Ablation of galectin-3 induces p27(KIP1)-dependent premature senescence without oncogenic stress.

Premature senescence induced by oncogenic stimuli or tumor suppressor activation plays opposing roles in tumorigenesis. Here, we propose that galectin-3, a ß-galactoside-binding lectin, regulates premature senescence without oncogenic stress. We detected premature senescence, decreased Skp2, and increased p27(KIP1) expression in galectin-3 knockout MEFs and galectin-3-depleted gastric cancer cells. Interestingly, galectin-3 depletion did not affect other senescence inducers such as p14(ARF), p16(INK4A), and p21(WAF1/CIP1), suggesting that galectin-3-regulated senescence is p27(KIP1) dependent. We demonstrate that galectin-3 depletion decreases retinoblastoma protein (Rb) phosphorylation (Ser780, Ser807/811), cyclin D1 and CDK4 expression, and E2F1 transcriptional activation. Galectin-3 directly interacts with the cyclin D1/CDK4 complex and promotes hyperphosphorylation of Rb. It also blocks the inhibition of E2F1 transcription, thereby increasing the expression of Skp2 and reducing the stability of p27(KIP1) to promote the proliferation of gastric cancer cells. Xenograft mice with galectin-3-depleted gastric cancer cells display tumor growth retardation that is reversed by Skp2 overexpression. Increased expression of galectin-3 is also associated with the advanced TNM (tumor, lymph node, metastasis) system, clinicopathological stage, and lymph node metastases. The probability of survival was significantly decreased in gastric cancer patients with galectin-3(high) p27(KIP1-low)cells. Taken together, our results show that galectin-3 may accelerate gastric tumorigenesis by inhibiting premature senescence.

Evaluación de la opinión de los pacientes con enfermedad renal crónica en diálisis respecto al fin de la vida y la planificación anticipada de cuidados / Exploring the opinion of CKD patients on dialysis regarding, End-of-Life and Advance Care Planning

La implantación del proceso de planificación anticipada de cuidados y del documento de voluntades anticipadas (DVA) es escasa en España. Por este motivo, el Grupo de Ética y Nefrología de la Sociedad Española de Nefrología (S.E.N.) elaboró una encuesta para conocer la opinión de los pacientes en programa de diálisis sobre el DVA y otras situaciones relacionadas con el fin de la vida. Los pacientes recibieron documentación explicativa sobre la naturaleza y significado del DVA y un cuestionario sobre su conocimiento y aceptación. Se recogió su punto de vista sobre diversos aspectos relacionados con el fin de la vida. La encuesta se realizó en siete unidades de diálisis hospitalarias con un total de 416 pacientes en diálisis en activo. El cuestionario se entregó a 265 pacientes, 154 contestaron la encuesta, el 69,2% respondió sin ayuda. El grado de implantación del DVA era muy bajo (7,9%) y también la designación de representante (6,6%). Los pacientes tenían una idea muy clara sobre sus deseos ante situaciones como coma irresoluble, estado vegetativo, demencia irreversible y enfermedad grave no tratable y más de un 65% no deseaban que se les aplicaran ventilación mecánica, alimentación por sonda, diálisis o maniobras de resucitación en caso de parada cardiorrespiratoria. Muchos opinaron que el DVA podría hacerse antes de comenzar el tratamiento de diálisis, pero la mayoría consideró que sólo debería ofrecerse a aquellas personas que lo pidieran (el 65 frente al 34%). En conclusión, los pacientes en diálisis tienen una postura bastante definida ante diversas situaciones asociadas con el fin de la vida, sin embargo esta voluntad no está reflejada documentalmente debido a la escasa implantación de los DVA (AU)

Advance care planning (ACP) and the subsequent advance directive document (ADD), previously known as "living wills", have not been widely used in Spain. The Ethics Group from the Spanish Society of Nephrology has developed a survey in order to investigate the opinion of dialysis patients regarding the ADD and end-of-life care. Patients received documentation explaining ACP and filled out a survey about their familiarity with and approval of the ADD. Seven hospital dialysis centres participated in the study for a total of 416 active dialysis patients. Questionnaires were distributed to 263 patients, 154 of which answered (69.2% completed them without assistance). The rates for ADD implementation (7.9%) and designation of a representative person (6.6%) were very low. Most of the patients clearly expressed their wishes about irreversible coma, vegetative state, dementia and untreatable disease. More than 65% did not want mechanical ventilation, chronic dialysis, tube feeding or resuscitation if cardiorespiratory arrest occurred. They reported that an ADD could be done before starting dialysis but most thought that it should be offered only to those who requested it (65% vs 34%). In conclusion, patients have clear wishes about end-of-life care, although these desires had not been documented due to the very low implementation of the ADD (AU)

Mechanisms of pain in distal symmetric polyneuropathy: a combined clinical and neurophysiological study.

