RESUMEN
AIM: To use meta-analytic techniques to quantitatively evaluate the efficacy of orlistat and lorcaserin in the treatment of people who are overweight and obese. METHODS: We identified publications from searches of electronic databases and extracted data from studies that compared orlistat or lorcaserin to lifestyle advice (standard care), placebo, sibutramine, rimonabant or metformin and collected information on waist circumference change or withdrawals due to adverse events (AEs). A mixed treatment comparison (MTC) meta-analysis was performed on the data extracted. RESULTS: Orlistat was found to be significantly better than placebo and standard care in reducing waist circumference at 6 and 12 months; orlistat reduced waist circumference by -6.96 cm [95% credible interval (CrI): -8.93, -4.96 cm] compared to standard care at 6 months. The results suggested that lorcaserin reduced waist circumference by a greater amount than all other interventions at 12 months, for example, lorcaserin lead to a greater reduction of -2.45 cm (95% CrI: -4.99, 0.08 cm) in comparison to placebo, although these differences were not statistically significant. Although data were very limited, metformin reduced waist circumference by a greater amount (-2.11 cm, 95% CI: -1.00, -3.22 cm) than orlistat at 6 months. On average, 6.5% of patients on orlistat and 5.4% of those on lorcaserin discontinued their treatment due to AEs at 12 months. CONCLUSIONS: Orlistat should be considered as an addition to lifestyle interventions in the treatment of obesity. Lorcaserin has recently been approved by the US Food and Drug Administration (FDA) and these results suggest that it is similar in both efficacy and safety compared to orlistat.
Asunto(s)
Fármacos Antiobesidad/administración & dosificación , Benzazepinas/administración & dosificación , Lactonas/administración & dosificación , Metformina/administración & dosificación , Obesidad/tratamiento farmacológico , Circunferencia de la Cintura/efectos de los fármacos , Fármacos Antiobesidad/efectos adversos , Benzazepinas/efectos adversos , Índice de Masa Corporal , Terapia Combinada , Esquema de Medicación , Femenino , Humanos , Lactonas/efectos adversos , Masculino , Metformina/efectos adversos , Orlistat , Conducta de Reducción del Riesgo , Resultado del Tratamiento , Pérdida de Peso/efectos de los fármacosRESUMEN
BACKGROUND: Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons. METHODS: The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale-Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly. RESULTS: Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50% or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23% unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials. CONCLUSION: Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Creatina/uso terapéutico , Adolescente , Adulto , Anciano , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/orina , Creatina/efectos adversos , Creatina/orina , Método Doble Ciego , Femenino , Humanos , Contracción Isométrica , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
A majority of psychiatric medications are known to generate weight gain and ultimately obesity in some patients. The authors undertook a comprehensive literature review in order to provide a better understanding of novel treatment options in regards to alleviating weight gained by use of antidepressants, antipsychotics, and mood stabilizers. There are no agents for management of this weight gain approved by the Food and Drug Administration (FDA), and existing studies on options are mainly uncontrolled, small-scale projects with limited power to produce coherent conclusions. There is a clear need for larger studies on existing options, and future psychotropics without these side-effects are currently in the pipeline.
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Antidepresivos/efectos adversos , Antipsicóticos/efectos adversos , Obesidad/inducido químicamente , Fármacos Antiobesidad/uso terapéutico , Antidepresivos/administración & dosificación , Antipsicóticos/administración & dosificación , Dieta , Humanos , Estilo de Vida , Trastornos Mentales/tratamiento farmacológico , Obesidad/epidemiología , Obesidad/prevención & control , Obesidad/terapia , Aumento de Peso/efectos de los fármacosRESUMEN
The crown gall opines heliopine from tumors induced by octopine type Agrobacterium tumefaciens strains A6, A136(pTiB6-806), E9, A652 and 1590-1 and vitopine from tumor induced by grapevine strains S4 and T2 are identical to synthetic N2-(1'R-carboxyethyl)-L-glutamine. Tumors produced by strains S4 and T2 do not contain octopine or lysopine, but they do contain heliopine and the new opine ridéopine identified as N-(4'-aminobutyl)-D-glutamic acid. Grapevine strains S4 and T2 grow normally on tumor heliopine or synthetic heliopine and on tumor and synthetic ridéopine as well as on ridéopine lactam as sole carbon source. While octopine strains A6 and A136(pTiB6-806) do not grow on heliopine, mutant colonies do appear after a few weeks. Heliopine catabolism by octopine strains is not induced by octopine.
