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2.
Ann Oncol ; 30(8): 1344-1355, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31147682

RESUMEN

BACKGROUND: Population ageing results in an increasing cancer burden in the elderly. We aimed to evaluate time-trends in cancer mortality for adults aged 65 and over for 17 major cancer types and all cancers combined in 11 countries worldwide over the period 1970-2015. MATERIALS AND METHODS: We obtained cancer death certification and population figures from the WHO and PAHO databases. We computed age-standardised (world standard population) rates for individuals aged 65 and over, and applied joinpoint regression models. RESULTS: Age-standardised mortality rates for all cancers combined showed a heterogeneous, but widespread decline. Lung cancer mortality rates have been decreasing among men, and increasing among women. Pancreatic cancer had unfavourable trends in all countries for both sexes. Despite variability across countries, other tobacco-related cancers (except kidney) showed overall favourable trends, except in Poland and Russia. Age-standardised mortality rates from stomach cancer have been declining in all countries for both sexes. Colorectal mortality has been declining, except in Poland and Russia. Liver cancer mortality increased in all countries, except in Japan, France and Italy, which had the highest rates in the past. Breast cancer mortality decreased for most countries, except for Japan, Poland and Russia. Trends for age-standardised uterine cancer rates in the USA, Canada and the UK were increasing over the last decade. Ovarian cancer rates showed declines in most countries. With the exception of Russia, prostate cancer rates showed overall declines. Lymphoid neoplasms rates have been declining in both sexes, except in Poland and Russia. CONCLUSION: Over the last decades, age-standardised cancer mortality in the elderly has been decreasing in major countries worldwide and for major cancer sites, with the major exception of lung and uterine cancer in women and liver, pancreatic and kidney cancers in both sexes. Cancer mortality for the elderly in central and eastern Europe remains comparatively high.


Asunto(s)
Carga Global de Enfermedades/tendencias , Mortalidad/tendencias , Neoplasias/mortalidad , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales/estadística & datos numéricos , Femenino , Humanos , Masculino , Organización Mundial de la Salud
3.
Adv Cancer Res ; 130: 113-35, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27037752

RESUMEN

Revolutionizing treatment strategies is an urgent clinical need in the fight against cancer. Recently the scientific community has recognized chromatin-associated proteins as promising therapeutic candidates. However, there is a need to develop more targeted epigenetic inhibitors with less toxicity. Sin3 family is one such target which consists of evolutionary conserved proteins with two paralogues Sin3A and Sin3B. Sin3A/B are global transcription regulators that provide a versatile platform for diverse chromatin-modifying activities. Sin3 proteins regulate key cellular functions that include cell cycle, proliferation, and differentiation, and have recently been implicated in cancer pathogenesis. In this chapter, we summarize the key concepts of Sin3 biology and elaborate the recent advancements in the role of Sin3 proteins in cancer with specific examples in multiple endocrine neoplasia type 2, pancreatic ductal adenocarcinoma, and triple negative breast cancer. Finally, a program to create an integrative approach for screening antitumor agents that target chromatin-associated factors like Sin3 is presented.


Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Neoplasias/genética , Proteínas Represoras/genética , Transcripción Genética/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Ciclo Celular/genética , Diferenciación Celular/genética , Proliferación Celular/genética , Cromatina , Humanos , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/patología , Neoplasias/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Complejo Correpresor Histona Desacetilasa y Sin3 , Neoplasias de la Mama Triple Negativas
4.
J Neurophysiol ; 114(3): 1554-64, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26156380

