo H9N2/efeitos dos fármacos , Ocimum sanctum/química , Extratos Vegetais , Animais , Antivirais/química , Antivirais/farmacologia , Antivirais/toxicidade , Embrião de Galinha , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade , Folhas de Planta/química , Reação em Cadeia da Polimerase em Tempo Real , Replicação Viral/efeitos dos fármacos
5.
Microb Pathog ; 97: 172-7, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27296706

RESUMO

An inactivated vaccine was developed using the rgH5N2 virus (6 + 2 reassortant) generated by plasmid based reverse genetics system (RGS) with WSN/33/H1N1 as backbone virus. Following mutation of the basic amino acid cleavage site RRRKKR*GLF to IETR*GLF, the H5-HA (haemagglutinin) gene of the selected donor H5N1 virus (A/chicken/West Bengal/80995/2008) of antigenic clade 2.2 was used along with the N2-NA gene from H9N2 field isolate (A/chicken/Uttar Pradesh/2543/2004) for generation of the rgH5N2 virus. A single dose (0.5 ml/bird) of the inactivated rgH5N2 vaccine protected 100% of the vaccinated chickens (n = 10) on 28(th) dpv (early challenge) and 90% of the vaccinated chickens (n = 10) on 200(th) dpv (late challenge) against high dose challenge with HPAI virus (10(9) EID50/bird). Challenge virus shedding via oropharynx and cloaca of the vaccinated chickens was detectable by realtime RT-PCR during 1-5 dpc and 1-9 days dpc in the early and the late challenge, respectively. The protective level of antibodies (mean HI titre > 128) was maintained without booster vaccination for 200 days. The present study provides the experimental evidence about the extent of protection provided by a reverse genetics based vaccine for clade 2.2 H5N1 viruses against challenge with high dose of field virus at two different time points (28 dpv and 200 dpv). The challenge study is uniquely different from the previous similar experiments on account of 1000 times higher dose of challenge and protection at 200 dpv. The protection and virus shedding data of the study may be useful for countries planning to use H5 vaccine in poultry especially against the clade 2.2 H5N1 viruses.


Assuntos
Virus da Influenza A Subtipo H5N1/imunologia , Vírus da Influenza A Subtipo H5N2/imunologia , Vacinas contra Influenza/imunologia , Influenza Aviária/prevenção & controle , Genética Reversa , Animais , Galinhas , Cloaca/virologia , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H5N2/genética , Vírus da Influenza A Subtipo H9N2/genética , Vírus da Influenza A Subtipo H9N2/imunologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/genética , Influenza Aviária/virologia , Orofaringe/virologia , Reação em Cadeia da Polimerase em Tempo Real , Resultado do Tratamento , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/genética , Vacinas de Produtos Inativados/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Eliminação de Partículas Virais
6.
Climacteric ; 19(6): 581-587, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27763798

RESUMO

OBJECTIVES: To assess the association between the type of symptom and women's self-reported view of menopause. METHODS: The study was conducted at Mayo Clinic, Rochester MN, between January 2006 and October 2014. Women aged 40-64 were included. Data from 1420 women were analyzed in a cross-sectional design. The Menopause Health Questionnaire was used for symptom assessment. Odds ratios (ORs) and population attributable risk (PAR) (OR × percent frequency) were calculated for each symptom. Logistic regression analyses were performed with the view of menopause as the dependent variable. RESULTS: Anxiety (2.34), depressed mood (2.24), irritability (2.22), vaginal itching (2.27), crying spells (2.1) and breast tenderness (2.08) were associated with highest odds of having a negative view of menopause. Highest PAR (population impact) symptoms were anxiety (22.27), weight gain (20.66), fatigue (20.28) and irritability (19.41). Hot flushes and night sweats, although common, were not associated with a negative view of menopause (OR 1.3 and 1.16; PAR 3.85 and 4.42, respectively). CONCLUSION: Mood symptoms, vaginal itching, weight gain, breast tenderness and fatigue, although less common than hot flushes, were noted to have greater association with a negative view of menopause. Specifically addressing these symptoms during menopausal consultation may improve patient satisfaction and outcomes.


