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Adenotonsillectomy is the commonest otorhinolaryngology surgery for paediatrics. The purpose of this study was to determine the safety and outcome of adenotonsillectomy in a tertiary center in Malaysia. This was achieved by studying the demographics, indications, co-morbidities of patients and its association with the complications of the procedure. This retrospective study was conducted from November 2011 until October 2016. Medical records of patients aged 2-12 years old who had adenotonsillectomy done in our center were retrieved for data collection. A total of 143 patients who fulfilled the inclusion and exclusion criteria were recruited. Median age was 7.52 (± 2.98 SD) years old. Allergic rhinitis was the commonest co-morbidity (40%). Recurrent tonsillitis was the main indication (60%), followed by sleep disordered breathing (SDB) without apnea (29%), obstructive sleep apnea (OSA) (7%) and other indications (4%). Post-operative paediatric intensive care unit (PICU) admission was very low (1.4%) and was reserved for those with severe OSA with complications. None of the patients admitted to PICU post-operative had respiratory complications. The prevalence of post-tonsillectomy bleeding was only 2.1%. There was no significant association between patient's co-morbidity with operative complications (p = 0.269). Adenotonsillectomy is indicated for children with recurrent tonsillitis and paediatric SDB. The two most severe complications, namely post-tonsillectomy haemorrhage and respiratory complications occurred but incidence was low. Criteria of post-operative PICU or paediatric high dependency unit admission for paediatric SDB has to be based on multiple clinical and logistics factors and not only patients co-morbidity and indication of surgery.
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Rat-bite fever caused by Streptobacillus moniliformis is a rare infection that may be fatal. An adolescent male presented with multiorgan failure, negative blood cultures and Gram-negative rods in blood smear. S. moniliformis was identified by 16S ribosomal RNA gene sequencing from the blood. He developed systemic hyperinflammatory syndrome resembling hemophagocytic lymphohistiocytosis, for which immune-globulins and steroids were added to the antibiotic regimen and he rapidly recovered.
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Ceftriaxona/uso terapéutico , Dexametasona/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Linfohistiocitosis Hemofagocítica/patología , Fiebre por Mordedura de Rata/diagnóstico , Streptobacillus/aislamiento & purificación , Adolescente , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Ceftriaxona/administración & dosificación , Dexametasona/administración & dosificación , Doxiciclina/administración & dosificación , Doxiciclina/uso terapéutico , Humanos , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Masculino , Fiebre por Mordedura de Rata/complicaciones , Fiebre por Mordedura de Rata/microbiologíaRESUMEN
We describe a screen for cellular response to drugs that makes use of haploid embryonic stem cells. We generated ten libraries of mutants with piggyBac gene trap transposon integrations, totalling approximately 100,000 mutant clones. Random barcode sequences were inserted into the transposon vector to allow the number of cells bearing each insertion to be measured by amplifying and sequencing the barcodes. These barcodes were associated with their integration sites by inverse PCR. We exposed these libraries to commonly used cancer drugs and profiled changes in barcode abundance by Ion Torrent sequencing in order to identify mutations that conferred sensitivity. Drugs tested included conventional chemotherapeutics as well as targeted inhibitors of topoisomerases, poly(ADP-ribose) polymerase (PARP), Hsp90 and WEE1.
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Elementos Transponibles de ADN , Células Madre Embrionarias de Ratones , Neoplasias , Animales , Antineoplásicos/farmacología , Estudio de Asociación del Genoma Completo , Haploidia , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
Small-molecule inhibitors of PARP1/2, such as olaparib, have been proposed to serve as a synthetic lethal therapy for cancers that harbor BRCA1 or BRCA2 mutations. Indeed, in clinical trials, PARP1/2 inhibitors elicit sustained antitumor responses in patients with germline BRCA gene mutations. In hypothesizing that additional genetic determinants might direct use of these drugs, we conducted a genome-wide synthetic lethal screen for candidate olaparib sensitivity genes. In support of this hypothesis, the set of identified genes included known determinants of olaparib sensitivity, such as BRCA1, RAD51, and Fanconi's anemia susceptibility genes. In addition, the set included genes implicated in established networks of DNA repair, DNA cohesion, and chromatin remodeling, none of which were known previously to confer sensitivity to PARP1/2 inhibition. Notably, integration of the list of candidate sensitivity genes with data from tumor DNA sequencing studies identified CDK12 deficiency as a clinically relevant biomarker of PARP1/2 inhibitor sensitivity. In models of high-grade serous ovarian cancer (HGS-OVCa), CDK12 attenuation was sufficient to confer sensitivity to PARP1/2 inhibition, suppression of DNA repair via homologous recombination, and reduced expression of BRCA1. As one of only nine genes known to be significantly mutated in HGS-OVCa, CDK12 has properties that should confirm interest in its use as a biomarker, particularly in ongoing clinical trials of PARP1/2 inhibitors and other agents that trigger replication fork arrest.
