RESUMEN
An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short-term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long-term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans-disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.
Asunto(s)
Trasplante de Órganos , Anciano , Asignación de Recursos para la Atención de Salud , Humanos , Inmunosupresores/uso terapéutico , Selección de Paciente , Justicia Social , Donantes de Tejidos , Resultado del TratamientoRESUMEN
Unknown factors present in the serum of older adults impair lymphocyte function and may be responsible for anergy (absence of delayed-type hypersensitivity (DTH)) present in many older adults. Polyunsaturated fatty acids (PUFAs) and their metabolites are immunomodulatory and may play a role in clinical conditions of advanced age, including immune dysfunction. We hypothesized that PUFAs could be the factor(s) present in serum that contribute to impaired immune responses in older adults. Prior studies of serum PUFAs in older adults neither adequately control dietary PUFA intake, nor investigated the relationship of PUFAs and DTH responses. We determined serum PUFA concentrations in young adults with normal immune responses, and older adults with impaired (anergic elderly) or normal immunity (nonanergic elderly) before and after administering a standardized diet. After controlling for dietary intake, advancing age was associated with markedly higher serum concentrations of arachidonic acid (AA), dihomo-gamma-linoleic acid (DGLA), and eicosapentaenoic acid (EPA) and a lower AA:EPA ratio. Other serum PUFAs and the AA:DGLA ratio were unaffected by age. However, there was no difference between older adults with or without anergy. These data suggest advanced age is associated with marked alterations of serum PUFAs that are only apparent after strictly controlling dietary intake. However, there was no association of serum PUFA concentrations with DTH status among older adults.
Asunto(s)
Envejecimiento/inmunología , Grasas Insaturadas en la Dieta/administración & dosificación , Ácidos Grasos Insaturados/sangre , Ácidos Grasos Insaturados/inmunología , Hipersensibilidad Tardía/sangre , Adyuvantes Inmunológicos/sangre , Adulto , Anciano , Envejecimiento/sangre , Análisis de Varianza , Ácido Araquidónico/sangre , Estudios de Casos y Controles , Ácido Eicosapentaenoico/sangre , Femenino , Humanos , Ácido Linoleico/sangre , MasculinoAsunto(s)
Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Ácido Araquidónico/metabolismo , Ácido Araquidónico/farmacología , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismo , Animales , Antineoplásicos/química , Ácido Araquidónico/química , Humanos , Ligandos , Estructura Molecular , Proliferadores de Peroxisomas/metabolismoRESUMEN
Older adults are at risk for malnutrition, which may contribute to their increased risk of infection. Nutritional supplementation strategies can reduce this risk and reverse some of the immune dysfunction associated with advanced age. This review discusses nutritional interventions that have been examined in clinical trials of older adults. The data support use of a daily multivitamin or trace-mineral supplement that includes zinc (elemental zinc, >20 mg/day) and selenium (100 microg/day), with additional vitamin E, to achieve a daily dosage of 200 mg/day. Specific syndromes may also be addressed by nutritional interventions (for example, cranberry juice consumption to reduce urinary tract infections) and may reduce antibiotic use in older adults, particularly those living in long-term care facilities. Drug-nutrient interactions are common in elderly individuals, and care providers should be aware of these interactions. Future research should evaluate important clinical end points rather than merely surrogate markers of immunity.