Assuntos
Atitude , Menopausa/fisiologia , Menopausa/psicologia , Adulto , Afeto , Ansiedade , Estudos Transversais , Depressão/psicologia , Fadiga/psicologia , Feminino , Fogachos , Humanos , Humor Irritável , Mastodinia/psicologia , Pessoa de Meia-Idade , Prurido/psicologia , Inquéritos e Questionários , Sudorese , Doenças Vaginais/psicologia , Aumento de Peso
7.
Vascular ; 23(6): 637-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26223533

RESUMO

An aberrant splenic artery arising from the superior mesenteric artery, also known as the splenomesenteric trunk, is a rare anatomical variant seen in less than 1% of the population and is more common in females. Aneurysms of the splenic artery originating anomalously from the superior mesenteric artery are extremely rare; only 35 cases of aneurysm of an aberrant splenic artery have been described so far in the English medical literature. We report an extremely rare case of aneurysm of aberrant splenic artery in a 28-year-old man in whom the lesion was detected during routine abdominal scanning and confirmed on computed tomography angiography. Aneurysms of an anomalous splenic artery originating from the superior mesenteric artery are extremely rare; however, they are clinically important because possible rupture could be catastrophic. Exploring these variations is important especially if surgical intervention is contemplated. This could greatly affect the surgical planning and avoid injuries to major arteries and organs intraoperatively.


Assuntos
Aneurisma , Artéria Mesentérica Superior/anormalidades , Artéria Esplênica/anormalidades , Malformações Vasculares , Adulto , Aneurisma/diagnóstico por imagem , Humanos , Achados Incidentais , Masculino , Artéria Mesentérica Superior/diagnóstico por imagem , Artéria Esplênica/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Malformações Vasculares/diagnóstico por imagem
8.
Nat Genet ; 23(3): 319-22, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10545950

RESUMO

Altered growth and function of synoviocytes, the intimal cells which line joint cavities and tendon sheaths, occur in a number of skeletal diseases. Hyperplasia of synoviocytes is found in both rheumatoid arthritis and osteoarthritis, despite differences in the underlying aetiologies of the two disorders. We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250) to identify biological pathways that lead to synoviocyte hyperplasia, the principal pathological feature of this syndrome. Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP. The CACP protein, which has previously been identified as both 'megakaryocyte stimulating factor precursor' and 'superficial zone protein', contains domains that have homology to somatomedin B, heparin-binding proteins, mucins and haemopexins. In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium. The similarity of CACP sequence to that of other protein families and the expression of CACP in non-skeletal tissues suggest it may have diverse biological activities.


Assuntos
Artropatias/genética , Pericardite/genética , Proteoglicanas/genética , Proteoglicanas/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Bovinos , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Artropatias/patologia , Masculino , Dados de Sequência Molecular , Mutação , Pericardite/patologia , Fenótipo , Proteoglicanas/química , RNA Mensageiro/análise , RNA Mensageiro/genética , Homologia de Sequência de Aminoácidos , Síndrome , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia
9.
Nat Genet ; 20(2): 175-9, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9771711

RESUMO

Over 200,000 new prostate cancer cases are diagnosed in the United States each year, accounting for more than 35% of all cancer cases affecting men, and resulting in 40,000 deaths annually. Attempts to characterize genes predisposing to prostate cancer have been hampered by a high phenocopy rate, the late age of onset of the disease and, in the absence of distinguishing clinical features, the inability to stratify patients into subgroups relative to suspected genetic locus heterogeneity. We previously performed a genome-wide search for hereditary prostate cancer (HPC) genes, finding evidence of a prostate cancer susceptibility locus on chromosome 1 (termed HPC1; ref. 2). Here we present evidence for the location of a second prostate cancer susceptibility gene, which by heterogeneity estimates accounts for approximately 16% of HPC cases. This HPC locus resides on the X chromosome (Xq27-28), a finding consistent with results of previous population-based studies suggesting an X-linked mode of HPC inheritance. Linkage to Xq27-28 was observed in a combined study population of 360 prostate cancer families collected at four independent sites in North America, Finland and Sweden. A maximum two-point lod score of 4.60 was observed at DXS1113, theta=0.26, in the combined data set. Parametric multipoint and non-parametric analyses provided results consistent with the two-point analysis. Significant evidence for genetic locus heterogeneity was observed, with similar estimates of the proportion of linked families in each separate family collection. Genetic mapping of the locus represents an important initial step in the identification of an X-linked gene implicated in the aetiology of HPC.


Assuntos
Predisposição Genética para Doença/genética , Neoplasias da Próstata/genética , Cromossomo X , Adulto , Idoso , Idoso de 80 Anos ou mais , Mapeamento Cromossômico , Marcadores Genéticos , Genótipo , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , Receptores Androgênicos/genética
10.
Nat Genet ; 30(2): 181-4, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11799394

RESUMO

Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States, little is known about inherited factors that influence its genetic predisposition. Here we report that germline mutations in the gene encoding 2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL) segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene. We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.