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Neoplasias Ováricas/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/enzimología , Cistadenocarcinoma Seroso/genética , Inhibidores Enzimáticos/farmacología , Femenino , Perfilación de la Expresión Génica , Genoma Humano , Estudio de Asociación del Genoma Completo , Mutación de Línea Germinal , Humanos , Inmunohistoquímica , Ratones , Ratones Desnudos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/enzimología , Ftalazinas/farmacología , Piperazinas/farmacología , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Distribución Aleatoria , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: PARP1/2 inhibitors are a class of anticancer agents that target tumor-specific defects in DNA repair. Here, we describe BMN 673, a novel, highly potent PARP1/2 inhibitor with favorable metabolic stability, oral bioavailability, and pharmacokinetic properties. EXPERIMENTAL DESIGN: Potency and selectivity of BMN 673 was determined by biochemical assays. Anticancer activity either as a single-agent or in combination with other antitumor agents was evaluated both in vitro and in xenograft cancer models. RESULTS: BMN 673 is a potent PARP1/2 inhibitor (PARP1 IC50 = 0.57 nmol/L), but it does not inhibit other enzymes that we have tested. BMN 673 exhibits selective antitumor cytotoxicity and elicits DNA repair biomarkers at much lower concentrations than earlier generation PARP1/2 inhibitors (such as olaparib, rucaparib, and veliparib). In vitro, BMN 673 selectively targeted tumor cells with BRCA1, BRCA2, or PTEN gene defects with 20- to more than 200-fold greater potency than existing PARP1/2 inhibitors. BMN 673 is readily orally bioavailable, with more than 40% absolute oral bioavailability in rats when dosed in carboxylmethyl cellulose. Oral administration of BMN 673 elicited remarkable antitumor activity in vivo; xenografted tumors that carry defects in DNA repair due to BRCA mutations or PTEN deficiency were profoundly sensitive to oral BMN 673 treatment at well-tolerated doses in mice. Synergistic or additive antitumor effects were also found when BMN 673 was combined with temozolomide, SN38, or platinum drugs. CONCLUSION: BMN 673 is currently in early-phase clinical development and represents a promising PARP1/2 inhibitor with potentially advantageous features in its drug class.
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Neoplasias de la Mama/tratamiento farmacológico , Trastornos por Deficiencias en la Reparación del ADN/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Ftalazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Western Blotting , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proliferación Celular/efectos de los fármacos , Femenino , Citometría de Flujo , Humanos , Ratones , Ratones Desnudos , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , ARN Interferente Pequeño/genética , Ratas , Células Tumorales Cultivadas , Ensayo de Tumor de Célula Madre , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Genetic perturbation screens have the potential to dissect a wide range of cellular phenotypes. Such screens have historically been difficult in diploid mammalian cells. The recent derivation of haploid embryonic stem cells provides an opportunity to cause loss of function mutants with a random mutagen in a mammalian cell with a normal genetic background. We describe an approach to genetic screens that exploits the highly active piggyBac transposon in haploid mammalian cells. As an example of haploid transposon (HTP) screening, we apply this approach to identifying determinants of cancer drug toxicity and resistance. In a screen for 6-thioguanine resistance we recovered components of the DNA mismatch repair pathway, a known requirement for toxicity. In a further screen for resistance to the clinical poly(ADP-ribose) polymerase (PARP) inhibitor olaparib we recovered multiple Parp1 mutants. Our results show that olaparib toxicity to normal cells is mediated predominantly via Parp1, and suggest that the clinical side effects of olaparib may be on target. The transposon mutant libraries are stable and can be readily reused to screen other drugs. The screening protocol described has several advantages over other methods such as RNA interference: it is rapid and low cost, and mutations can be easily reverted to establish causality.