RESUMEN

Gain-of-function missense mutations in voltage-gated sodium channel Nav1.7 have been linked to small-fiber neuropathy, which is characterized by burning pain, dysautonomia and a loss of intraepidermal nerve fibers. However, the mechanistic cascades linking Nav1.7 mutations to axonal degeneration are incompletely understood. The G856D mutation in Nav1.7 produces robust changes in channel biophysical properties, including hyperpolarized activation, depolarized inactivation, and enhanced ramp and persistent currents, which contribute to the hyperexcitability exhibited by neurons containing Nav1.8. We report here that cell bodies and neurites of dorsal root ganglion (DRG) neurons transfected with G856D display increased levels of intracellular Na(+) concentration ([Na(+)]) and intracellular [Ca(2+)] following stimulation with high [K(+)] compared with wild-type (WT) Nav1.7-expressing neurons. Blockade of reverse mode of the sodium/calcium exchanger (NCX) or of sodium channels attenuates [Ca(2+)] transients evoked by high [K(+)] in G856D-expressing DRG cell bodies and neurites. We also show that treatment of WT or G856D-expressing neurites with high [K(+)] or 2-deoxyglucose (2-DG) does not elicit degeneration of these neurites, but that high [K(+)] and 2-DG in combination evokes degeneration of G856D neurites but not WT neurites. Our results also demonstrate that 0 Ca(2+) or blockade of reverse mode of NCX protects G856D-expressing neurites from degeneration when exposed to high [K(+)] and 2-DG. These results point to [Na(+)] overload in DRG neurons expressing mutant G856D Nav1.7, which triggers reverse mode of NCX and contributes to Ca(2+) toxicity, and suggest subtype-specific blockade of Nav1.7 or inhibition of reverse NCX as strategies that might slow or prevent axon degeneration in small-fiber neuropathy.


Asunto(s)
Calcio/metabolismo , Eritromelalgia/metabolismo , Ganglios Espinales/metabolismo , Mutación Missense , Canal de Sodio Activado por Voltaje NAV1.3/metabolismo , Neuritas/metabolismo , Canales de Sodio/metabolismo , Intercambiador de Sodio-Calcio/metabolismo , Animales , Calcio/toxicidad , Células Cultivadas , Ganglios Espinales/citología , Humanos , Canal de Sodio Activado por Voltaje NAV1.3/genética , Neuritas/patología , Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , Sodio/metabolismo , Canales de Sodio/genética , Intercambiador de Sodio-Calcio/antagonistas & inhibidores
5.
J Neurol Sci ; 341(1-2): 8-12, 2014 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-24690348

RESUMEN

Axon degeneration has been identified as a major contributor to non-remitting neurological deficits in patients with multiple sclerosis (MS), which has elicited substantial interest in the development of neuroprotective therapies. Sodium channel blockers, including phenytoin, carbamazepine, flecainide and lamotrigine, have been shown to protect axons from degeneration, attenuate immune cell infiltrates and slow the acquisition of neurological deficits in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. However, the sudden withdrawal of sodium channel blockers, phenytoin and carbamazepine, is associated with severe exacerbation of EAE characterized by massive inflammatory infiltrates and high mortality. In the present study, we asked whether a slow, tapered withdrawal of phenytoin treatment from mice with EAE produced sudden worsening similar to that of sudden withdrawal. Our results demonstrate that gradual withdrawal of phenytoin treatment from mice with EAE is associated with worsening of clinical scores which approach non-treated levels, but was not associated with increased immune cell infiltrates or deaths as have been observed with abrupt withdrawal. These observations support sodium channel blockers as a potential therapeutic agent in the treatment of MS, but indicate caution if treatment is ceased.


Asunto(s)
Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Fármacos Neuroprotectores/administración & dosificación , Fenitoína/administración & dosificación , Animales , Modelos Animales de Enfermedad , Esquema de Medicación , Encefalomielitis Autoinmune Experimental/inducido químicamente , Ratones , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito/toxicidad , Examen Neurológico , Fragmentos de Péptidos/toxicidad , Factores de Tiempo
6.
Neurobiol Dis ; 67: 180-90, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24657915

