Remyelination after chronic spinal cord injury is associated with proliferation of endogenous adult progenitor cells after systemic administration of guanosine

Axonal demyelination is a consistent pathological sequel to chronic brain and spinal cord injuries and disorders that slows or disrupts impulse conduction, causing further functional loss. Since oligodendroglial progenitors are present in the demyelinated areas, failure of remyelination may be due to lack of sufficient proliferation and differentiation of oligodendroglial progenitors. Guanosine stimulates proliferation and differentiation of many types of cells in vitro and exerts neuroprotective effects in the central nervous system (CNS). Five weeks after chronic traumatic spinal cord injury (SCI), when there is no ongoing recovery of function, intraperitoneal administration of guanosine daily for 2 weeks enhanced functional improvement correlated with the increase in myelination in the injured cord. Emphasis was placed on analysis of oligodendrocytes and NG2-positive (NG2+) cells, an endogenous cell population that may be involved in oligodendrocyte replacement. There was an increase in cell proliferation (measured by bromodeoxyuridine staining) that was attributable to an intensification in progenitor cells (NG2+ cells) associated with an increase in mature oligodendrocytes (determined by Rip+ staining). The numbers of astroglia increased at all test times after administration of guanosine whereas microglia only increased in the later stages (14 days). Injected guanosine and its breakdown product guanine accumulated in the spinal cords; there was more guanine than guanosine detected. We conclude that functional improvement and remyelination after systemic administration of guanosine is due to the effect of guanosine/guanine on the proliferation of adult progenitor cells and their maturation into myelin-forming cells. This raises the possibility that administration of guanosine may be useful in the treatment of spinal cord injury or demyelinating diseases such as multiple sclerosis where quiescent oligodendroglial progenitors exist in demyelinated plaques

The creatine kinase system and pleiotropic effects of creatine

The pleiotropic effects of creatine (Cr) are based mostly on the functions of the enzyme creatine kinase (CK) and its high-energy product phosphocreatine (PCr). Multidisciplinary studies have established molecular, cellular, organ and somatic functions of the CK/PCr system, in particular for cells and tissues with high and intermittent energy fluctuations. These studies include tissue-specific expression and subcellular localization of CK isoforms, high-resolution molecular structures and structure–function relationships, transgenic CK abrogation and reverse genetic approaches. Three energy-related physiological principles emerge, namely that the CK/PCr systems functions as (a) an immediately available temporal energy buffer, (b) a spatial energy buffer or intracellular energy transport system (the CK/PCr energy shuttle or circuit) and (c) a metabolic regulator. The CK/PCr energy shuttle connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases). Thus, diffusion limitations of ADP and ATP are overcome by PCr/Cr shuttling, as most clearly seen in polar cells such as spermatozoa, retina photoreceptor cells and sensory hair bundles of the inner ear. The CK/PCr system relies on the close exchange of substrates and products between CK isoforms and ATP-generating or -consuming processes. Mitochondrial CK in the mitochondrial outer compartment, for example, is tightly coupled to ATP export via adenine nucleotide transporter or carrier (ANT) and thus ATP-synthesis and respiratory chain activity, releasing PCr into the cytosol. This coupling also reduces formation of reactive oxygen species (ROS) and inhibits mitochondrial permeability transition, an early event in apoptosis. Cr itself may also act as a direct and/or indirect anti-oxidant, while PCr can interact with and protect cellular membranes. Collectively, these factors may well explain the beneficial effects of Cr supplementation. The stimulating effects of Cr for muscle and bone growth and maintenance, and especially in neuroprotection, are now recognized and the first clinical studies are underway. Novel socio-economically relevant applications of Cr supplementation are emerging, e.g. for senior people, intensive care units and dialysis patients, who are notoriously Cr-depleted. Also, Cr will likely be beneficial for the healthy development of premature infants, who after separation from the placenta depend on external Cr. Cr supplementation of pregnant and lactating women, as well as of babies and infants are likely to be of benefit for child development. Last but not least, Cr harbours a global ecological potential as an additive for animal feed, replacing meat- and fish meal for animal (poultry and swine) and fish aqua farming. This may help to alleviate human starvation and at the same time prevent over-fishing of oceans

Transcriptome 3′end organization by PCF11 links alternative polyadenylation to formation and neuronal differentiation of neuroblastoma

In gene regulation, diversification at the transcriptome 3′end is linked to differentiation and dedifferentiation. Here, the authors discover extensive transcriptome 3′end-alterations in neuroblastoma, regulated by PCF11, and provide an interactive data repository of transcriptome-wide alternative polyadenylation

The Detection of Mupirocin Resistance and the Distribution of Methicillin-resistant Staphylococcus aureus at the University Hospital of the West Indies, Jamaica