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Agrobacterium tumefaciens/patogenicidad , Glutamina/análogos & derivados , Glutamina/química , Enfermedades de las Plantas/microbiología , Vitis/fisiología , Glutamina/farmacología , Helianthus/microbiología , Espectroscopía de Resonancia Magnética/métodos , Conformación Molecular , Estructura Molecular , Tumores de Planta/inducido químicamente , Tumores de Planta/microbiología , Plásmidos , Vitis/microbiologíaRESUMEN
The functional diversity of gap junction intercellular channels arising from the large number of connexin isoforms is significantly increased by heterotypic interactions between members of this family. This is particularly evident in the rectifying behavior of Cx26/Cx32 heterotypic channels (. Proc. Natl. Acad. Sci. USA. 88:8410-8414). The channel properties responsible for producing the rectifying current observed for Cx26/Cx32 heterotypic gap junction channels were determined in transfected mouse neuroblastoma 2A (N2A) cells. Transfectants revealed maximum unitary conductances (gamma(j)) of 135 pS for Cx26 and 53 pS for Cx32 homotypic channels in 120 mM KCl. Anionic substitution of glutamate for Cl indicated that Cx26 channels favored cations by 2.6:1, whereas Cx32 channels were relatively nonselective with respect to charge. In Cx26/Cx32 heterotypic cell pairs, the macroscopic fast rectification of the current-voltage relationship was fully explained at the single-channel level by a rectifying gamma(j) that increased by a factor of 2.9 as the transjunctional voltage (V(j)) changed from -100 to +100 mV with the Cx26 cell as the positive pole. A model of electrodiffusion of ions through the gap junction pore based on Nernst-Planck equations for ion concentrations and the Poisson equation for the electrical potential within the junction is developed. Selectivity characteristics are ascribed to each hemichannel based on either pore features (treated as uniform along the length of the hemichannel) or entrance effects unique to each connexin. Both analytical GHK approximations and full numerical solutions predict rectifying characteristics for Cx32/Cx26 heterotypic channels, although not to the full extent seen empirically. The model predicts that asymmetries in the conductance/permeability properties of the hemichannels (also cast as Donnan potentials) will produce either an accumulation or a depletion of ions within the channel, depending on voltage polarity, that will result in rectification.
