Delineating the contribution of ageing and physical activity to changes in mitochondrial characteristics across the lifespan.

Ageing is associated with widespread physiological changes prominent within all tissues, including skeletal muscle and the brain, which lead to a decline in physical function. To tackle the growing health and economic burdens associated with an ageing population, the concept of healthy ageing has become a major research priority. Changes in skeletal muscle mitochondrial characteristics have been suggested to make an important contribution to the reductions in skeletal muscle function with age, and age-related changes in mitochondrial content, respiratory function, morphology, and mitochondrial DNA have previously been reported. However, not all studies report changes in mitochondrial characteristics with ageing, and there is increasing evidence to suggest that physical activity (or inactivity) throughout life is a confounding factor when interpreting age-associated changes. Given that physical activity is a potent stimulus for inducing beneficial adaptations to mitochondrial characteristics, delineating the influence of physical activity on the changes in skeletal muscle that occur with age is complicated. This review aims to summarise our current understanding and knowledge gaps regarding age-related changes to mitochondrial characteristics within skeletal muscle, as well as to provide some novel insights into brain mitochondria, and to propose avenues of future research and targeted interventions. Furthermore, where possible, we incorporate discussions of the modifying effects of physical activity, exercise, and training status, to purported age-related changes in mitochondrial characteristics.

Multimodal cell atlas of the ageing human skeletal muscle.

Muscle atrophy and functional decline (sarcopenia) are common manifestations of frailty and are critical contributors to morbidity and mortality in older people1. Deciphering the molecular mechanisms underlying sarcopenia has major implications for understanding human ageing2. Yet, progress has been slow, partly due to the difficulties of characterizing skeletal muscle niche heterogeneity (whereby myofibres are the most abundant) and obtaining well-characterized human samples3,4. Here we generate a single-cell/single-nucleus transcriptomic and chromatin accessibility map of human limb skeletal muscles encompassing over 387,000 cells/nuclei from individuals aged 15 to 99 years with distinct fitness and frailty levels. We describe how cell populations change during ageing, including the emergence of new populations in older people, and the cell-specific and multicellular network features (at the transcriptomic and epigenetic levels) associated with these changes. On the basis of cross-comparison with genetic data, we also identify key elements of chromatin architecture that mark susceptibility to sarcopenia. Our study provides a basis for identifying targets in the skeletal muscle that are amenable to medical, pharmacological and lifestyle interventions in late life.

Cross-Cultural Adaptation of the Scale of the Nursing Work Index With Nurses From Seven Countries.

Background and Purpose: The aims of this study are as follows: to adapt and validate the psychometric properties of the Spanish version of the Practice Environment Scale of the Nursing Work Index (PES-NWI) adapted to the nursing home environment across seven Spanish-speaking countries and to cross-culturally adapt the Scale of the Nursing Work Index with nurses from seven countries. Methods: Adaptation process and psychometric validation of the instrument included translation and back-translation, content validity, test-retest reliability, internal consistency, and construct validity. Results: A total of 134 nursing homes belonging to the same religious order were randomly selected from seven Spanish-speaking countries with a sample of 378 nurses. The exploratory factor analysis explained a five-factor structure (56% of the explained variance) with adequate goodness-of-fit indices in the final factor solution. Conclusions: The validation process indicates that the Spanish language version of the PES-NWI with five factors and 31 items, for long-term care facilities for the elderly, is valid and reliable in its current version and can be used to measure the environment of nurses working in clinical practice in Spanish-speaking nursing homes.

Physical Interventions Restore Physical Frailty and the Expression of CXCL-10 and IL-1ß Inflammatory Biomarkers in Old Individuals and Mice.

BACKGROUND: Frailty is a geriatric syndrome associated with negative health outcomes that represents a dynamic condition with a potential of reversibility after physical exercise interventions. Typically, inflammatory and senescence markers are increased in frail individuals. However, the impact that physical exercise exerts on inflammatory and senescence biomarkers remains unknown. We assessed the effect of physical intervention in old individuals and mice and determined the expression of inflammatory and senescence markers. METHODS: Twelve elderly individuals were enrolled from a primary care setting to a 3-month intervention. Frailty was measured by SPPB and the expression of biomarkers by cytokine array and RT-qPCR. In addition, 12 aged C57BL/6 mice completed an intervention, and inflammation and senescence markers were studied. RESULTS: The physical intervention improved the SPPB score, reducing frail and pre-frail individuals. This was correlated with a reduction in several pro-inflammatory biomarkers such as IL-6, CXCL-1, CXCL-10, IL-1ß, IL-7, GM-CSF as well as p16INK4a and p21CIP1 senescence markers. Otherwise, the levels of anti-inflammatory biomarker IL-4 were significantly increased. Moreover, the physical intervention in mice also improved their functional capacity and restored the expression of inflammatory (Il-1ß, Cxcl-10, Il-6, and Cxcl-1) and senescence (p21Cip1) markers. Additionally, PLSDA and ROC curve analysis revealed CXCL-10 and IL-1ß to be the biomarkers of functional improvement in both cohorts. CONCLUSIONS: Our results showed that a physical intervention improves physical frailty, and reverses inflammation and senescence biomarkers comprising CXCL-10 and IL-1ß.