In patients with distal symmetric polyneuropathy we assessed non-nociceptive Abeta- and nociceptive Adelta-afferents to investigate their role in the development of neuropathic pain. We screened 2240 consecutive patients with sensory disturbances and collected 150 patients with distal symmetric polyneuropathy (68 with pain and 82 without). All patients underwent the Neuropathic Pain Symptom Inventory to rate ongoing, paroxysmal and provoked pains, a standard nerve conduction study (NCS) to assess Abeta-fibre function, and laser-evoked potentials (LEPs) to assess Adelta-fibre function. Patients with pain had the same age (P>0.50), but a longer delay since symptom onset than those without (P<0.01). Whereas the LEP amplitude was significantly lower in patients with pain than in those without (P<0.0001), NCS data did not differ between groups (P>0.50). LEPs were more severely affected in patients with ongoing pain than in those with provoked pain (P<0.0001). Our findings indicate that the impairment of Abeta-fibres has no role in the development of ongoing or provoked pain. In patients with ongoing pain the severe LEP suppression and the correlation between pain intensity and LEP attenuation may indicate that this type of pain reflects damage to nociceptive axons. The partially preserved LEPs in patients with provoked pain suggest that this type of pain is related to the abnormal activity arising from partially spared and sensitised nociceptive terminals. Because clinical and neurophysiological abnormalities followed similar patterns regardless of aetiology, pain should be classified and treated on mechanism-based grounds.

Estrategias en salud renal: un proyecto de la Sociedad Española de Nefrología / No disponible

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4-1 BB stimulation inhibits allergen-specific immunoglobulin E production and airway hyper-reactivity but partially suppresses bronchial eosinophilic inflammation in a mouse asthma model.

BACKGROUND: 4-1 BB, a member of the tumour necrosis factor receptor superfamily, functions as a co-stimulatory molecule. Recently, stimulation of the 4-1 BB pathway was shown to suppress antigen-specific CD4(+) T cell and subsequent T cell-dependent humoral immune responses. OBJECTIVE: We examined the effect of agonistic anti-4-1 BB monoclonal antibody (mAb) treatment on allergic asthma, in which allergen-specific type 2 helper T cells (Th2) have been shown to play an important role. METHODS: BALB/c mice were systemically sensitized with intraperitoneal injections of ovalbumin (OVA) and alum on days 0 and 14, and then challenged with inhaled OVA on days 28, 29 and 30. In test groups, the agonistic anti-4-1 BB mAb was administered at the time of initial systemic sensitization with OVA. On day 31, mice were challenged with inhaled methacholine, and enhanced pause was measured as an index of airway hyper-responsiveness (AHR). Levels of OVA-specific IgE in serum, and levels of various cytokines in bronchoalveolar lavage (BAL) fluids were measured. The severity of airway inflammation was determined by differential cell counts in BAL fluids and histopathologic lung analysis. To evaluate local immunity, we cultured lymphocytes from draining perihilar lymph nodes and evaluated the proliferative response to OVA and the levels of IL-5 in the culture supernatant. In addition, the functional mechanism of 4-1 BB stimulation was evaluated in splenocytes obtained at day 7 after systemic OVA sensitization. RESULTS: We found that treatment with the anti-4-1 BB mAb significantly decreased AHR and the production of allergen-specific IgE. Bronchial inflammation, however, had only partially improved and the levels of IL-4 and IL-5 in BAL fluids showed only a small degree of reduction compared with the control Ig-treated mice. Thoracic lymphocytes from anti-4-1 BB-treated mice showed significant suppression of OVA-induced proliferation and IL-5 production. In anti-4-1 BB-treated mice, splenocytes exhibited poor proliferation and marked apoptosis 7 days after systemic OVA challenge. CONCLUSION: These results suggest that stimulation of the 4-1 BB pathway effectively suppresses some features of allergic asthma, including allergen-specific IgE production and AHR, through deletion of allergen-specific Th2 cells. However, we found that bronchial allergic inflammation was not strictly mediated by suppression of the Th2 immune response in this murine model of asthma. Despite these somewhat contradictory effects, intervention in the 4-1 BB pathway might provide a potential novel immunotherapeutic approach for treatment of allergic asthma.