Asunto(s)
Envejecimiento/inmunología , Infecciones/dietoterapia , Infecciones/inmunología , Anciano , Estimulantes del Apetito/uso terapéutico , Suplementos Dietéticos , Interacciones Alimento-Droga , Humanos , Infecciones/etiología , Trastornos Nutricionales/complicaciones , Trastornos Nutricionales/diagnóstico , Trastornos Nutricionales/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de RiesgoRESUMEN
This study tested the hypothesis that certain secretory phospholipase A(2) (sPLA(2)) isotypes act in a cytokine-like fashion through cell surface receptors to influence mast cell survival. Initial experiments revealed that sPLA(2) activity and sPLA(2) receptor expression are increased, and mast cells lost their capacity to maintain membrane asymmetry upon cytokine depletion. Groups IB and III, but not group IIA PLA(2), prevented the loss of membrane asymmetry. Similarly, group IB prevented nucleosomal DNA fragmentation in mast cells. Providing putative products of sPLA(2) hydrolysis to cytokine-depleted mast cells did not influence survival. Furthermore, catalytic inactivation of sPLA(2) did not alter its capacity to prevent apoptosis. Inhibition of protein synthesis using cycloheximide or actinomycin reversed the antiapoptotic effect of sPLA(2). Additionally, both wild-type and catalytically inactive group IB PLA(2) induced IL-3 synthesis in mast cells. However, adding IL-3-neutralizing Ab did not change Annexin V(FITC) binding and only partially inhibited thymidine incorporation in sPLA(2)-supplemented mast cells. In contrast, IL-3-neutralizing Ab inhibited both Annexin V(FITC) binding and thymidine incorporation in mast cells maintained with IL-3. sPLA(2) enhanced phosphoinositide 3'-kinase activity, and a specific inhibitor of phosphoinositide 3'-kinase reversed the antiapoptotic effects of sPLA(2). Likewise, sPLA(2) increased the degradation of I-kappaBalpha, and specific inhibitors of nuclear factor kappa activation (NF-kappaB) reversed the antiapoptotic effects of sPLA(2). Together, these experiments reveal that certain isotypes of sPLA(2) enhance the survival of mast cells in a cytokine-like fashion by activating antiapoptotic signaling pathways independent of IL-3 and probably via sPLA(2) receptors rather than sPLA(2) catalytic products.
Asunto(s)
Células de la Médula Ósea/inmunología , Mastocitos/inmunología , Fosfolipasas A/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Anexina A5/metabolismo , Apoptosis , Ácido Araquidónico/farmacología , Células de la Médula Ósea/citología , Supervivencia Celular , Interleucina-3 , Isoenzimas/metabolismo , Lisofosfolípidos/farmacología , Mastocitos/citología , Ratones , FN-kappa B/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Unión Proteica , Biosíntesis de Proteínas , Receptores de Fosfolipasa A2 , Transducción de Señal , Transcripción GenéticaRESUMEN
Cyclopentenone prostaglandin derivatives of arachidonic acid are potent inducers of apoptosis in a variety of cancer cell types. Several investigators have shown that the terminal derivative of prostaglandin J(2) (PGJ(2)) metabolism, 15-deoxy-Delta(12,14)-PGJ(2) (15dPGJ(2)), induces apoptosis in breast cancer cells and is a potent activator of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma), but 15dPGJ(2) effects can be mediated by PPARgamma-dependent and PPARgamma-independent mechanisms. Here we report that 15dPGJ(2) regulates early gene expression critical to apoptosis. Specifically, 15dPGJ(2) induces potent and irreversible S phase arrest that is correlated with expression of genes critical to cell cycle arrest and apoptosis, including the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) (p21). Inhibition of RNA or protein synthesis abrogates apoptosis induced by 15dPGJ(2) in breast cancer cells but potentiates apoptosis induced by tumor necrosis factor-alpha or CD95/Fas ligand. Additionally, 15dPGJ(2) induces caspase activation that is blocked by peptide caspase inhibitors. These data show that de novo gene transcription is necessary for 15dPGJ(2)-induced apoptosis in breast cancer cells. Critical candidate genes are likely to be revealed through analysis of differential cDNA array expression.
Asunto(s)
Apoptosis , Neoplasias de la Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Factores Inmunológicos/farmacología , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacología , Apoptosis/efectos de los fármacos , Northern Blotting , Western Blotting , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Caspasas/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/metabolismo , Cicloheximida/farmacología , ADN Complementario/metabolismo , Dactinomicina/farmacología , Regulación hacia Abajo , Activación Enzimática , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Ligandos , Microscopía Fluorescente , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Análisis de Secuencia por Matrices de Oligonucleótidos , Inhibidores de la Síntesis de la Proteína/farmacología , Receptores Citoplasmáticos y Nucleares/metabolismo , Fase S/efectos de los fármacos , Factores de Tiempo , Factores de Transcripción/metabolismo , Transcripción Genética , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) has become a potential target for the prevention and treatment of breast cancer. However, recent in vitro and in vivo studies have raised the question of whether activation of PPARgamma leads to the promotion or reduction of tumor formation. Studies using several cancer cell lines, animal models, and a variety of PPARgamma agonists have shown discordant results, including changes in cellular proliferation, differentiation, and apoptosis of cancer cells and tumors. METHODS: We studied the effects of low-, moderate-, and high-dose treatment of the PPARgamma ligands 15-deoxy-delta1214 prostaglandin J2 (15dPGJ2) and troglitazone (TGZ) on parameters of cell growth, differentiation, and apoptosis in the epithelial breast cancer cell line MDA-MB-231. RESULTS: The biologic effects of these compounds depend largely on ligand concentration and the degree of PPARgamma activation. For example, low concentrations of 15dPGJ2 (<2.5 microM) and TGZ (<5 microM) increased cellular proliferation, but concentrations of 15dPGJ2 > or = 10 microM and of TGZ at 100 microM blocked cell growth. TGZ (100 microM) slowed cell cycle progression, and 15dPGJ2 (10 microM) caused an S-phase arrest in the cell cycle and induced morphological characteristics consistent with apoptosis. Expression of CD36, a marker of differentiation in these cells, was induced by 2.5 microM 15dPGJ2 or 5 to 100 microM TGZ. However, higher concentrations of 15dPGJ2 did not alter CD36 expression. Transcriptional activation studies demonstrated that 15dPGJ2 is a more potent PPARgamma ligand than TGZ. Regardless of the ligand used, though, low transcriptional activation correlated with an increased cellular proliferation, whereas higher levels of activation correlated with cell cycle arrest and apoptosis. CONCLUSIONS: PPARgamma activation induces several important and seemingly opposite changes in neoplastic cells, depending on the magnitude of PPARgamma activation. These data may explain, at least in part, some of the discordant results previously reported.
Asunto(s)
Neoplasias de la Mama/patología , Cromanos/farmacología , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacología , Receptores Citoplasmáticos y Nucleares/fisiología , Tiazoles/farmacología , Tiazolidinedionas , Factores de Transcripción/fisiología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Femenino , Humanos , Activación Transcripcional/efectos de los fármacos , Troglitazona , Células Tumorales CultivadasAsunto(s)
Neoplasias/metabolismo , Prostaglandina D2/análogos & derivados , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismo , Apoptosis/fisiología , Diferenciación Celular/fisiología , División Celular/fisiología , Humanos , Neoplasias/patología , Prostaglandina D2/fisiologíaRESUMEN
This study was undertaken to investigate the influence of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonists on the proliferation, apoptosis and tumorigenesis of breast cancer cells. PPARgamma investigation has been largely restricted to adipose tissue, where it plays a key role in differentiation, but recent data reveal that PPARgamma is expressed in several transformed cells. However, the function of PPARgamma activation in neoplastic cells is unclear. Activation of PPARgamma with the known prostanoid agonist 15-deoxy-Delta12,14-prostaglandin J(2) (15dPGJ(2)) or the thiazolidinedione (TZD) agonist troglitazone (TGZ) attenuated cellular proliferation of the estrogen receptor-negative breast cancer cell line MDA-MB-231, as well as the estrogen receptor-positive breast cancer cell line MCF-7. This was marked by a decrease in total cell number and by an inhibition of cell cycle progression. Addition of 15dPGJ(2) was not associated with an increase in cellular differentiation, as has been seen in other neoplastic cells, but rather induction of cellular events associated with programmed cell death, apoptosis. Video time-lapse microscopy revealed that 15dPGJ(2) induced morphological changes associated with apoptosis, including cellular rounding, blebbing, the production of echinoid spikes, blistering and cell lysis. In contrast, TGZ caused only a modest induction of apoptosis. These results were verified by histochemistry using the specific DNA stain DAPI to observe nuclear condensation, a marker of apoptosis. Finally, a brief exposure of MDA-MB-231 cells to 15dPGJ(2) initiated an irreversible apoptotic pathway that inhibited the growth of tumors in a nude mouse model. These findings illustrate that induction of apoptosis may be the primary biological response resulting from PPARgamma activation in some breast cancer cells and further suggests a potential role for PPARgamma ligands for the treatment of breast cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Transformación Celular Neoplásica/efectos de los fármacos , Prostaglandina D2/análogos & derivados , Animales , Secuencia de Bases , Diferenciación Celular/efectos de los fármacos , División Celular , Cartilla de ADN , Humanos , Ratones , Prostaglandina D2/farmacología , ARN Mensajero/genética , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Células Tumorales CultivadasRESUMEN