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Elementos Transponibles de ADN/efectos de los fármacos , Elementos Transponibles de ADN/genética , Pruebas Genéticas , Haploidia , Ftalazinas/farmacología , Piperazinas/farmacología , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Animales , Células Madre Embrionarias/efectos de los fármacos , Células Madre Embrionarias/metabolismo , Humanos , Ratones , Mutación , Poli(ADP-Ribosa) Polimerasa-1 , Inhibidores de Poli(ADP-Ribosa) PolimerasasRESUMEN
Analyses of in vitro and patient-derived in vivo models of breast cancer reveal that a combination of inhibitors of the enzymes PARP and phosphoinositide 3-kinase (PI3K) is a potentially effective treatment regimen for breast cancer tumors with elevated activity of the PI3K pathway.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteína BRCA1/biosíntesis , Proteína BRCA2/biosíntesis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Inhibidores Enzimáticos/uso terapéutico , Genes BRCA1 , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Femenino , HumanosRESUMEN
BACKGROUND: Double-hit lymphoma is a complex and highly aggressive sub-type of B-cell lymphoma, which has recently been classified and is an area of active research interest due to the poor prognosis for patients with this disease. It is characterized by the presence of both an activating MYC chromosomal translocation and a simultaneous additional oncogenic translocation, often of the BCL2 gene. Recently, a cell line was established from a patient with this complex lymphoma and analyzed using conventional tools revealing it contains both MYC and BCL2 translocation events. FINDINGS: In this work, we reanalyzed the genome of the cell line using next generation whole genome sequencing technology in order to catalogue translocations, insertions and deletions which may contribute to the pathology of this lymphoma type. CONCLUSIONS: We describe the cell line in much greater detail, and pinpoint the exact locations of the chromosomal breakpoints. We also find several rearrangements within cancer-associated genes, which were not found using conventional tools, suggesting that high throughput sequencing may reveal novel targets for therapy, which could be used concurrently with existing treatments.
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Reordenamiento Génico , Linfoma de Células B/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Análisis de Secuencia de ADN , Secuencia de Bases , Línea Celular Tumoral , Puntos de Rotura del Cromosoma , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Mutagénesis Insercional , Análisis de Secuencia de ADN/métodos , Translocación GenéticaRESUMEN
This article focuses on elucidating the key presentation features of neurotrophic ligands at polymer interfaces. Different biointerfacial configurations of the human neural cell adhesion molecule L1 were established on two-dimensional films and three-dimensional fibrous scaffolds of synthetic tyrosine-derived polycarbonate polymers and probed for surface concentrations, microscale organization, and effects on cultured primary neurons and neural stem cells. Underlying polymer substrates were modified with varying combinations of protein A and poly-D-lysine to modulate the immobilization and presentation of the Fc fusion fragment of the extracellular domain of L1 (L1-Fc). When presented as an oriented and multimeric configuration from protein A-pretreated polymers, L1-Fc significantly increased neurite outgrowth of rodent spinal cord neurons and cerebellar neurons as early as 24 h compared to the traditional presentation via adsorption onto surfaces treated with poly-D-lysine. Cultures of human neural progenitor cells screened on the L1-Fc/polymer biointerfaces showed significantly enhanced neuronal differentiation and neuritogenesis on all protein A oriented substrates. Notably, the highest degree of ßIII-tubulin expression for cells in 3-D fibrous scaffolds were observed in protein A oriented substrates with PDL pretreatment, suggesting combined effects of cell attachment to polycationic charged substrates with subcellular topography along with L1-mediated adhesion mediating neuronal differentiation. Together, these findings highlight the promise of displays of multimeric neural adhesion ligands via biointerfacially engineered substrates to "cooperatively" enhance neuronal phenotypes on polymers of relevance to tissue engineering.