Análise da relação entre mudanças posturais na coluna e alterações visuais / Analysis of relation between spine postural changes and eye troubles

Durante muito tempo o olho foi visto apenas como um órgão receptor de estímulos visuais. Atualmente, numerosos estudos têm demonstrado o papel do olho como participante do controle do sistema postural e, portanto, a influência da visão no posicionamento corporal. Este trabalho tem como objetivo analisar se uma população com desvantagens visuais pode sofrer alterações no ajuste postural, o que poderia ocasionar mudanças no alinhamento corporal e deformidades na coluna. A amostra estudada foi composta por 29 pacientes, de ambos os sexos, na faixa etária de 10 a 38 anos. Os integrantes foram encaminhados para consulta oftalmológica completa e submetidos a exames radiográficos da coluna, avaliação fotográfica e postural. Os dados obtidos foram analisados e relacionados através de recursos da estatística descritiva. Os achados sugerem existir efetivamente uma relação entre mudanças posturais e distúrbios visuais, no entanto não podemos confirmar a influência direta da visão nas alterações posturais. Desta forma, propomos a realização de novos estudos e uma maior integração entre oftalmologistas e fisioterapeutas.

For a long time the eye was seen only as a recipient organ of visual stimulus. Nowadays many studies have demonstrated the eye function as a participant in the control of the posture system and therefore the influence of vision in the body posture. Therefore, the main purpose of this study was to analyze if a population with visual disadvantage can suffer alterations in the posture adjustment that may cause changes in the body alignment and deformity in the spinal cord. The study group was composed by 29 patients, from both sex, 10 to 38 years old. These patients were directed for a complete ophthalmologic consultation, radiographic exam of spinal cord, photographic and postural evaluation. The results were analyzed and related through descriptive statistic analyses. The final result suggests that exists a relation between postural changes and eye troubles, but we cannot confirm the direct influence of the vision in the postural alterations. In this case, we suggest the development of a new study and a better integration between ophthalmologist and physical therapist.

Reconocimiento de factor de impacto: el nuevo reto de 'Archivos de la Sociedad Española de Oftalmología' / Impact factor recognition: a new challenge for 'Archivos de la Sociedad Española de Oftalmología'

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Blockade of 4-1BB (CD137)/4-1BB ligand interactions increases allograft survival.

We investigated the role of 4-1BB, a T cell co-stimulatory molecule, in alloimmune responses. In vivo mixed lymphocyte reactions showed that 4-1BB was preferentially expressed on actively dividing CD4(+) and CD8(+) T cells. Furthermore, following alloantigen challenge, the draining lymph nodes contained subpopulations of 4-1BB-expressing CD4(+) and CD8(+) T cells. 4-1BB-deficient C57BL/6 mice showed a delayed rejection of cardiac transplants mismatched for the major histocompatibility complex. Longer transplant survival was induced by blockade of 4-1BB/4-1BB ligand (4-1BBL) interactions using an anti-4-1BBL monoclonal antibody. Histological analysis showed that prolonged transplant survival in the 4-1BB-deficient and anti-4-1BBL-treated mice correlated with reduced lymphocytic infiltration and vasculitis in the donor heart tissue. Taken together, our data suggest that blockade of 4-1BB/4-1BBL interactions inhibited the expansion of alloreactive T cells and reduced CTL activity against host alloantigen, which in turn resulted in the prolongation of allograft survival. Blockade of the 4-1BB co-stimulatory pathway may be useful for preventing allograft rejection.

Contaminación de la cánula de aspiración en artroplastía total de cadera / Suction tip contamination in total hip arthroplasty

La infección periprotésica es una de las complicaciones más devastadoras de la artroplastía total de cadera. Un alto porcentaje de éstas se originan por contaminación intraoperatoria. Uno de los factores involucrados en esta contaminación sería la cánula de aspiración. Se realizó un estudio prospectivo para determinar la contaminación de las cánulas de aspiración en artroplastía total de cadera. Se estudiaron 60 pacientes sometidos a artroplastía total de cadera primaria por atrosis. Se utilizó aspiración continua con cánula desechable tipo Yankauer, la que se cultivó al cabo de una hora de cirugía. De las sesenta cánulas cultivadas, en 13 (21,6 por ciento) hubo desarrollo de bacterias, siendo la bacteria identificada con mayor frecuencia el estafilococo coagulasa negativo (76,9 por ciento). No existieron evidencias de complicaciones infecciosas en ninguno de los pacientes, tanto en el postoperatorio inmediato como alejado (8-24 meses). Concluimos que el uso prolongado de una cánula de aspiración puede ser una potencial fuente de contaminación en artroplastía total de cadera

Capillary electrophoretic profiling and pattern recognition analysis of urinary nucleosides from uterine myoma and cervical cancer patients.