Recent studies have demonstrated that arachidonic acid (AA) may serve as an important signal that blocks cell proliferation of certain neoplastic cells. The current study was conducted to determine whether disruption of AA homeostasis influences breast cancer cell proliferation and death. Initial experiments revealed that inhibition of AA remodeling through membrane phospholipids by inhibitors of the enzyme, coenzyme A-independent transacylase (CoA-IT), attenuates the proliferation of the estrogen receptor-negative, MDA-MB-231, and estrogen receptor-positive, MCF-7 breast cancer cell lines. This growth inhibition was accompanied by a marked accumulation of AA in both free fatty acid and triglyceride forms, a marker of intracellular AA stress within mammalian cells. Cell cycle synchronization experiments revealed that the CoA-IT inhibitor, SB-98625, blocked MDA-MB-231 cell replication in early to mid G1 phase. Time-lapse video microscopy, used to observe the changes in cell morphology associated with apoptosis, indicated that SB-98625 treatment induced early rounding and occasional blebbing but not late apoptotic events, blistering, and lysis. The cyclooxygenase inhibitors, NS-398 and indomethacin, were found to be less potent blockers of cell proliferation and poor inducers of cellular AA accumulation than CoA-IT inhibitors in these breast cancer cell lines. Finally, AA provided exogenously blocked the proliferation of MCF-7 cells, and this effect could be attenuated in MCF-7 cells overexpressing the glutathione peroxidase gene, GSHPx-1. Taken together, these experiments suggest that disruption of AA remodeling in a manner that increases intracellular AA may represent a novel therapeutic strategy to reduce cancer cell proliferation and that an oxidized AA metabolite is likely to mediate this effect.
Asunto(s)
Aciltransferasas/antagonistas & inhibidores , Apoptosis , Ácido Araquidónico/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/farmacología , Aciltransferasas/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Ácidos Grasos no Esterificados/farmacología , Humanos , Distribución Tisular , Células Tumorales CultivadasRESUMEN
Immunologic function, particularly cell-mediated immunity, declines with age, contributing to the increased incidence of infectious diseases in the elderly. Nutrition may play a pivotal role in maintaining immune competence in older adults. Most studies to date have focused on micronutrient deficiencies and supplementation, sometimes using "mega-dose" formulations. Multivitamin/mineral supplements or specific micronutrients such as zinc and vitamin E may be of value; however, data suggest there is likely a therapeutic range for many micronutrients, and oversupplementation may be harmful. Specific alterations of dietary lipids may also be useful for modulating immune responses in the elderly. This review summarizes the prevalence of vitamin and mineral deficiencies in older adults and highlights the outcomes of trials of micronutrient supplementation to augment immune function in the elderly.
Asunto(s)
Envejecimiento/inmunología , Suplementos Dietéticos , Micronutrientes , Minerales/administración & dosificación , Vitaminas/administración & dosificación , Anciano , Anciano de 80 o más Años , Avitaminosis/epidemiología , Enfermedades Carenciales/epidemiología , HumanosRESUMEN
A link between infectious agents and atherosclerosis has been postulated for decades. This review describes the epidemiological and biological evidence linking cytomegalovirus and Chlamydia pneumoniae to atherosclerotic disease. Case-control studies and histologic evidence from atheromatous specimens support an association between atherosclerosis and infection with these two microorganisms, and small interventional trials appear to confirm the link with C. pneumoniae, but these findings require confirmation in larger studies. A lack of clinically relevant animal models has hampered investigations regarding biological mechanisms, particularly for C. pneumoniae.
Asunto(s)
Arteriosclerosis/microbiología , Arteriosclerosis/virología , Infecciones por Chlamydia/complicaciones , Chlamydophila pneumoniae/patogenicidad , Infecciones por Citomegalovirus/complicaciones , Animales , Infecciones por Chlamydia/microbiología , Citomegalovirus/patogenicidad , Infecciones por Citomegalovirus/virología , Humanos , MasculinoRESUMEN
Although adults aged 65 years and older constitute the most rapidly growing segment of the U.S. population, geriatric issues have not typically been a focus of training in infectious diseases (ID). Underrecognition of the unique aspects of geriatric care, apathy toward this population, and the feeling that "we're all geriatricians" (and thus know geriatric medicine) all contribute to this problem. This article summarizes the recent meeting focused on integrating geriatric principles within ID training at all levels. The ID/geriatric interface as an attractive area for basic and clinical research is emphasized.