Assuntos
Endorribonucleases/genética , Mutação em Linhagem Germinativa , Oncogenes , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Nucleotídeos de Adenina/metabolismo , Sequência de Bases , Estudos de Casos e Controles , Análise Mutacional de DNA , DNA de Neoplasias/genética , Feminino , Ligação Genética , Heterozigoto , Homozigoto , Humanos , Perda de Heterozigosidade , Linfócitos/enzimologia , Masculino , Oligorribonucleotídeos/metabolismo , Linhagem
11.
Nat Genet ; 32(4): 676-80, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12434154

RESUMO

We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.


Assuntos
Adenoma/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Hiperparatireoidismo/genética , Neoplasias das Paratireoides/genética , Proteínas/genética , Adenoma/patologia , Sequência de Aminoácidos , Sequência de Bases , Cromossomos Humanos Par 1 , Éxons , Etiquetas de Sequências Expressas , Genes Supressores de Tumor , Ligação Genética , Testes Genéticos , Genótipo , Heterozigoto , Humanos , Repetições de Microssatélites , Dados de Sequência Molecular , Fases de Leitura Aberta , Neoplasias das Paratireoides/química , Neoplasias das Paratireoides/patologia , Linhagem , Proteínas/química , Síndrome , Proteínas Supressoras de Tumor
13.
Natl Med J India ; 25(2): 101-8, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22686720

RESUMO

In spite of the existence of a dual system of postgraduation, one under the Medical Council of India (MCI) and the other on a parallel track under the National Board of Examinations, postgraduate medical education in India is beset with several problems. For example, the curriculum has not been revised comprehensively for several decades. The diploma course under the MCI has become unpopular and is largely a temporary refuge for those who do not get admission to degree courses. The level of skills of the outgoing graduate is falling and the increase in the number of seats is taking place in a haphazard manner, without reference to the needs. In spite of increase in seats, there is a shortage of specialists at the secondary and tertiary care levels, especially in medical colleges, to share teaching responsibilities. Further, the distribution of specialists is skewed, with some states having far more than others. To remedy these ills and fulfil the requirements of the country over the next two decades, a working group appointed by the erstwhile governors of the MCI was asked to suggest suitable modifications to the existing postgraduate system. After an extensive review of the lacunae in the present system, the needs at various levels and the pattern of postgraduate education in other countries, it was felt that a competency-based model of a 2-year postgraduate course across all specialties, the use of offsite facilities for training and a criterion-based evaluation system entailing continuous monitoring would go a long way to correct some of the deficiencies of the existing system. The details of the proposal and its merits are outlined for wider discussion and to serve as a feedback to the regulatory agencies engaged in the task of improving the medical education system in India. We feel that the adoption of the proposed system would go a long way in improving career options, increasing the availability of teachers and dissemination of specialists to the secondary and primary levels, and improving the quality of outgoing postgraduates.


Assuntos
Educação de Pós-Graduação em Medicina/organização & administração , Educação de Pós-Graduação em Medicina/normas , Médicos/normas , Especialização , Currículo , Necessidades e Demandas de Serviços de Saúde , Humanos , Índia , Internato e Residência , Médicos/provisão & distribuição , Recursos Humanos
14.
Gene Ther ; 18(11): 1098-102, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21544094

RESUMO

Oncolytic viruses have been combined with standard cancer therapies to increase therapeutic efficacy. Given the sequential activation of herpes viral genes (herpes simplex virus-1, HSV-1) and the temporal cellular changes induced by ionizing radiation, we hypothesized an optimal temporal sequence existed in combining oncolytic HSV-1 with ionizing radiation. Murine U-87 glioma xenografts were injected with luciferase encoding HSV-1, and ionizing radiation (IR) was given at times before or after viral injection. HSV-1 replication and tumor-volume response were followed. Radiation given 6-9 h after HSV-1 injection resulted in maximal viral luciferase expression and infectious viral production in tumor xenografts. The greatest xenograft regression was also seen with radiation given 6 h after viral injection. We then tested if HSV-1 replication had a dose response to ionizing radiation. HSV-1 luciferase expression exhibited a dose response as xenografts were irradiated from 0 to 5 Gy. There was no difference in viral luciferase expression as IR dose increased from 5 Gy up to 20 Gy. These results suggest that the interaction of IR with the HSV-1 lytic cycle can be manipulated for therapeutic gain by delivering IR at a specific time within viral replicative cycle.