Capillary electrophoretic (CE) profiling analysis combined with pattern recognition methods is described for the correlation between urinary nucleoside profiles and uterine cervical cancer. Nucleosides were extracted from urine specimens by solid-phase extraction in affinity mode using phenylboronic acid gel. CE separation was carried out with an uncoated fused-silica capillary (570 mm x 50 microm I.D.) maintained at 20 degrees C, using 25 mM borate-42.5 mM phosphate buffer (pH 6.7) containing 200 mM sodium dodecyl sulfate as the run buffer under the applied voltage of 20 kV. A total of 15 nucleosides were positively identified in urine samples (2 ml) from eight uterine myoma (benign tumor group), 10 uterine cervical cancer (malignant tumor group) patients and 10 healthy females (normal group) studied. The star symbol plots drawn based on each mean concentration of nucleosides normalized to that in normal group enabled one to discriminate malignant and benign groups from normal group. In addition, canonical discriminant analysis performed on the nucleoside data of 28 individual urine specimens correctly classified into three separate clusters according to groups in the canonical plot.

Preparation and characterization of the micelle-forming polymeric drug indomethacin-incorporated poly(ethylene oxide)-poly(beta-benzyl L-aspartate) block copolymer micelles.

To estimate the feasibility of novel containers for drugs, poly(ethylene oxide)-poly(beta-benzyl L-aspartate) (PEO-PBLA) micelles were prepared by dialysis against water using different solvents. The solvent selected is very important because it drastically affects the stability of polymeric micelles. The critical micelle concentration (cmc) of the prepared micelles in distilled water was determined by a fluorescence probe technique using pyrene. Indomethacin (IMC) as a model drug was incorporated into the micelles by dialysis and an oil/water emulsion method. Characteristics of PEO-PBLA micelles without and with the physically trapped IMC in the inner core of the micelles (IMC/PEO-PBLA) were studied by dynamic light scattering and gel permeation chromatography/HPLC as well as an in vitro release test of IMC from the micelles. For the PEO-PBLA block copolymers, N,N-dimethylacetamide (DMAc) was found to be the best of the solvents tested to form stable polymeric micelles with a narrow size distribution and avoid its aggregation, and the cmc of PEO-PBLA micelles thus prepared was determined to be ca. 18 mg/L in water. The diameters of PEO-PBLA micelles and IMC/PEO-PBLA micelles in number averaged scale were observed to be ca. 19 and 25-29 nm, respectively. The release study of IMC from IMC/PEO-PBLA micelles in various buffer solutions at the pH range from 1.2 to 7.4 at 37 degrees C revealed that the release rate of IMC from the micelles was increased by increasing the pH of the medium and indicated that the release rate of IMC from the micelles are controlled by the partition coefficient of IMC based on the pH of the medium and interaction between IMC and the hydrophobic portion of the micelles.

Current methods of estimating severity for occupational injuries and illnesses: data from the 1986 Michigan Comprehensive Compensable Injury and Illness Database.

National and state estimates of the severity of occupational injuries and illnesses (severity = lost work time = missed work days+restricted work days) have come from the annual Survey of Occupational Injuries and Illnesses (Survey) produced by the U.S. Bureau of Labor Statistics. However, we show that the Survey practice of collecting injury information soon after the accident year reduces substantially the accuracy of missed work day estimates, which constitute 85.3% of the Survey lost work time estimate. To develop an independent estimate of missed work days, the research team created the Michigan Comprehensive Compensable Occupational Injury Database (Michigan Database) by linking state files with injury characteristics to files with workers' compensation information for injuries occurring in 1986. The measure of missed work time (days, weeks, or years) is the cumulative duration of compensation from the "date disability commenced," noted on the first payment form, through follow-up to March 1, 1990. Cumulative missed work time has been calculated or estimated for 72,057 injured workers, more than 97% of the 73,609 Michigan workers with compensable occupational injuries in 1986 identified through the close of the study. Our "best" estimate of missed work days, to follow-up, attributable to both fatal and nonfatal compensable occupational injuries and illnesses is 7,518,784, a figure four times that reported for Michigan by the Survey. When insurance industry data on disbursements are also considered, the estimate of missed work days increases to 8,919,079, a figure 4.75 times that reported by the Survey. When insurance data on reserves for future payments are also considered, the estimate of missed work days increases to 16,103,398, a figure 8.58-fold greater than that obtained for Michigan in the Survey. The Michigan data suggest that the national Survey may have failed to identify almost 373 million of 421 million missed work days in the private sector that have resulted, or will result, from 1986 occupational injuries. The present federal/state system for estimating occupational injury severity by measuring lost work days seriously underestimates the magnitude of the problem. The current policy of obtaining incidence and severity data from the same Survey should be reconsidered. We recommend that national estimates of injury severity be obtained from representative states by using state compensation data and that such estimates be used to evaluate current prevention and rehabilitation strategies. The redesigned occupational safety and health Survey (ROSH Survey) should be revised to permit linkage to compensation data.