RESUMEN

In excitatory neurons, SCN2A (NaV1.2) and SCN8A (NaV1.6) sodium channels are enriched at the axon initial segment. NaV1.6 is implicated in several mouse models of absence epilepsy, including a missense mutation identified in a chemical mutagenesis screen (Scn8a(V929F)). Here, we confirmed the prior suggestion that Scn8a(V929F) exhibits a striking genetic background-dependent difference in phenotypic severity, observing that spike-wave discharge (SWD) incidence and severity are significantly diminished when Scn8a(V929F) is fully placed onto the C57BL/6J strain compared with C3H. Examination of sequence differences in NaV subunits between these two inbred strains suggested NaV1.2(V752F) as a potential source of this modifier effect. Recognising that the spatial co-localisation of the NaV channels at the axon initial segment (AIS) provides a plausible mechanism for functional interaction, we tested this idea by undertaking biophysical characterisation of the variant NaV channels and by computer modelling. NaV1.2(V752F) functional analysis revealed an overall gain-of-function and for NaV1.6(V929F) revealed an overall loss-of-function. A biophysically realistic computer model was used to test the idea that interaction between these variant channels at the AIS contributes to the strain background effect. Surprisingly this modelling showed that neuronal excitability is dominated by the properties of NaV1.2(V752F) due to "functional silencing" of NaV1.6(V929F) suggesting that these variants do not directly interact. Consequent genetic mapping of the major strain modifier to Chr 7, and not Chr 2 where Scn2a maps, supported this biophysical prediction. While a NaV1.6(V929F) loss of function clearly underlies absence seizures in this mouse model, the strain background effect is apparently not due to an otherwise tempting Scn2a variant, highlighting the value of combining physiology and genetics to inform and direct each other when interrogating genetic complex traits such as absence epilepsy.


Asunto(s)
Encéfalo/fisiopatología , Epilepsia Tipo Ausencia/genética , Epilepsia Tipo Ausencia/fisiopatología , Canal de Sodio Activado por Voltaje NAV1.2/genética , Canal de Sodio Activado por Voltaje NAV1.2/metabolismo , Canal de Sodio Activado por Voltaje NAV1.6/genética , Canal de Sodio Activado por Voltaje NAV1.6/metabolismo , Animales , Axones/fisiología , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Mutantes , Modelos Neurológicos
7.
Exp Neurol ; 253: 174-9, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24424281

RESUMEN

Osmoregulation in mammals is tightly controlled by the release of vasopressin and oxytocin from magnocellular neurosecretory cells (MSC) of the supraoptic nucleus (SON). The release of vasopressin and oxytocin in the neurohypophysis by axons of MSC is regulated by bursting activity of these neurons, which is influenced by multiple sources, including intrinsic membrane properties, paracrine contributions of glial cells, and extrinsic synaptic inputs. Previous work has shown that bursting activity of MSC is tetrodotoxin (TTX)-sensitive, and that TTX-S sodium channels Nav1.2, Nav1.6 and Nav1.7 are expressed by MSC and upregulated in response to osmotic challenge in rats. The TTX-resistant sodium channels, NaV1.8 and Nav1.9, are preferentially expressed, at relatively high levels, in peripheral neurons, where their properties are linked to repetitive firing and subthreshold electrogenesis, respectively, and are often referred to as "peripheral" sodium channels. Both sodium channels have been implicated in pain pathways, and are under study as potential therapeutic targets for pain medications which might be expected to have minimal CNS side effects. We show here, however, that Nav1.9 is expressed by vasopressin- and oxytocin-producing MSC of the rat supraoptic nucleus (SON). We also show that cultured MSC exhibit sodium currents that have characteristics of Nav1.9 channels. In contrast, Nav1.8 is not detectable in the SON. These results suggest that Nav1.9 may contribute to the firing pattern of MSC of the SON, and that careful assessment of hypothalamic function be performed as NaV1.9 blocking agents are studied as potential pain therapies.


Asunto(s)
Expresión Génica/fisiología , Canal de Sodio Activado por Voltaje NAV1.9/metabolismo , Neuronas/metabolismo , Núcleo Supraóptico/citología , Animales , Células Cultivadas , Estimulación Eléctrica , Activación del Canal Iónico/efectos de los fármacos , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/genética , Canal de Sodio Activado por Voltaje NAV1.9/genética , Neuronas/efectos de los fármacos , Oxitocina/metabolismo , Técnicas de Placa-Clamp , Ratas , Bloqueadores de los Canales de Sodio/farmacología , Tetrodotoxina/farmacología , Vasopresinas/metabolismo
8.
Leukemia ; 27(2): 315-24, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22751450