Pharmacological and genetic increases in liver NADPH levels ameliorate NASH progression in female mice.

Non-alcoholic steatohepatitis (NASH) is one of the fastest growing liver diseases worldwide, and oxidative stress is one of NASH main key drivers. Nicotinamide adenine dinucleotide phosphate (NADPH) is the ultimate donor of reductive power to a number of antioxidant defences. Here, we explored the potential of increasing NADPH levels to prevent NASH progression. We used nicotinamide riboside (NR) supplementation or a G6PD-tg mouse line harbouring an additional copy of the human G6PD gene. In a NASH mouse model induced by feeding mice a methionine-choline deficient (MCD) diet for three weeks, both tools increased the hepatic levels of NADPH and ameliorated the NASH phenotype induced by the MCD intervention, but only in female mice. Boosting NADPH levels in females increased the liver expression of the antioxidant genes Gsta3, Sod1 and Txnrd1 in NR-treated mice, or of Gsr for G6PD-tg mice. Both strategies significantly reduced hepatic lipid peroxidation. NR-treated female mice showed a reduction of steatosis accompanied by a drop of the hepatic triglyceride levels, that was not observed in G6PD-tg mice. NR-treated mice tended to reduce their lobular inflammation, showed a reduction of the NK cell population and diminished transcription of the damage marker Lcn2. G6PD-tg female mice exhibited a reduction of their lobular inflammation and hepatocyte ballooning induced by the MCD diet, that was related to a reduction of the monocyte-derived macrophage population and the Tnfa, Ccl2 and Lcn2 gene expression. As conclusion, boosting hepatic NADPH levels attenuated the oxidative lipid damage and the exhausted antioxidant gene expression specifically in female mice in two different models of NASH, preventing the progression of the inflammatory process and hepatic injury.

Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models.

Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood-brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis.

Glucose 6-P Dehydrogenase-An Antioxidant Enzyme with Regulatory Functions in Skeletal Muscle during Exercise.

Hypomorphic Glucose 6-P dehydrogenase (G6PD) alleles, which cause G6PD deficiency, affect around one in twenty people worldwide. The high incidence of G6PD deficiency may reflect an evolutionary adaptation to the widespread prevalence of malaria, as G6PD-deficient red blood cells (RBCs) are hostile to the malaria parasites that infect humans. Although medical interest in this enzyme deficiency has been mainly focused on RBCs, more recent evidence suggests that there are broader implications for G6PD deficiency in health, including in skeletal muscle diseases. G6PD catalyzes the rate-limiting step in the pentose phosphate pathway (PPP), which provides the precursors of nucleotide synthesis for DNA replication as well as reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is involved in the detoxification of cellular reactive oxygen species (ROS) and de novo lipid synthesis. An association between increased PPP activity and the stimulation of cell growth has been reported in different tissues including the skeletal muscle, liver, and kidney. PPP activity is increased in skeletal muscle during embryogenesis, denervation, ischemia, mechanical overload, the injection of myonecrotic agents, and physical exercise. In fact, the highest relative increase in the activity of skeletal muscle enzymes after one bout of exhaustive exercise is that of G6PD, suggesting that the activation of the PPP occurs in skeletal muscle to provide substrates for muscle repair. The age-associated loss in muscle mass and strength leads to a decrease in G6PD activity and protein content in skeletal muscle. G6PD overexpression in Drosophila Melanogaster and mice protects against metabolic stress, oxidative damage, and age-associated functional decline, and results in an extended median lifespan. This review discusses whether the well-known positive effects of exercise training in skeletal muscle are mediated through an increase in G6PD.

Recent Approaches to Determine Static and Dynamic Redox State-Related Parameters.