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Proliferación Celular , Materiales Biocompatibles Revestidos , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Células-Madre Neurales/fisiología , Polímeros , Animales , Células Cultivadas , Ratas , Técnicas de Cultivo de Tejidos/métodos , Andamios del TejidoRESUMEN
We evaluated a DNA plasmid-vectored vaccine and a recombinant modified vaccinia virus Ankara vaccine (MVA-mBN32), each encoding cytotoxic and helper T-lymphocyte epitopes of human immunodeficiency virus type 1 (HIV-1) in a randomized, double-blinded, placebo-controlled trial in 36 HIV-1-uninfected adults using a heterologous prime-boost schedule. HIV-1-specific cellular immune responses, measured as interleukin-2 and/or gamma interferon production, were induced in 1 (4%) of 28 subjects after the first MVA-mBN32 immunization and in 3 (12%) of 25 subjects after the second MVA-mBN32 immunization. Among these responders, polyfunctional T-cell responses, including the production of tumor necrosis factor alpha and perforin, were detected. Vaccinia virus-specific antibodies were induced to the MVA vector in 27 (93%) of 29 and 26 (93%) of 28 subjects after the first and second immunizations with MVA-mBN32. These peptide-based vaccines were safe but were ineffective at inducing HIV-1-specific immune responses and induced much weaker responses than MVA vaccines expressing the entire open reading frames of HIV-1 proteins.
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Vacunas contra el SIDA/inmunología , Epítopos de Linfocito T/inmunología , VIH-1/inmunología , Linfocitos T/inmunología , Vacunas de ADN/inmunología , Virus Vaccinia/genética , Vacunas Virales/inmunología , Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/genética , Adolescente , Adulto , Método Doble Ciego , Epítopos de Linfocito T/genética , Femenino , Vectores Genéticos , VIH-1/genética , Humanos , Interferón gamma/metabolismo , Interleucina-2/metabolismo , Masculino , Perforina/biosíntesis , Placebos/administración & dosificación , Factor de Necrosis Tumoral alfa/metabolismo , Vacunas de ADN/administración & dosificación , Vacunas de ADN/genética , Vacunas Virales/administración & dosificación , Vacunas Virales/genética , Adulto JovenRESUMEN
The crustacean intestine and hepatopancreas display a variety of solute transport mechanisms for transmembrane transfer of dietary contents from lumen to epithelial cytosol. An in vitro intestinal perfusion apparatus was used to characterize mucosal to serosoal (MS) and serosal to mucosal (SM) Zn(2+) -dependent (3)H-L-leucine transport by the intestine of the American lobster, Homarus americanus. Transmural 20 µM MS (3)H-L-leucine fluxes across lobster intestine were a hyperbolic function of luminal zinc concentration (1-50 µM) following Michaelis-Menten kinetics (K(m) = 2.67 ± 0.74 µM; J(max) = 19.56 ± 2.22 pmol/cm(2) ×min). Transmural 20 µM SM (3)H-L-leucine fluxes were not affected by serosal zinc, resulting in a highly significant stimulation of net amino acid transfer to the blood by luminal metal. MS fluxes of 20 µM (3)H-L-leucine were also hyperbolic functions of luminal [Cu(2+)], [Mn(2+)], [Na(+)], and [H(+)]. MS flux of (3)H-L-leucine was a sigmoidal function of luminal [L-leucine] and was stimulated by the addition of 20 µM luminal zinc at both pH 7.0 and 5.5. A greater enhanced amino acid transport occurred at the lower pH 5.5. MS flux of 20 µM (3)H-L-leucine in the presence of 20 µM zinc was significantly inhibited by addition of 100 µM luminal glycylsarcosine, and MS flux of 20 µM (3)H-glycylsarcosine was inhibited by 100 µM L-leucine in the presence of 20 µM zinc. Results suggest that (3)H-L-leucine and metals form a complex (e.g., Leu-Zn-Leu] that may functionally mimic dipeptides and use a dipeptide-like transporter during MS fluxes as suggested for fish and mammals.