RESUMEN

Arsenic trioxide (ATO) induces disease remission in acute promyelocytic leukemia (APL) patients, but not in non-APL acute myeloid leukemia (AML) patients. ATO at therapeutic concentrations (1-2 µM) induces APL NB4, but not non-APL HL-60, cells to undergo apoptosis through the mitochondrial pathway. The role of antiapoptotic protein Mcl-1 in ATO-induced apoptosis was determined. The levels of Mcl-1 were decreased in NB4, but not in HL-60, cells after ATO treatment through proteasomal degradation. Both glycogen synthase kinase-3ß (GSK-3ß) inhibitor SB216763 and siRNA blocked ATO-induced Mcl-1 reduction as well as attenuated ATO-induced apoptosis in NB4 cells. Silencing Mcl-1 sensitized HL-60 cells to ATO-induced apoptosis. Both ERK and AKT inhibitors decreased Mcl-1 levels and enhanced ATO-induced apoptosis in HL-60 cells. Sorafenib, an Raf inhibitor, activated GSK-3ß by inhibiting its phosphorylation, decreased Mcl-1 levels and decreased intracellular glutathione levels in HL-60 cells. Sorafenib plus ATO augmented reactive oxygen species production and apoptosis induction in HL-60 cells and in primary AML cells. These results indicate that ATO induces Mcl-1 degradation through activation of GSK-3ß in APL cells and provide a rationale for utilizing ATO in combination with sorafenib for the treatment of non-APL AML patients.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Arsenicales/farmacología , Glucógeno Sintasa Quinasa 3/metabolismo , Leucemia Mieloide Aguda/patología , Óxidos/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Trióxido de Arsénico , Western Blotting , Regulación hacia Abajo , Activación Enzimática/efectos de los fármacos , Citometría de Flujo , Glutatión/metabolismo , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3 beta , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Fosforilación , ARN Interferente Pequeño/genética , Especies Reactivas de Oxígeno/metabolismo , Células Tumorales Cultivadas
9.
Clin Genet ; 82(4): 351-8, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22803682

RESUMEN

Small fiber neuropathy (SFN) is a disorder typically dominated by neuropathic pain and autonomic dysfunction, in which the thinly myelinated Aδ-fibers and unmyelinated C-fibers are selectively injured. The diagnosis SFN is based on a reduced intraepidermal nerve fiber density and/or abnormal thermal thresholds in quantitative sensory testing. The etiologies of SFN are diverse, although no apparent cause is frequently seen. Recently, SCN9A-gene variants (single amino acid substitutions) have been found in ∼30% of a cohort of idiopathic SFN patients, producing gain-of-function changes in sodium channel Na(V)1.7, which is preferentially expressed in small diameter peripheral axons. Functional testing showed that these variants altered fast inactivation, slow inactivation or resurgent current and rendered dorsal root ganglion neurons hyperexcitable. In this review, we discuss the role of Na(V)1.7 in pain and highlight the molecular genetics and pathophysiology of SCN9A-gene variants in SFN. With increasing knowledge regarding the underlying pathophysiology in SFN, the development of specific treatment in these patients seems a logical target for future studies.


Asunto(s)
Canalopatías/genética , Variación Genética , Canal de Sodio Activado por Voltaje NAV1.7/genética , Fibras Nerviosas Amielínicas/patología , Polineuropatías/genética , Animales , Humanos , Polineuropatías/patología
10.
Neurology ; 78(21): 1635-43, 2012 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-22539570

RESUMEN

OBJECTIVES: Although small fiber neuropathy (SFN) often occurs without apparent cause, the molecular etiology of idiopathic SFN (I-SFN) has remained enigmatic. Sodium channel Na(v)1.7 is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons and their small-diameter peripheral axons. We recently reported the presence of Na(v)1.7 variants that produce gain-of-function changes in channel properties in 28% of patients with painful I-SFN and demonstrated impaired slow-inactivation in one of these mutations after expression within HEK293 cells. Here we show that the I739V Na(v)1.7 variant in a patient with biopsy-confirmed I-SFN impairs slow-inactivation within DRG neurons and increases their excitability. METHODS: A patient with SFN symptoms including pain, and no identifiable underlying cause, was evaluated by skin biopsy, quantitative sensory testing, nerve conduction studies, screening of genomic DNA for variants in SCN9A, and functional analysis. RESULTS: Voltage-clamp analysis following expression within DRG neurons revealed that the Na(v)1.7/I739V substitution impairs slow-inactivation, depolarizing the midpoint (V(1/2)) by 5.6 mV, and increasing the noninactivating component at 10 mV from 16.5% to 22.2%. Expression of I739V channels within DRG neurons rendered these cells hyperexcitable, reducing current threshold and increasing the frequency of firing evoked by graded suprathreshold stimuli. CONCLUSIONS: These observations provide support, from a patient with biopsy-confirmed SFN, for the suggestion that functional variants of Na(v)1.7 that impair slow-inactivation can produce DRG neuron hyperexcitability that contributes to pain in SFN. Na(v)1.7 channelopathy-associated SFN should be considered in the differential diagnosis of cases of SFN in which no other cause is found.