Assuntos
Neoplasias Encefálicas/terapia , Glioma/terapia , Herpesvirus Humano 1/crescimento & desenvolvimento , Terapia Viral Oncolítica/métodos , Radiação Ionizante , Replicação Viral/efeitos da radiação , Animais , Terapia Combinada , Relação Dose-Resposta à Radiação , Herpesvirus Humano 1/efeitos da radiação , Camundongos , Camundongos Nus , Vírus Oncolíticos/crescimento & desenvolvimento , Vírus Oncolíticos/efeitos da radiação , Replicação Viral/genética
15.
Ann Med Surg (Lond) ; 50: 14-23, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31908774

RESUMO

BACKGROUND: Palliative care patients, those suffering from at least one chronic lifelong medical condition and hospice care patients, those with a life expectancy less than 6 months, are regularly hospitalised in general internal medicine wards. By means of a clinical case, this review aims to equip the internist with an approach to bleeding in this population. Firstly, practical advice on platelet transfusions will be provided. Secondly, the management of bleeding in site-specific situations will be addressed (from the ENT/pulmonary sphere, gastrointestinal - urogenital tract and cutaneous ulcers). Finally, an algorithm pertaining to the management of catastrophic bleeding is proposed. METHODS: Electronic databases, including EMBASE, Pubmed, Google Scholar and the Cochrane Library were studied as primary resources, in association with local guidelines, to identify papers exploring platelet transfusions and alternative management of site-specific bleeding in palliative care patients. RESULTS: Haemorrhagic complications are frequent in palliative care patients in the internal medicine ward. Current guidelines propose a therapeutic-only platelet transfusion policy. Nonetheless, prophylactic and/or therapeutic transfusion remains a physician-dependent decision. Site-specific therapeutic options are based on expert opinion and case reports. While invasive measures may be pertinent in certain situations, their application must be compatible with patient goals. Catastrophic bleeding requires caregivers' comforting presence; pharmacological management is secondary. CONCLUSION: Literature is lacking regarding management of bleeding in the palliative care population hospitalised in an acute medical setting. Recommendations are of limited quality, the majority based on case reports or expert opinion. Further studies, exploring for example the impact on patient quality of life, are desirable to improve the management of this frequently encountered complication.

16.
Lung Cancer ; 147: 115-122, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32688194

RESUMO

BACKGROUND: The Lung Cancer Screening Trial demonstrated improved overall survival (OS) and lung cancer specific survival (LCSS), likely due to finding early-stage NSCLC. The purpose of our investigation is to evaluate whether long-term surveillance strategies (4+ years after surgical resection of the initial lung cancer(1LC)) would be beneficial in NSCLC patients by assessing the rates of second lung cancers(2LC) and the OS/LCSS in patients undergoing definitive surgery in 1LC as compared to 2LC (>48 months after 1LC) populations. METHODS: SEER13/18 database was reviewed for patients during 1998-2013. Log-rank tests were used to determine the OS/LCSS differences between the 1LC and 2LC in the entire surgical group(EG) and in those having an early-stage resectable tumors (ESR, tumors <4 cm, node negative). Joinpoint analysis was used to determine rates of second cancers 4-10 year after 1LC using SEER-9 during years 1985-2014. RESULTS: The rate of 2LCs was significantly less than all other second cancers until 2001 when the incidence of 2LCs increased sharply and became significantly greater than all other second cancers in females starting in year 2005 and in men starting in year 2010. OS/LCSS, adjusted for propensity score by using inverse probability weighting, demonstrated similar OS, but worse LCSS for 2LCs in the EG, but similar OS/LCSSs in the ESR group. CONCLUSION: Because the rate of 2LCs are increasing and because the OS/LCSS of the 1LC and 2LC are similar in early-stage lesions, we feel that continued surveillance of patients in order to find early-stage disease may be beneficial.


Assuntos
Neoplasias Pulmonares , Segunda Neoplasia Primária , Detecção Precoce de Câncer , Feminino , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Estadiamento de Neoplasias , Segunda Neoplasia Primária/epidemiologia , Pneumonectomia , Modelos de Riscos Proporcionais , Programa de SEER
17.
Science ; 154(3747): 388-90, 1966 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-17751707

RESUMO

Application of high pres sure at 250 degrees C irreversibly dehydrated five inorganic compounds containing molecular water to lower hydrates or to anhydrous forms. Compression at 250 degrees C also lead to ten new reversible phase transformations in another group of nine hydrates. Maximum pressure applied was 22.6 kilobars.