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Sistemas de Transporte de Aminoácidos/metabolismo , Dipéptidos/metabolismo , Leucina/metabolismo , Nephropidae/metabolismo , Zinc/metabolismo , Animales , Cationes/metabolismo , Citosol/metabolismo , Hepatopáncreas/metabolismo , Mucosa Intestinal/metabolismo , Cinética , Masculino , Membranas/metabolismo , TritioRESUMEN
The promise of personalized therapy for breast cancer is that therapeutic efficacy will be increased while toxic effects are reduced to a minimum. To achieve this goal, there is now an emphasis on the design of therapies that are based not only on the clinical manifestations of the disease, but also on the underlying molecular and cellular biology of cancer. However, identifying targets for personalized therapies in breast cancer is challenging. Here, we describe how biological concepts such as synthetic lethality and oncogene addiction can be used to identify new therapeutic targets and approaches. We discuss the current clinical developments in implementing synthetic lethality therapies, and highlight new ways in which this approach could be used to target specific subsets of breast cancer.
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Neoplasias de la Mama/tratamiento farmacológico , Terapia Molecular Dirigida , Proteínas de Neoplasias/antagonistas & inhibidores , Oncogenes , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Medicina de Precisión/tendencias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteína BRCA1/deficiencia , Proteína BRCA1/fisiología , Proteína BRCA2/deficiencia , Proteína BRCA2/fisiología , Biomarcadores de Tumor , Neoplasias de la Mama/genética , Manejo de Caso , Ensayos Clínicos como Asunto/estadística & datos numéricos , Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Masculino , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Mutación , Proteínas de Neoplasias/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Ftalazinas/farmacología , Ftalazinas/uso terapéutico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Interferencia de ARNRESUMEN
Crustaceans present a very interesting model system to study the process of calcification and calcium (Ca(2+)) transport because of molting-related events and the deposition of CaCO(3) in the new exoskeleton. Dilocarcinus pagei, a freshwater crab endemic to Brazil, was studied to understand Ca(2+) transport in whole gill cells using a fluorescent probe. Cells were dissociated, all of the gill cell types were loaded with fluo-3 and intracellular Ca(2+) change was monitored by adding Ca as CaCl(2) (0, 0.1, 0.25, 0.50, 1.0 and 5 mM), with a series of different inhibitors. For control gill cells, Ca(2+) transport followed Michaelis-Menten kinetics with K(m) = 0.42 +/- 0.04 mM and V(max) = 0.50 +/- 0.02 microM (Ca(2+) change x initial intracellular Ca(-1) x 180 s(-1); N = 14, r (2) = 0.99). Verapamil (a Ca(2+) channel inhibitor) and amiloride (a Na(+)/Ca(2+) exchanger [NCX] inhibitor) completely reduced intracellular Ca(2+) transport, while nifedipine, another Ca(2+) channel inhibitor, did not. Vanadate, a plasma membrane Ca(2+)-ATPase inhibitor (PMCA), increased intracellular Ca(2+) in gill cells through a decrease in the efflux of Ca(2+). Ouabain increased intracellular Ca(2+), similar to the effect of KB-R, a specific NCX inhibitor for Ca(2+) in the influx mode. Alterations in extracellular [Na] in the saline did not affect intracellular Ca(2+) transport. Caffeine, responsible for inducing Ca release from sarcoplasmic reticulum in vertebrate muscle, increased intracellular Ca(2+) compared to control, suggesting an effect of this inhibitor in gill epithelial cells of Dilocarcinus pagei, probably through release of intracellular stores. We also demonstrate here that intracellular Ca(2+) in gill cells of Dilocarcinus pagei was kept relatively constant in face of an extracellular Ca concentration of 50-fold, suggesting that crustaceans are able to display Ca(2+) homeostasis through various Ca(2+) intracellular sequestration mechanisms and/or plasma membrane Ca(2+) influx and outflux that are highly regulatory. In summary, studies using whole gill cells are an interesting approach for working with real regulatory Ca(2+) mechanisms in intact cells under physiological Ca levels (mM range), compared to earlier work using isolated vesicles of various epithelial cells.