Asunto(s)
Ganglios Espinales/patología , Polineuropatías/diagnóstico , Polineuropatías/genética , Canales de Sodio/fisiología , Exones , Femenino , Células HEK293 , Humanos , Persona de Mediana Edad , Canal de Sodio Activado por Voltaje NAV1.7 , Técnicas de Placa-Clamp , Polineuropatías/patología
11.
Spinal Cord ; 50(6): 404-12, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22310319

RESUMEN

STUDY DESIGN: International validation study using self-administered surveys. OBJECTIVES: To investigate the utility and reliability of the International Spinal Cord Injury Pain (ISCIP) Classification as used by clinicians. METHODS: Seventy-five clinical vignettes (case histories) were prepared by the members of the ISCIP Classification group and assigned to a category by consensus. Vignettes were incorporated into an Internet survey distributed to clinicians. Clinicians were asked, for each vignette, to decide on the number of pain components present and to classify each using the ISCIP Classification. RESULTS: The average respondent had 86% of the questions on the number of pain components correct. The overall correctness in determining whether pain was nociceptive was 79%, whereas the correctness in determining whether pain was neuropathic was 77%. Correctness in determining if pain was musculoskeletal was 84%, whereas for visceral pain, neuropathic at-level spinal cord injury (SCI) and below-level SCI pain it was 85%, 57% and 73%, respectively. Using strict criteria, the overall correctness in determining pain type was 68% (versus an expected 95%), but with maximally relaxed criteria, it increased to 85%. CONCLUSIONS: The reliability of use of the ISCIP Classification by clinicians (who received minimal training in its use) using a clinical vignette approach is moderate. Some subtypes of pain proved challenging to classify. The ISCIP should be tested for reliability by applying it to real persons with pain after SCI. Based on the results of this validation process, the instructions accompanying the ISCIP Classification for classifying subtypes of pain have been clarified.


Asunto(s)
Dimensión del Dolor/clasificación , Dimensión del Dolor/métodos , Dolor/clasificación , Traumatismos de la Médula Espinal/complicaciones , Recolección de Datos , Humanos , Dolor/etiología , Reproducibilidad de los Resultados
12.
Spinal Cord ; 50(6): 413-7, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22182852

RESUMEN

STUDY DESIGN: Discussion of issues and development of consensus. OBJECTIVE: Present the background, purpose, development process, format and definitions of the International Spinal Cord Injury Pain (ISCIP) Classification. METHODS: An international group of spinal cord injury (SCI) and pain experts deliberated over 2 days, and then via e-mail communication developed a consensus classification of pain after SCI. The classification was reviewed by members of several professional organizations and their feedback was incorporated. The classification then underwent validation by an international group of clinicians with minimal exposure to the classification, using case study vignettes. Based upon the results of this study, further revisions were made to the ISCIP Classification. RESULTS: An overall structure and terminology has been developed and partially validated as a merger of and improvement on previously published SCI pain classifications, combined with basic definitions proposed by the International Association for the Study of Pain and pain characteristics described in published empiric studies of pain. The classification is designed to be comprehensive and to include pains that are directly related to the SCI pathology as well as pains that are common after SCI but are not necessarily mechanistically related to the SCI itself. CONCLUSIONS: The format and definitions presented should help experienced and non-experienced clinicians as well as clinical researchers classify pain after SCI.