Oxidative stress refers to an imbalance between oxidant and antioxidant molecules, which is usually associated with oxidative damage to biomolecules and mitochondrial malfunction. Redox state-related parameters include (1) the direct measurement of ROS, (2) the assessment of the antioxidant defense status, and (3) the analysis of the resulting oxidative damage to molecules. Directly measuring ROS appears to be the preferred method among scientists, but most ROS are extremely unstable and difficult to measure. The processes of determining both the oxidative damage to biomolecules and the antioxidant system status, although both are indirect approaches, provide a reliable method to measure oxidative stress on a given sample. Recently, the Seahorse XF and the Oroboros O2k systems have provided new insights into the redox state from a more dynamic point of view. These techniques assess mitochondrial oxidative phosphorylation function and bioenergetics on isolated mitochondria, cultured cells, or specific tissues such as permeabilized fibers. This review describes a range of methodologies to measure redox state-related parameters, their strengths, and their limitations. In conclusion, all these techniques are valid and none of them can be replaced by another. Indeed, they have the potential to complement each other for a complete evaluation of the redox state of a given sample.

Glucosamine Supplementation Improves Physical Performance in Trained Mice.

INTRODUCTION: d-Glucosamine (GlcN) is one of the most widely consumed dietary supplements and complementary medicines in the world and has been traditionally used to attenuate osteoarthritis in humans. GlcN extends life span in different animal models. In humans, its supplementation has been strongly associated with decreased total mortality and improved vascular endothelial function. GlcN acts as a suppressor of inflammation, and by inhibiting glycolysis, it can activate the metabolism of stored fat and mitochondrial respiration. METHODS: The conventional human GlcN dose is 1500 mg·d-1, but extensive evidence indicates that much higher doses are well tolerated. GlcN is one of the supplements that has experienced a greater use in the last years in elite athletes mainly because of its potential chondroprotective effects that may promote cartilage health. However, the possibility of it being an ergogenic aid has not been explored. We aimed to study the potential beneficial effects of GlcN on mitochondrial content, physical performance, and oxidative stress in mice that were aerobically trained and supplemented with three different doses of glucosamine (250, 500, and 1000 mg·kg-1) for 6 wk. We measured exercise performance (grip strength, motor coordination, and running capacity) before and after the training period. Proteins involved in mitochondrial biogenesis (AMPK, PGC-1, NRF-1, SIRT-1, cytochrome c, citrate synthase), markers of oxidative stress (GSSG/GSH) or damage (malondialdehyde, carbonylated proteins), antioxidant enzymes (NRF-2, SOD1, SOD2, catalase, and PRDX6), and MAPKs (p38 and ERK1/2 were also determined in skeletal muscle. RESULTS AND CONCLUSIONS: Our results show that GlcN supplementation in aerobically trained mice, at doses equivalent to those conventionally used in humans, increases the protein levels of mitochondrial biogenesis markers, improves motor coordination, and may have a synergistic effect with exercise training on running distance.

Muscle repair after physiological damage relies on nuclear migration for cellular reconstruction.

Regeneration of skeletal muscle is a highly synchronized process that requires muscle stem cells (satellite cells). We found that localized injuries, as experienced through exercise, activate a myofiber self-repair mechanism that is independent of satellite cells in mice and humans. Mouse muscle injury triggers a signaling cascade involving calcium, Cdc42, and phosphokinase C that attracts myonuclei to the damaged site via microtubules and dynein. These nuclear movements accelerate sarcomere repair and locally deliver messenger RNA (mRNA) for cellular reconstruction. Myofiber self-repair is a cell-autonomous protective mechanism and represents an alternative model for understanding the restoration of muscle architecture in health and disease.

Glucose 6-P dehydrogenase delays the onset of frailty by protecting against muscle damage.