Objectives: The objectives of this study were to determine the susceptibility of Methicillin Resistant Staphylococcus aureus (MRSA) isolates to Mupirocin and other antimicrobial agents and to record the prevalence and distribution of this organism at the University Hospital of the West Indies (UHWI). Methods: MRSA isolates collected between January 1, 2008 and December 31, 2008, were tested for low and high level resistance to Mupirocin. Susceptibility testing to other antibiotics including cotrimoxazole, minocycline, tetracycline, clindamycin, erythromycin, gentamicin and vancomycin was also done. Laboratory records for all patients from whom MRSA was recovered were reviewed and data on type and source of isolates, clinical diagnosis, history of previous hospitalization and use of mupirocin were extracted. In addition, the laboratory records for 2004 and 2005 were also reviewed to determine prevalence during these periods. Results: Seven per cent of Staphylococcus aureus isolates were resistant to methicillin (MRSA) and of these, 30% and 24% showed low level and high level resistance to mupirocin, respectively. Ninety-four per cent of MRSA strains were resistant to erythromycin while 52% showed resistance to clindamycin. Resistance to tetracycline, co-trimoxazole and minocycline was 27%, 12% and 6%, respectively, while about one-third of the isolates were resistant to gentamicin. There was no resistance to vancomycin. More than half (58%) of the isolates were from skin and soft tissue specimens while isolates from respiratory and urinary tracts and the bloodstream accounted for 19%, 13% and 4%, respectively. There has been a steady increase in prevalence from 4% in 2004 to 5% in 2007 and 7% in 2008. Conclusion: Resistance of MRSA to mupirocin appears to be an emerging problem at the UHWI and must be monitored carefully. There is also significant resistance to commonly used antimicrobial agents and strict adherence to antibiotic policy is required to preserve the usefulness of these agents. Keywords: Methicillin-resistant Staphylococcus aureus, Mupirocin, Resistant "Detección de la Resistencia a la Mupirocina y Distribución de Staphylococcus aureus Resistente a la Meticilina en el Hospital Universitario de West Indies, Jamaica" AM Nicholson, C Thoms, H Wint, M Didier, R Willis, N McMorris, D Castle, N Maharaj, FA Orrett RESUMEN Objetivos: Los objetivos de este estudio fueron determinar la susceptibilidad de aislados de Staphylococcus aureus resistentes (MRSA) frente a la mupirocina y otros agentes antimicrobianos, y grabar la prevalencia y distribución de este organismo en el Hospital Universitario de West Indies (UHWI). Métodos: Aislados de MRSA recogidos entre el 1ero. de enero de 2008 y el 31 de diciembre de 2008, fueron sometidos a prueba a fin de determinar sus niveles bajo y alto de resistencia a la mupirocina. También se investigó la susceptibilidad frente a otros antibióticos tales como co-trimoxazol, minociclina, tetraciclina, clindamicina, eritromicina, gentamicina y vancomicina. Se revisaron las historias de laboratorio de todos los pacientes de quienes de recobró MRSA, y se extrajeron datos sobre el tipo y fuente de los aislados, el diagnóstico clínico, la historia de hospitalización previa, y el uso de mupirocina. Además, se revisaron las historias clínicas delaboratorio de 2004 y 2005 a fin de determinar la prevalencia durante estos periodos. Resultados: Setenta por ciento de los ailados de estafilococo dorado era resistente a la meticilina (MRSA) y de éstos, 30% y 24% mostraron un bajo nivel y un alto nivel de resistencia a la mupirocina, respectivamente. Noventa y cuatro por ciento de las cepas de MRSA eran resistentes a la eritromicina, mientras que el 52% mostró resistencia a la clindamicina. La resistencia a la tetraciclina, el cotrimoxazol, y la minociclina fue de 27%, 12% y 6%, respectivamente, mientras que aproximadamente un tercio de los aislados eran resistentes a la gentamicina. No hubo resistencia a la vancomicina. Más de la mitad (58%) de los aislados procedían de especimenes de tejido blando y de la piel, mientras que los aislados de las vías respiratorias y urinarias así como del torrente sanguíneo constituyeron el 19%, 13% y 4%, respectivamente. Ha habido un aumento constante de la prevalencia de 4% en 2004 a 5% en 2007 y 7% en 2008. Conclusión: La resistencia de MRSA a la mupirocina parece ser un problema emergente en el HUWI y debe monitorearse cuidadosamente. Hay también una resistencia significativa a los agentes antimicrobianos normalmente usados y se requiere una adhesión estricta a la política antibiótica a fin de preservar la utilidad de estos agentes. Palabras claves: Staphylococcus aureus resistente a la meticilina, mupirocina, resistent