Asunto(s)
Dimensión del Dolor/clasificación , Dolor/clasificación , Dolor/etiología , Traumatismos de la Médula Espinal/complicaciones , Humanos , Dimensión del Dolor/métodos
15.
J Physiol ; 588(Pt 11): 1915-27, 2010 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-20123784

RESUMEN

Ion channel missense mutations cause disorders of excitability by changing channel biophysical properties. As an increasing number of new naturally occurring mutations have been identified, and the number of other mutations produced by molecular approaches such as in situ mutagenesis has increased, the need for functional analysis by patch-clamp has become rate limiting. Here we compare a patch-clamp robot using planar-chip technology with human patch-clamp in a functional assessment of a previously undescribed Nav1.7 sodium channel mutation, S211P, which causes erythromelalgia. This robotic patch-clamp device can increase throughput (the number of cells analysed per day) by 3- to 10-fold. Both modes of analysis show that the mutation hyperpolarizes activation voltage dependence (8 mV by manual profiling, 11 mV by robotic profiling), alters steady-state fast inactivation so that it requires an additional Boltzmann function for a second fraction of total current (approximately 20% manual, approximately 40% robotic), and enhances slow inactivation (hyperpolarizing shift--15 mV by human,--13 mV robotic). Manual patch-clamping demonstrated slower deactivation and enhanced (approximately 2-fold) ramp response for the mutant channel while robotic recording did not, possibly due to increased temperature and reduced signal-to-noise ratio on the robotic platform. If robotic profiling is used to screen ion channel mutations, we recommend that each measurement or protocol be validated by initial comparison to manual recording. With this caveat, we suggest that, if results are interpreted cautiously, robotic patch-clamp can be used with supervision and subsequent confirmation from human physiologists to facilitate the initial profiling of a variety of electrophysiological parameters of ion channel mutations.


Asunto(s)
Técnicas de Placa-Clamp/instrumentación , Robótica , Canales de Sodio/genética , Canales de Sodio/fisiología , Adolescente , Algoritmos , Interpretación Estadística de Datos , Electrofisiología , Eritromelalgia/genética , Humanos , Activación del Canal Iónico/fisiología , Masculino , Canal de Sodio Activado por Voltaje NAV1.7 , Técnicas de Placa-Clamp/métodos , Plásmidos , Transfección
16.
Int J Impot Res ; 21(3): 165-70, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19212325

RESUMEN

Men's health issues have increasingly gained attention not only in the mass media, but also among most health-care providers. The diagnosis and treatment of male-related health problems, unfortunately, can lead to complications and error-related injuries resulting in claims of medical malpractice. This review article will look at the most common claims relating to complications and injuries in the management of men's health issues. Reviews of the literature over the past three decades using multiple search engines including PubMed were utilized. The most pertinent articles were selected on the basis of their relevance to men's health issues, complications and medico-legal ramifications. An evaluation of the literature reveals that although the number of claims against urologists has not increased over the past several decades, indemnity payments have continued to rise significantly. Claims can be divided into those relating to diagnosis and those relating to treatment. Providers of men's health care may become involved in claims of medical malpractice at some time during their careers. Patients' care can result in complications and injuries, most of which do not lead to claims. Certain areas of men's health lead to more claims than others. The keys to prevention and management of those claims are good communication, informed consent and documentation.


Asunto(s)
Enfermedades de los Genitales Masculinos/complicaciones , Enfermedades de los Genitales Masculinos/terapia , Mala Praxis , Urología/legislación & jurisprudencia , Adulto , Circuncisión Masculina , Disfunción Eréctil/etiología , Genitales Masculinos/lesiones , Humanos , Masculino , Enfermedades de la Próstata/diagnóstico , Enfermedades de la Próstata/cirugía , Escroto/patología , Enfermedades de Transmisión Sexual/terapia , Torsión del Cordón Espermático/etiología , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/cirugía , Vasectomía
17.
Int J Impot Res ; 21(2): 145-8, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19020522