18.
Indian J Public Health ; 53(4): 218-22, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20469758

RESUMO

Re-orientation of medical education in India has not been fully successful because the development of medical teacher, a critical component has not been adequately addressed. Faculty development is a key factor. We have identified six shifting trends in faculty development that can contribute to the development of a medical educator in India. These include a shift from: One time training to continuing professional development; information based approach to project based approach; training to scholarship; lack of accountability to accountability and recognition; individual efforts to networking; and role of treatment providers to health promoters. We have discussed how these shifts are in tune with the global trends. We recommend that the initiatives taken in India in the recent past, viz., constitution of a Task Force by the Ministry of Health and Family Welfare, establishment of several medical education centers should be harnessed by forming a national working group. Such a group would provide policy directions for faculty development which will lead to a concrete plan for implementation and thereby addressing a critical component of the re-orientation of medical education.


Assuntos
Educação Médica/organização & administração , Docentes de Medicina/organização & administração , Competência Profissional/normas , Educação Médica/normas , Docentes de Medicina/normas , Humanos , Índia , Desenvolvimento de Pessoal/métodos
19.
Burns ; 45(4): 869-875, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30935702

RESUMO

INTRODUCTION: Electrical injuries are associated with significant morbidity for affected patients. While cardiac and surgical interventions have been extensively reported, no practice guidelines or studies have specifically addressed fluid delivery and associated outcomes of patients with electrical injuries. The study objective was to evaluate the differences in fluid delivery in patients with high (≥1000V) and low (<1000V) voltage electrical injuries. METHODS: This retrospective, observational study included adult electrical injury patients admitted for acute care. Patients with reported voltages were classified into high and low voltage subgroups. Primary outcomes of fluid administration and urine output over the first 24h after injury were assessed between subgroups. Secondary outcomes included renal, cardiac, surgical, and additional complications such as mortality, cost, and length of stay. RESULTS: Data were analyzed in 36 patients with reported voltages, including 26 patients in the high and 10 patients in the low voltage subgroups. Patients in the high voltage subgroup had a statistically significant higher median (IQR) total IV fluid given [46.6 (22.4-61.9) vs. 22.5 (8.3-31.4) mL/kg, p=0.033] in the first 24h to achieve a similar urine output to the low voltage subgroup. The high voltage patients had higher rates of myoglobinuria, rhabdomyolysis, and creatinine kinase elevation. Patients in the high voltage vs. low voltage group had significantly longer median (IQR) length of stay (days) [11 (2-19) vs. 1 (1-6); p=0.015] and higher cost of hospital stay [$124,608 (19,486-296,991) vs. $16,165 (12,409-69,659); p=0.033]. CONCLUSIONS: These results reinforce the importance of assessing electrical injuries and obtaining a voltage to provide patient-specific care, as high voltage electrical injuries receive more fluid than estimated maintenance rates. This study is the first of its kind to characterize fluid given for high and low voltage electrical injuries and effects on patient outcomes.


Assuntos
Injúria Renal Aguda/epidemiologia , Queimaduras por Corrente Elétrica/terapia , Hidratação/métodos , Injúria Renal Aguda/urina , Adulto , Feminino , Custos de Cuidados de Saúde/estatística & dados numéricos , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Mioglobinúria/epidemiologia , Estudos Retrospectivos , Rabdomiólise/epidemiologia , Urina
20.
J Stomatol Oral Maxillofac Surg ; 120(1): 11-15, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30739640

RESUMO

The objective of the study was to evaluate and compare the relative efficacy of treating linear non-comminuted mandibular fracture of symphysis and parasymphysis region using single 2.0-mm AO locking reconstruction plate or using two conventional miniplates. In this study, 80 patients of symphysis or parasymphysis fracture were divided randomly in two equal groups and treated with open reduction and internal fixation using two 2.5-mm miniplates or with a single 2.0-mm AO locking reconstruction plate. Operating time in case of open reduction and fixation using a single 2.0-mm locking reconstruction plate was significantly less when compared to open reduction and fixation using two conventional miniplates. Both groups showed satisfactory fracture reduction and healing. No postoperative malocclusion was noted, and both groups showed comparable improvement in masticatory efficiency. In conclusion, fracture fixation using a single 2.0-mm AO locking reconstruction plate without use of a second plate at the superior border for treatment of linear non comminuted mandibular fracture in symphysis and parasymphysis region gives comparable results as with treatment by conventional miniplate system and provides significant savings in operating time, ease of use and decrease in amount of hardware incorporated in the body.


Assuntos
Placas Ósseas , Fraturas Mandibulares , Fixação de Fratura , Fixação Interna de Fraturas , Humanos , Mandíbula
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