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Conexinas/metabolismo , Uniones Comunicantes/metabolismo , Canales Iónicos/metabolismo , Animales , Fenómenos Biofísicos , Biofisica , Línea Celular , Conexina 26 , Conexinas/genética , Conductividad Eléctrica , Femenino , Técnicas In Vitro , Activación del Canal Iónico , Canales Iónicos/genética , Ratones , Modelos Biológicos , Oocitos/metabolismo , Transfección , Xenopus , Proteína beta1 de Unión ComunicanteRESUMEN
The biosynthesis of DIMBOA, a pesticidal secondary metabolite of maize, branches off the tryptophan pathway. We have previously demonstrated that indole is the last intermediate common to both the tryptophan and hydroxamic acid pathways. The earliest discovered mutant in the DIMBOA pathway, bxbx (benzoxazineless), is deficient in the production of DIMBOA and related compounds. This paper presents evidence that a gene identified by Kramer and Koziel [Kramer, V. C. & Koziel, M. G. (1995) Plant Mol. Biol. 27, 1183-1188] as maize tryptophan synthase alpha (TSA) is the site of the genetic lesion in the DIMBOA-deficient mutant maize line bxbx. We demonstrate that the TSA gene has sustained a 924-bp deletion in bxbx compared with its counterpart in wild-type maize. We report that the TSA gene maps to the same location as the bxbx mutation, on the short arm of chromosome 4. We present evidence that the very early and very high level of expression of TSA corresponds to the timing and level of DIMBOA biosynthesis but is strikingly different from the expression of the maize tryptophan synthase beta (TSB) genes. We show that feeding indole to bxbx seedlings restores their ability to synthesize DIMBOA. We conclude that the maize enzyme initially named tryptophan synthase alpha in fact is a DIMBOA biosynthetic enzyme, and we propose that it be renamed indole synthase. This work confirms and enlarges upon the findings of Frey et al. [Frey, M., Chomet, P., Glawischniq, E., Stettner, C., Grün, S., Winklmair, A., Eisenreich, W., Bacher, A., Meeley, R. B., Briggs, S. P., Simcox, K. & Gierl, A. (1997) Science 277, 696-699], which appeared while the present paper was in review.
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Oxazinas , Triptófano Sintasa/genética , Zea mays/genética , Benzoxazinas , Mapeo Cromosómico , Regulación Enzimológica de la Expresión Génica , Cinética , Mutación , Fenotipo , Triptófano/biosíntesis , Zea mays/enzimologíaRESUMEN
We describe a plant protoplast transformation method that provides transformants with a simple pattern of integration of a foreign gene. The approach is to deliver into plant protoplasts by direct gene transfer the Agrobacterium virulence genes virD1 and virD2 with or without virE2, together with a target plasmid containing a gene of interest flanked by Agrobacterium T-DNA border repeat sequences of 25 bp. We present evidence of T-DNA formation in maize protoplasts and its integration into the maize genome. The frequency of VirD1-VirD2-mediated integration events was about 20-35% of the total number of transformants. The addition of virE2 doubled the transformation efficiency. The method described here is of sufficient efficiency and simplicity to be useful for the production of transgenic plants with single-copy well-defined transgenic inserts.
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Proteínas Bacterianas/genética , ADN Bacteriano/genética , ADN de Cadena Simple/genética , Factores de Virulencia , Zea mays/genética , Proteínas Bacterianas/biosíntesis , Secuencia de Bases , ADN Bacteriano/metabolismo , ADN de Cadena Simple/metabolismo , Técnicas de Transferencia de Gen , Datos de Secuencia Molecular , Protoplastos , Secuencias Repetitivas de Ácidos Nucleicos , Rhizobium/genética , Rhizobium/patogenicidad , Virulencia , Zea mays/microbiologíaAsunto(s)
Plantas Modificadas Genéticamente , Zea mays , Animales , Seguridad , beta-Lactamasas/genéticaRESUMEN
We describe a novel plant transformation technique, termed "agrolistic," that combines the advantages of the Agrobacterium transformation system with the high efficiency of biolistic DNA delivery. Agrolistic transformation allows integration of the gene of interest without undesired vector sequence. The virulence genes virD1 and virD2 from Agrobacterium tumefaciens that are required in bacteria for excision of T-strands from the tumor-inducing plasmid were placed under the control of the CaMV35S promoter and codelivered with a target plasmid containing border sequences flanking the gene of interest. Transient expression assays in tobacco and in maize cells indicated that vir gene products caused strand-specific nicking in planta at the right border sequence, similar to VirD1/VirD2-catalyzed T-strand excision observed in Agrobacterium. Agrolistically transformed tobacco calli were obtained after codelivery of virD1 and virD2 genes together with a selectable marker flanked by border sequences. Some inserts exhibited right junctions with plant DNA that corresponded precisely to the sequence expected for T-DNA (portion of the tumor-inducing plasmid that is transferred to plant cells) insertion events. We designate these as "agrolistic" inserts, as distinguished from "biolistic" inserts. Both types of inserts were found in some transformed lines. The frequency of agrolistic inserts was 20% that of biolistic inserts.