RESUMEN

This report details the incidence and description of trauma to the external genitalia experienced during Operation Iraqi Freedom at a United States Army Combat Support Hospital, and demonstrates that acceptable rates of testicular salvage are possible in the combat setting. The operating room logs and the Joint Theater Trauma Registry were used to conduct a retrospective review of the patients who sustained genitourinary (GU) injuries at an US Army Combat Support Hospital (CSH) in Iraq from 27 February 2007 to 14 August 2007. Of the 3595 battle trauma injuries seen at the CSH during the time period, 168 (4.7%) had one or more GU injuries for a total of 172 GU injuries. Of these patients, 115 (68%) with GU injuries had one or more injuries to the external genitalia for a total of 119 external GU injuries. Penetrating trauma to the penis and scrotum accounted for 59 of the injuries. In total, 43 testicles were injured in 34 patients (9 had bilateral injuries). In total, 32 testes were repaired primarily and 11 were removed. Injuries to the external genitalia continue to account for the vast majority of GU trauma in a combat setting. Of patients who presented with penetrating testicular trauma, there was a 74.4% salvage rate, which is higher than previous reports of combat external genitalia injuries. Treatment of penetrating trauma to the external genitalia in a combat setting requires attention to tissue preservation while coordinating associated surgical procedures.


Asunto(s)
Genitales Masculinos/lesiones , Guerra , Heridas Penetrantes/complicaciones , Adulto , Genitales Masculinos/diagnóstico por imagen , Humanos , Irak , Masculino , Personal Militar , Pene/diagnóstico por imagen , Pene/lesiones , Estudios Retrospectivos , Escroto/diagnóstico por imagen , Escroto/lesiones , Testículo/diagnóstico por imagen , Testículo/lesiones , Tomografía Computarizada por Rayos X , Estados Unidos , Heridas Penetrantes/diagnóstico por imagen
18.
J Vet Pharmacol Ther ; 31(6): 496-500, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19000270

RESUMEN

The purpose of this study was to describe and compare the pharmacokinetic properties of different formulations of erythromycin in dogs. Erythromycin was administered as lactobionate (10 mg/kg, IV), estolate tablets (25 mg/kg p.o.) and ethylsuccinate tablets or suspension (20 mg/kg p.o.). After intravenous (i.v.) administration, the principal pharmacokinetic parameters were (mean +/- SD): AUC((0-infinity)) 4.20 +/- 1.66 microg x h/mL; C(max) 6.64 +/- 1.38 microg/mL; V(z) 4.80 +/- 0.91 L/kg; Cl(t) 2.64 +/- 0.84 L/h.kg; t((1/2)lambda) 1.35 +/- 0.40 h and MRT 1.50 +/- 0.47 h. After the administration of estolate tablets and ethylsuccinate suspension, the principal pharmacokinetic parameters were (mean +/- SD): C(max), 0.30 +/- 0.17 and 0.17 +/- 0.09 microg/mL; t(max), 1.75 +/- 0.76 and 0.69 +/- 0.30 h; t((1/2)lambda), 2.92 +/- 0.79 and 1.53 +/- 1.28 h and MRT, 5.10 +/- 1.12 and 2.56 +/- 1.77 h, respectively. The administration of erythromycin ethylsuccinate tablets did not produce measurable serum concentrations. Only the i.v. administration rendered serum concentrations above MIC(90) = 0.5 microg/mL for 2 h. However, these results should be cautiously interpreted as tissue erythromycin concentrations have not been measured in this study and, it is recognized that they can reach much higher concentrations than in blood, correlating better with clinical efficacy.


Asunto(s)
Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Estolato de Eritromicina/administración & dosificación , Estolato de Eritromicina/farmacocinética , Etilsuccinato de Eritromicina/farmacocinética , Administración Oral , Animales , Antibacterianos/sangre , Área Bajo la Curva , Estudios Cruzados , Perros , Formas de Dosificación , Estolato de Eritromicina/sangre , Etilsuccinato de Eritromicina/administración & dosificación , Etilsuccinato de Eritromicina/sangre , Femenino , Semivida , Inyecciones Intravenosas , Modelos Lineales , Masculino , Tasa de Depuración Metabólica
19.
J Neurosci ; 28(43): 11079-88, 2008 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-18945915