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Braquiuros/fisiología , Calcio/metabolismo , Branquias/citología , Branquias/metabolismo , Homeostasis/fisiología , Amilorida/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Cafeína/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Células Cultivadas , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Cinética , Nifedipino/farmacología , Ouabaína/farmacología , Sodio/metabolismo , Intercambiador de Sodio-Calcio/antagonistas & inhibidores , Tiourea/análogos & derivados , Tiourea/farmacología , Vanadatos/farmacología , Verapamilo/farmacologíaRESUMEN
OBJECTIVE: Males with chronic obstructive pulmonary disease (COPD) are at increased risk for developing osteoporosis (OP) with subsequent vertebral compression fractures. Such fractures with resultant increased thoracic kyphotic angle (TKA) may interfere with these patients' already compromised pulmonary function. A retrospective cross-sectional study was performed to evaluate the recognition and treatment of vertebral fractures in male patients with COPD. METHODS: The study population included male patients with COPD aged 55 years and older who had a lateral chest X-ray (index film) performed between January 1, 2001 and July 5, 2005. Vertebral fractures and the TKA were determined independently by two different radiologists. One radiologist (reviewer #1) used direct measurement including quantitative morphometric analysis to determine fractures and the TKA, whereas the second radiologist (reviewer #2) used visual inspection only. Inter-reader agreement for vertebral fractures and TKA was assessed. The computerized charts were reviewed to determine the initial recognition of vertebral fractures and the subsequent therapy. Logistic regression was employed to determine significant risk factors for vertebral fractures in this male population. RESULTS: Three hundred and fifty male study subjects and their index lateral chest X-rays were reviewed. Ages ranged from 52 to 90 and 9/350 (2.6%) of the study subjects had vertebral fractures identified on the initial radiology report. None of these nine patients were subsequently treated with anti-osteoporotic agents other than calcium and vitamin D, and two of them had a follow-up central bone density. Reviewer #1 measured 361 fractures in 181 subjects and determined the mean TKA to be 31.43 (+/-8.62) degrees. Reviewer #2 identified 27 fractures in 19 subjects and with an estimated mean TKA of 24.84 (+/-8.53) degrees. There was little inter-observer agreement with vertebral fractures (kappa=0.07), but there was a strong positive correlation with the TKA (r=0.79). There was a weak to moderate correlation with the TKA and the presence of vertebral fractures (r=0.26). Significant risk factors for vertebral fractures included smoking status (odds ratio 1.84 [1.08-3.15]) and age (odds ratio 1.06 [1.03-1.09] for each year increase in age). CONCLUSION: A large number of vertebral fractures in males with COPD goes undiagnosed. In those patients with diagnosed vertebral fractures, follow-up therapy is under-utilized. When analyzing lateral chest X-rays for vertebral fractures, visual inspection alone without direct measurement may not be an adequate technique for identifying fractures.
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Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/etiología , Anciano , Anciano de 80 o más Años , Conservadores de la Densidad Ósea/uso terapéutico , Calcio/uso terapéutico , Competencia Clínica , Utilización de Medicamentos/estadística & datos numéricos , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Humanos , Cifosis/diagnóstico por imagen , Cifosis/etiología , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Osteoporosis/inducido químicamente , Osteoporosis/diagnóstico por imagen , Osteoporosis/tratamiento farmacológico , Osteoporosis/etiología , Radiografía , Fracturas de la Columna Vertebral/prevención & control , Vitamina D/uso terapéuticoRESUMEN
OBJECTIVE: To determine the prevalence of the polycystic ovary syndrome (PCOS) among women seeking electrology, clients presenting to nine electrology centers completed a questionnaire. STUDY DESIGN: Women with potential risk factors were referred to the University of Alabama at Birmingham. They underwent a detailed history and physical examination, including hirsutism scoring by a modified Ferriman-Gallwey (F-G) method. Serum was assayed for total testosterone, sex hormone binding globulin and dehydroepiandrosterone sulfate. RESULTS: Three hundred fifteen (40%) of 779 patients had potential risk factors for hyperandrogenism and were referred. Eighty-two (26%) completed their evaluation. Six were excluded secondary to prepubertal or menopausal status. Of the remaining 76 patients, 20% had F-G scores of 7 or 8, 13% had scores of 9 or 10, and 21% had scores > 10. Forty-nine (64%) patients reported irregular menstrual cycles. Sixty-four patients were not receiving hormonal therapy: 25 reported regular menstrual cycles, and 39 reported irregular cycles. Seventeen (68%) of the 25 had at least one abnormal androgen value, while 33 (85%) of the 39 women had at least one abnormal value (nonsignificant difference). Overall, PCOS was evident in 39 of the 76 women, or 12% of the 315 patients who were referred for further evaluation. CONCLUSION: Thirty-nine of the 315 referred patients (12%) fulfilled the diagnostic criteria for PCOS. However, they were not receiving medical care for this condition. In addition, this percentage is a conservative estimate in that 74% of the referred patients did not pursue a medical evaluation. Therefore, efforts to educate both electrologists and their clients of the possibility of underlying endocrine disorders and subsequent metabolic morbidity should be undertaken.