Asunto(s)
Certificación , Enfermedades Transmisibles , Educación Médica Continua , Educación Médica , Geriatría/educación , Investigación/educación , Especialización , Adulto , HumanosRESUMEN
Cyclosporin A, tacrolimus, and sirolimus are immunosuppressive agents initially described as antifungal compounds with different activities for Aspergillus species. The outcome of invasive aspergillosis in mice treated with each agent was investigated in outbred CD-1 mice. Immunosuppressant or vehicle alone was administered from days -1 to +14. Mice were infected on day 0 with resting Aspergillus conidia via lateral tail vein injection. Survival was significantly greater with most regimens than for mice treated with cyclosporin A (100 mg/kg/day; median survival, 3 days): tacrolimus, 1 mg/kg/day (6.5 days, P = .003); sirolimus, 1 or 10 mg/kg/day (7.5 and 9.5 days, respectively; P = .002 and .0001); and vehicle alone (6.5 days, P = .001). However, mice treated with 10 mg/kg/day of tacrolimus survived a median of 4.5 days (P = .25). Survival in the 10-mg sirolimus group did not differ from that of mice given vehicle alone (P = .55). Histologic evaluation suggested the improved survival with tacrolimus and sirolimus may be due in part to direct anti-Aspergillus activity.
Asunto(s)
Aspergilosis/microbiología , Aspergillus/efectos de los fármacos , Ciclosporina/farmacología , Inmunosupresores/farmacología , Polienos/farmacología , Tacrolimus/farmacología , Animales , Antifúngicos/farmacología , Aspergilosis/inmunología , Encéfalo/microbiología , Ratones , SirolimusRESUMEN
The records of 206 patients with advanced infection due to human immunodeficiency virus type 1 who were receiving prophylaxis with clindamycin/primaquine (C/P), trimethoprim-sulfamethoxazole (TMP-SMZ), or dapsone to prevent Pneumocystis carinii pneumonia (PCP) were retrospectively examined. Two hundred sixty-two patient-years of prophylaxis were accrued (176.2 of TMP-SMZ, 63.4 of dapsone, and 22.8 of C/P). The rates of PCP in the TMP-SMZ, dapsone, and C/P groups were 3.4, 11.0, and 30.7 per 100 patient-years, respectively. Pairwise comparisons showed C/P to be less effective than TMP-SMZ (relative risk [RR], 9.02; 95% confidence interval [CI], 3.03-26.83). A similar trend was apparent for C/P vs. dapsone (RR, 2.78; 95% CI, 0.98-7.93). When only those receiving primary prophylaxis were analyzed, C/P recipients remained at greater risk than TMP-SMZ recipients (RR, 13.19; 95% CI, 3.54-49.12) and dapsone recipients (RR, 3.85; 95% CI, 1.12-13.31). Failure of C/P prophylaxis could be due, at least in part, to underdosing (clindamycin, 300 mg/d; primaquine, 15 mg/d). C/P recipients had more nonspecific diarrhea than did TMP-SMZ recipients (RR, 2.99; 95% CI, 1.61-5.55).
Asunto(s)
Antibacterianos/uso terapéutico , Antimaláricos/uso terapéutico , Clindamicina/uso terapéutico , Infecciones por VIH/complicaciones , VIH-1 , Neumonía por Pneumocystis/tratamiento farmacológico , Neumonía por Pneumocystis/prevención & control , Primaquina/uso terapéutico , Adulto , Antibacterianos/efectos adversos , Antiinfecciosos/efectos adversos , Antiinfecciosos/uso terapéutico , Antimaláricos/efectos adversos , Recuento de Linfocito CD4 , Clindamicina/efectos adversos , Dapsona/efectos adversos , Dapsona/uso terapéutico , Diarrea/complicaciones , Diarrea/diagnóstico , Diarrea/microbiología , Hipersensibilidad a las Drogas , Quimioterapia Combinada , Femenino , Enfermedades Gastrointestinales/complicaciones , Enfermedades Hematológicas/complicaciones , Humanos , Masculino , Primaquina/efectos adversos , Estudios Retrospectivos , Combinación Trimetoprim y Sulfametoxazol/efectos adversos , Combinación Trimetoprim y Sulfametoxazol/uso terapéuticoAsunto(s)
Antiinfecciosos/toxicidad , Ciclosporina/toxicidad , Inmunosupresores/toxicidad , Polienos/toxicidad , Tacrolimus/toxicidad , Animales , Antiinfecciosos/uso terapéutico , Antivirales/toxicidad , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Infecciones Bacterianas/tratamiento farmacológico , Ciclosporina/uso terapéutico , VIH/efectos de los fármacos , Humanos , Inmunosupresores/uso terapéutico , Enfermedades Parasitarias/tratamiento farmacológico , Polienos/uso terapéutico , Sirolimus , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Tacrolimus/uso terapéutico , Virosis/tratamiento farmacológicoRESUMEN
The activities of the immunosuppressive, antifungal compounds cyclosporin A (CsA), FK-506, and rapamycin are dependent upon high affinity binding proteins collectively termed immunophilins. We report the isolation, biochemical characterization, and amino acid sequences of two major CsA-binding proteins, cyclophilins, from the pathogenic protozoan, Toxoplasma gondii. The 18.5- and 20-kDa molecular mass proteins exhibit peptidylproline cis-trans-isomerase activity, which is inhibitable by 10(-8) M CsA. The amino acid sequences of these two proteins, deduced from cDNA clones, reveal up to 70% amino acid identity to previously isolated cyclophilins. The 18.5-kDa protein appears to be synthesized as a precursor with a 15 amino acid signal peptide. The amino-terminal region of the mature 20-kDa protein has significant homology to the B subunit of the calmodulin-dependent phosphatase, calcineurin. The two T. gondii cyclophilins are products of different genes and appear to have different subcellular distributions.