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Agrobacterium tumefaciens/genética , Genes Bacterianos , Genes de Plantas , Plantas/genética , Transfección/genética , Vectores Genéticos , Datos de Secuencia MolecularRESUMEN
Connexins form a variety of gap junction channels that vary in their developmental and tissue-specific levels of expression, modulation of gating by transjunctional voltage and posttranslational modification, and unitary channel conductance (gamma j). Despite a 10-fold variation in gamma j, whether connexin-specific channels possess distinct ionic and molecular permeabilities is presently unknown. A major assumption of the conventional model for a gap junction channel pore is that gamma j is determined primarily by pore diameter. Hence, molecular size permeability limits should increase and ionic selectivity should decrease with increasing channel gamma j (and pore diameter). Equimolar ion substitution of 120 mmol/L KCl for potassium glutamate was used to determine the unitary conductance ratios for rat connexin40 and connexin43, chicken connexin43 and connexin45, and human connexin37 channels functionally expressed in communication-deficient mouse neuroblastoma (N2A) cells. Comparison of experimental and predicted conductance ratios based on the aqueous mobilities of all ions according to the Goldman-Hodgkin-Katz current equation was used to determine relative anion-to-cation permeability ratios. Direct correlation of junctional conductance with dye transfer of two fluorescein-derivatives (2 mmol/L 6-carboxyfluorescein or 2',7'-dichlorofluorescein) was also performed. Both approaches revealed a range of selectivities and permeabilities for all five different connexins that was independent of channel conductance. These results are not consistent with the conventional simple aqueous pore model of a gap junction channel and suggest a new model for connexin channel conductance and permselectivity based on electrostatic interactions. Divergent conductance and permeability properties are features of other classes of ion channels (eg, Na+ and K+ channels), implying similar mechanisms for selectivity.
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Conexinas/metabolismo , Uniones Comunicantes/metabolismo , Canales Iónicos/metabolismo , Animales , Northern Blotting , Células Cultivadas , Pollos , Conexinas/genética , Difusión , Conductividad Eléctrica , Electrofisiología , Fluoresceínas , Colorantes Fluorescentes , Uniones Comunicantes/fisiología , Vectores Genéticos , Humanos , Canales Iónicos/genética , Canales Iónicos/fisiología , Liposomas , Ratones , Modelos Anatómicos , Modelos Biológicos , Peso Molecular , Neuroblastoma , Técnicas de Placa-Clamp , Fosfatidiletanolaminas , Plásmidos/genética , Ratas , Sistemas de Mensajero Secundario , Propiedades de Superficie , TransfecciónRESUMEN
Inducible virulence (vir) genes of the Agrobacterium tumefaciens tumor-inducing (Ti) plasmid are under control of a two-component regulatory system. In response to environmental factors (phenolic compounds, sugars, pH) VirA protein phosphorylates VirG, which in turn interacts with the promoters of other vir genes, causing induction. A mutation of virG, virGN54D (which codes for a Asn-54-->Asp amino acid change in the product), causes constitutive expression of other vir genes independent of virA. We have investigated whether providing Agrobacterium with a plasmid containing virGN54D augments the efficiency of transfer of the T-DNA (transferred DNA). For both tobacco and cotton, we observed an enhancement of transformation efficiency when the inciting Agrobacterium strain carries the virGN54D mutation. We also tested whether supplying Agrobacterium with a similar plasmid containing wild-type virG affects the efficiency of T-DNA transfer. An intermediate efficiency was observed when this plasmid was employed. Using a beta-glucuronidase (GUS) reporter gene to assess transient expression of T-DNA after transfer to tobacco and maize tissues, we observed a higher frequency of GUS-expressing foci after inoculation with Agrobacterium strains carrying virGN54D than with Agrobacterium carrying the wild-type virG. Gene-transfer efficiency to maize by an octopine strain was greatly improved upon introduction of virGN54D. Multiple copies of wild-type virG were equally effective in promoting transient expression efficiency in tobacco but were virtually ineffective in maize. We propose the use of virGN54D to improve the efficiency of Agrobacterium-mediated transformation, especially for recalcitrant plant species.