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Hirsutismo/etiología , Hiperandrogenismo/diagnóstico , Síndrome del Ovario Poliquístico/epidemiología , Adulto , Estudios Transversales , Terapia por Estimulación Eléctrica , Femenino , Hirsutismo/terapia , Humanos , Hiperandrogenismo/complicaciones , Incidencia , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/diagnóstico , Factores de RiesgoRESUMEN
Beginning with a patient presenting with an atrial septal defect (ASD) of the secundum type, the genealogy was identified in four affected individuals who belonged to three successive generations of the same family. The defects were visually confirmed in all individuals and were found to be anatomically similar. No other congenital malformations were present in these individuals. The genealogy was identified in 1972, when ASD recurred in two generations, and it was concluded that the mechanism of transmission was autosomal recessive. The fifth individual, identified 21 years later, and having an anomaly identical to that of the others, was the child of a couple who had no consaguinity and whose mother was a member of the previously studied genealogy. Considering the absence of phenotype in the parents and the rarity of the ASD gene in the general population, the occurrence of the uniparental disomy for this family nucleus, and the same autosomal recessive mechanism of transmission by this affected individual is possible. This study reports the familial occurrence of ASD by genetic mechanisms of transmission, emphasizing the necessity for genetic-clinical studies in members of the familial nucleus in order to detect new carriers, who usually are asymptomatic, thereby allowing for early and adequate treatment of individuals who may be affected.
Asunto(s)
Defectos del Tabique Interatrial/genética , Femenino , Humanos , Masculino , LinajeRESUMEN
OBJECTIVE: Our purpose was to compare the safety and effectiveness of intravaginally administered misoprostol at doses of 25 micrograms and 50 micrograms for indicated labor induction in patients with an unfavorable cervix. STUDY DESIGN: Three hundred ninety-nine patients received either 25 micrograms or 50 micrograms of misoprostol, placed intravaginally in the posterior fornix, in this randomized double-blind trial. The dose was repeated every 3 hours until adequate labor was achieved (at least three contractions in 10 minutes). RESULTS: Among 399 patients evaluated, 192 patients were allocated to the 25 micrograms group and 207 patients to the 50 micrograms group. The start-to-delivery interval was shorter in the 50 micrograms group (826 minutes vs 970 minutes, p = 0.02). The incidence of vaginal delivery after one dose was higher in the 50 micrograms group (38.2% vs 25.0%, p = 0.007). Patients receiving 25 micrograms required oxytocin augmentation more frequently than did those receiving 50 micrograms (27.1% vs 16.9%, p = 0.02). No differences were noted in the cesarean or other operative delivery rates among patients in the two treatment groups. The incidence of newborns with a cord pH < 7.16 was greater in the 50 micrograms group (13.0% vs 6.8%, p = 0.04). Although the incidence of hyperstimulation was similar between the groups, the incidence of tachysystole was higher in the 50 micrograms group (32.8% vs 15.6%, p = 0.0001). CONCLUSIONS: Although a dose of 50 micrograms is associated with a shorter start-to-delivery interval and a higher incidence of vaginal delivery after one dose, 25 micrograms of intravaginal misoprostol is effective and associated with a lower incidence of tachysystole and cord pH values < 7.16.