RESUMEN

Gain-of-function mutations of Na(V)1.7 have been shown to produce two distinct disorders: Na(V)1.7 mutations that enhance activation produce inherited erythromelalgia (IEM), characterized by burning pain in the extremities; Na(V)1.7 mutations that impair inactivation produce a different, nonoverlapping syndrome, paroxysmal extreme pain disorder (PEPD), characterized by rectal, periocular, and perimandibular pain. Here we report a novel Na(V)1.7 mutation associated with a mixed clinical phenotype with characteristics of IEM and PEPD, with an alanine 1632 substitution by glutamate (A1632E) in domain IV S4-S5 linker. Patch-clamp analysis shows that A1632E produces changes in channel function seen in both IEM and PEPD mutations: A1632E hyperpolarizes (-7 mV) the voltage dependence of activation, slows deactivation, and enhances ramp responses, as observed in Na(V)1.7 mutations that produce IEM. A1632E depolarizes (+17mV) the voltage dependence of fast inactivation, slows fast inactivation, and prevents full inactivation, resulting in persistent inward currents similar to PEPD mutations. Using current clamp, we show that A1632E renders dorsal root ganglion (DRG) and trigeminal ganglion neurons hyperexcitable. These results demonstrate a Na(V)1.7 mutant with biophysical characteristics common to PEPD (impaired fast inactivation) and IEM (hyperpolarized activation, slow deactivation, and enhanced ramp currents) associated with a clinical phenotype with characteristics of both IEM and PEPD and show that this mutation renders DRG and trigeminal ganglion neurons hyperexcitable. These observations indicate that IEM and PEPD mutants are part of a physiological continuum that can produce a continuum of clinical phenotypes.


Asunto(s)
Alanina/genética , Eritromelalgia/genética , Ácido Glutámico/genética , Mutación , Canales de Sodio/genética , Trastornos Somatomorfos/genética , Animales , Animales Recién Nacidos , Células Cultivadas , Niño , Relación Dosis-Respuesta en la Radiación , Estimulación Eléctrica , Eritromelalgia/complicaciones , Ganglios Espinales/citología , Humanos , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/genética , Potenciales de la Membrana/efectos de la radiación , Modelos Moleculares , Canal de Sodio Activado por Voltaje NAV1.7 , Neuronas/fisiología , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Trastornos Somatomorfos/complicaciones , Factores de Tiempo , Transfección
20.
Oncogene ; 27(39): 5260-6, 2008 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-18504436

RESUMEN

Translocations of the retinoic acid receptor-alpha (RARalpha) locus with the promyelocytic leukemia zinc-finger (PLZF) or PML genes lead to expression of oncogenic PLZF-RARalpha or PML-RARalpha fusion proteins, respectively. These fusion oncoproteins constitutively repress RARalpha target genes, in large part through aberrant recruitment of multiprotein co-repressor complexes. PML and PML-RARalpha have previously been shown to associate with the retinoblastoma (Rb) tumour suppressor protein in its hypophosphorylated state. Here, we demonstrate that PLZF also interacts with Rb in vitro and in vivo. The interaction between PLZF and Rb is mediated through the Rb pocket and the region of PLZF that lies between its transcriptional repression (poxvirus and zinc-finger, POZ) and DNA-binding (zinc-finger) domains. In addition, Rb can simultaneously interact with PLZF and the E2F1 S phase-inducing transcription factor, suggesting that these proteins can exist in the same multiprotein complex. In contrast to the interaction of Rb with PML or E2F1, the PLZF-Rb interaction is not dependent on hypophosphorylation of Rb. These data are supported by chromatin immunoprecipitation analysis, which indicates that PLZF associates with the promoter region of CDC6, a known E2F/Rb target gene. Co-expression of PLZF and Rb results in enhancement of transcriptional repression of PLZF and E2F/Rb target genes, indicating functional co-operation between the two proteins. Both PLZF and Rb have been shown to function in stem cells and taken together these data suggest that interactions between PLZF and Rb could be important in stem cell biology.


Asunto(s)
Factores de Transcripción de Tipo Kruppel/metabolismo , Regiones Promotoras Genéticas , Proteína de Retinoblastoma/metabolismo , Inmunoprecipitación de Cromatina , Humanos , Fosforilación , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Unión Proteica , Transcripción Genética
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