Asunto(s)
Isomerasas de Aminoácido/genética , Proteínas Portadoras/genética , Genes Protozoarios , Proteínas Protozoarias/genética , Toxoplasma/inmunología , Isomerasas de Aminoácido/antagonistas & inhibidores , Isomerasas de Aminoácido/química , Isomerasas de Aminoácido/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Calcineurina , Proteínas de Unión a Calmodulina/química , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Compartimento Celular , Ciclosporinas/metabolismo , Ciclosporinas/farmacología , Cartilla de ADN/química , ADN Complementario , Humanos , Datos de Secuencia Molecular , Isomerasa de Peptidilprolil , Fosfoproteínas Fosfatasas/química , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Toxoplasma/genéticaRESUMEN
BACKGROUND: The incidence of infection increases with the prolonged use of central vascular catheters, but it is unclear whether changing catheters every three days, as some recommend, will reduce the rate of infection, It is also unclear whether it is safer to change a catheter over a guide wire or insert it at a new site. METHODS: We conducted a controlled trial in adult patients in intensive care units who required central venous or pulmonary-artery catheters for more than three days. Patients were assigned randomly to undergo one of four methods of catheter exchange: replacement every three days either by insertion at a new site (group 1) or by exchange over a guide wire (group 2), or replacement when clinically indicated either by insertion at a new site (group 3) or by exchange over a guide wire (group 4). RESULTS: Of the 160 patients, 5 percent had catheter-related bloodstream infections, 16 percent had catheters that became colonized, and 9 percent had major mechanical complications. The incidence rates (per 1000 days of catheter use) of bloodstream infection were 3 in group 1, 6 in group 2, 2 in group 3, and 3 in group 4; the incidence rates of mechanical complications were 14, 4, 8, and 3, respectively. Patients randomly assigned to guide-wire-assisted exchange were more likely to have bloodstream infection after the first three days of catheterization (6 percent vs. 0, P = 0.06). Insertions at new sites were associated with more mechanical complications (5 percent vs. 1 percent, P = 0.005). CONCLUSIONS: Routine replacement of central vascular catheters every three days does not prevent infection. Exchanging catheters with the use of a guide wire increases the risk of bloodstream infection, but replacement involving insertion of catheters at new sites increases the risk of mechanical complications.
Asunto(s)
Cateterismo Venoso Central/métodos , Cateterismo/métodos , Arteria Pulmonar , Antisepsia , Bacteriemia/prevención & control , Bacterias/aislamiento & purificación , Cateterismo/efectos adversos , Cateterismo Venoso Central/efectos adversos , Catéteres de Permanencia/efectos adversos , Contaminación de Equipos , Falla de Equipo , Humanos , Factores de TiempoRESUMEN
We report a case of yeast perinephric abscess and review 11 other published cases. This rare entity occurs primarily in patients who have diabetes mellitus, who have recently undergone surgery, or who have urinary tract obstruction. The clinical illness is often subacute or chronic with nonspecific symptoms. Candida and Torulopsis species are the reported etiologic agents. Successful therapy usually consists of percutaneous or surgical drainage of the abscess. Overall mortality is 25%; however, no patient in this series died as a direct result of perinephric infection.