PIP: The safety and effectiveness of 25 and 50 mcg of intravaginally administered misoprostol for cervical ripening and labor induction were evaluated in a randomized double-blind trial involving 395 US women. The most frequent indications for labor induction in both dosage groups were pregnancy-induced hypertension and premature rupture of the membranes. The prostaglandin dosage was repeated every 3 hours until labor was induced. The mean start-to-delivery interval among the 192 women in the 25 mcg group was 970 minutes, compared to only 826 minutes among the 207 women in the 50 mcg group. 82% of women in the 25 mcg group and 84% of those in the 50 mcg group were delivered within 24 hours. The incidence of vaginal delivery after 1 dose was higher in the 50 mcg group (38.2%) than in the 25 mcg group (25.0%) and women in the lower-dose group required oxytocin administration more frequently than those in the 50 mcg group (27.1% and 16.9%, respectively). On the other hand, the incidence of newborns with a cord pH under 7.16 was greater in the 50 mcg group (13.0%) than in the 25 mcg group (6.8%), and the incidence of tachysystole was higher (32.8% and 15.6%, respectively). Thus, despite the greater effectiveness of the 50 mcg dosage, a regimen of 25 mcg of misoprostol administered intravaginally every 3 hours is indicated to minimize neonatal morbidity.
Asunto(s)
Trabajo de Parto Inducido , Misoprostol/administración & dosificación , Oxitócicos/administración & dosificación , Administración Intravaginal , Adulto , Parto Obstétrico , Método Doble Ciego , Femenino , Humanos , Concentración de Iones de Hidrógeno , Misoprostol/efectos adversos , Misoprostol/uso terapéutico , Oxitócicos/uso terapéutico , Oxitocina/administración & dosificación , Embarazo , Factores de TiempoRESUMEN
OBJECTIVE: Our purpose was to determine the efficacy and safety of a trial of labor in patients previously delivered at least once by a lower uterine vertical cesarean section. STUDY DESIGN: A retrospective review was performed at a single tertiary perinatal center, The University of Florida Health Science Center, Jacksonville. The medical records of all patients with a previous low vertical cesarean section who underwent a trial of labor during a 72-month period from January 1988 until December 1993 were reviewed. The medical records of the next two patients who did not have a prior uterine incision admitted to labor and delivery after the index case served as the controls. The duration and outcome of labor, including mode of delivery, maternal and perinatal morbidity, and birth trauma were evaluated. RESULTS: Of 77 patients with a previous low vertical cesarean incision, 11 (14.3%) had a repeat operation compared with 14 of 154 patients (9.0%) in the no previous cesarean section group (not significant). No differences were noted in the incidences of operative vaginal deliveries or prolonged duration of the first or second stages of labor, or in the rate or maximum dose of oxytocin infusion between the two groups. One patient in the previous cesarean section group had uterine rupture. The incidence of umbilical artery pH < or = 7.20 was similar. No difference in the number of infants with 1- or 5-minute Apgar scores < or = 7 was noted. CONCLUSION: A trial of labor in women with previous low vertical cesarean sections results in an acceptable rate of vaginal delivery and appears safe for both mother and fetus.
Asunto(s)
Cesárea , Esfuerzo de Parto , Parto Vaginal Después de Cesárea , Adulto , Cesárea/efectos adversos , Cesárea/métodos , Distribución de Chi-Cuadrado , Femenino , Humanos , Embarazo , Resultado del Embarazo , Estudios Retrospectivos , Rotura Uterina/etiologíaRESUMEN
OBJECTIVE: Our purpose was to compare the efficacy, safety, and cost of commercially available dinoprostone cervical gel 0.5 mg with a hospital-compounded formulation. STUDY DESIGN: One hundred thirty-four patients undergoing labor induction were randomly assigned to one of two cervical ripening groups. Commercially available dinoprostone gel 0.5 mg or a compounded formulation of 0.5 mg of prostaglandin E2 gel was administered endocervically. On the basis of cervical scores, gel was reapplied at 6-hour intervals for a maximum of three doses. Physicians managing labor were blinded as to treatment group allocation. RESULTS: Among 134 patients evaluated, 70 were allocated to the commercially available gel and 64 to the compounded gel. No statistically significant differences were noted between the treatment groups with respect to start-to-delivery interval, number of doses, amount of oxytocin, or neonatal adverse outcomes. However, cesarean delivery was performed less frequently in patients in the group receiving the commercially available gel (12.9%) than in the group receiving the compounded gel (28.1%) (p = 0.03). Because of the higher cesarean delivery rate in the compound group, use of this formulation was not associated with cost savings. CONCLUSIONS: The two prostaglandin E2 formulations appeared equivalent with respect to efficacy. An unexplained higher cesarean section rate, however, was associated with the use of the compounded preparation.