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Agrobacterium tumefaciens/genética , Agrobacterium tumefaciens/patogenicidad , Transformación Celular Neoplásica , Proteínas de Unión al ADN , Genes Bacterianos/genética , Factores de Transcripción , Transformación Genética , Proteínas Bacterianas/genética , Regulación Bacteriana de la Expresión Génica , Gossypium/microbiología , Plantas Tóxicas , Nicotiana/microbiología , Transcripción Genética , Virulencia/genética , Zea mays/microbiologíaRESUMEN
A method is described for detecting plant metabolites capable of inducing the virulence genes of Agrobacterium tumefaciens. The method uses A. tumefaciens containing a plasmid with an inducible virulence gene fused to a galactosidase gene (virE::lacZ). Thin layer chromatography plates are overlayed with agar containing the indicator bacterium and a chromogenic galactoside (X-gal). Virulence gene inducing plant metabolites induce galactosidase which releases an aglycone readily oxidized by air to a blue pigmented zone at the Rf of the inducer. The method has been used to demonstrate the presence of virulence gene inducers in corn, wheat and rye. The uninduced background level of galactosidase also permits detection of bacterial growth inhibitors after a longer incubation period.
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Traumatismos en Atletas/terapia , Dolor de la Región Lumbar/terapia , Vértebras Lumbares/lesiones , Traumatismos en Atletas/tratamiento farmacológico , Terapia por Ejercicio , Humanos , Dolor de la Región Lumbar/tratamiento farmacológico , Traumatismos Vertebrales/tratamiento farmacológico , Traumatismos Vertebrales/terapiaRESUMEN
This paper presents the map and DNA sequence analysis of pRi8196 transferred DNA (T-DNA) genes encoding root-inducing and mannopine synthesis functions. A canonical 24-base-pair border repeat as well as two "pseudoborders" are present at the functional right T-DNA border. To the left of this border are homologs of the mas1' and mas2' genes of TR pRiA4. Next to these are five open reading frames (ORFs) homologous to ORFs 10-14 of TL of pRiA4. ORFs 10-12 (rolA, rolB, and rolC) are less related to their pRiA4 homologs than are the other large ORFs analyzed here. In contrast to T-DNA genes of pRiA4, pRi8196 T-DNA ORFs 11 and 12 (rolB and rolC) are sufficient to induce hairy roots on carrot disks.
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ADN Bacteriano/genética , Genes Bacterianos , Manitol/análogos & derivados , Plásmidos , Rhizobium/genética , Secuencia de Bases , Clonación Molecular , Manitol/metabolismo , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Plantas/microbiología , Mapeo Restrictivo , Rhizobium/metabolismo , Rhizobium/fisiologíaRESUMEN
Homogenates of corn seedlings inhibit both growth of Agrobacterium tumefaciens and induction of its Ti plasmid virulence (vir) genes by acetosyringone (AS). The heat-labile inhibitor has been identified as 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (DIMBOA), present in 2-week-old seedlings (B73) at a concentration of 1.5 mM or greater. A concentration of 0.3 mM DIMBOA is sufficient to block growth of A. tumefaciens completely for 220 hr. DIMBOA at 0.1 mM concentration completely inhibited vir gene induction by 100 microM AS and reduced growth rate by 50%. Thus, DIMBOA can be expected to have a significant effect on attempts to transform corn by using A. tumefaciens as a vector.