BACKGROUND: Frailty is a major age-associated syndrome leading to disability. Oxidative damage plays a significant role in the promotion of frailty. The cellular antioxidant system relies on reduced nicotinamide adenine dinucleotide phosphate (NADPH) that is highly dependent on glucose 6-P dehydrogenase (G6PD). The G6PD-overexpressing mouse (G6PD-Tg) is protected against metabolic stresses. Our aim was to examine whether this protection delays frailty. METHODS: Old wild-type (WT) and G6PD-Tg mice were evaluated longitudinally in terms of frailty. Indirect calorimetry, transcriptomic profile, and different skeletal muscle quality markers and muscle regenerative capacity were also investigated. RESULTS: The percentage of frail mice was significantly lower in the G6PD-Tg than in the WT genotype, especially in 26-month-old mice where 50% of the WT were frail vs. only 13% of the Tg ones (P < 0.001). Skeletal muscle transcriptomic analysis showed an up-regulation of respiratory chain and oxidative phosphorylation (P = 0.009) as well as glutathione metabolism (P = 0.035) pathways in the G6PD-Tg mice. Accordingly, the Tg animals exhibited an increase in reduced glutathione (34.5%, P < 0.01) and a decrease on its oxidized form (-69%, P < 0.05) and in lipid peroxidation (4-HNE: -20.5%, P < 0.05). The G6PD-Tg mice also showed reduced apoptosis (BAX/Bcl2: -25.5%, P < 0.05; and Bcl-xL: -20.5%, P < 0.05), lower levels of the intramuscular adipocyte marker FABP4 (-54.7%, P < 0.05), and increased markers of mitochondrial content (COX IV: 89.7%, P < 0.05; Grp75: 37.8%, P < 0.05) and mitochondrial OXPHOS complexes (CII: 81.25%, P < 0.01; CIII: 52.5%, P < 0.01; and CV: 37.2%, P < 0.05). Energy expenditure (-4.29%, P < 0.001) and the respiratory exchange ratio were lower (-13.4%, P < 0.0001) while the locomotor activity was higher (43.4%, P < 0.0001) in the 20-month-old Tg, indicating a major energetic advantage in these mice. Short-term exercise training in young C57BL76J mice induced a robust activation of G6PD in skeletal muscle (203.4%, P < 0.05), similar to that achieved in the G6PD-Tg mice (142.3%, P < 0.01). CONCLUSIONS: Glucose 6-P dehydrogenase deficiency can be an underestimated risk factor for several human pathologies and even frailty. By overexpressing G6PD, we provide the first molecular model of robustness. Because G6PD is regulated by pharmacological and physiological interventions like exercise, our results provide molecular bases for interventions that by increasing G6PD will delay the onset of frailty.

Redox-related biomarkers in physical exercise.

Research in redox biology of exercise has made considerable advances in the last 70 years. Since the seminal study of George Pake's group calculating the content of free radicals in skeletal muscle in resting conditions in 1954, many discoveries have been made in the field. The first section of this review is devoted to highlight the main research findings and fundamental changes in the exercise redox biology discipline. It includes: i) the first steps in free radical research, ii) the relation between exercise and oxidative damage, iii) the redox regulation of muscle fatigue, iv) the sources of free radicals during muscle contractions, and v) the role of reactive oxygen species as regulators of gene transcription and adaptations in skeletal muscle. In the second section of the manuscript, we review the available biomarkers for assessing health, performance, recovery during exercise training and overtraining in the sport population. Among the set of biomarkers that could be determined in exercise studies we deepen on the four categories of redox biomarkers: i) oxidants, ii) antioxidants, iii) oxidation products (markers of oxidative damage), and iv) measurements of the redox balance (markers of oxidative stress). The main drawbacks, strengths, weaknesses, and methodological considerations of every biomarker are also discussed.

Physical exercise in the prevention and treatment of Alzheimer's disease.

Dementia is one of the greatest global challenges for health and social care in the 21st century. Alzheimer's disease (AD), the most common type of dementia, is by no means an inevitable consequence of growing old. Several lifestyle factors may increase, or reduce, an individual's risk of developing AD. Much has been written over the ages about the benefits of exercise and physical activity. Among the risk factors associated with AD is a low level of physical activity. The relationship between physical and mental health was established several years ago. In this review, we discuss the role of exercise (aerobic and resistance) training as a therapeutic strategy for the treatment and prevention of AD. Older adults who exercise are more likely to maintain cognition. We address the main protective mechanism on brain function modulated by physical exercise by examining both human and animal studies. We will pay especial attention to the potential role of exercise in the modulation of amyloid ß turnover, inflammation, synthesis and release of neurotrophins, and improvements in cerebral blood flow. Promoting changes in lifestyle in presymptomatic and predementia disease stages may have the potential for delaying one-third of dementias worldwide. Multimodal interventions that include the adoption of an active lifestyle should be recommended for older populations.

Marital Satisfaction in Spanish and Dominican Couples / Satisfacción Marital en Parejas Españolas y Dominicanas

Abstract Marriage is an appreciated worldwide institution, although nearly half of first marriages end in divorce. Thus, the relevance of understanding how people choose their partners and what features can predict a satisfactory relationship. More specifically, in search of data supporting similarity or complementarity approaches on marital satisfaction, the current study analyzes the association between different assortative mating options (homogamy, and heterogamy) and marital satisfaction in Spanish and Dominican couples. A stratified quota sampling of 600 participants was selected, corresponding to 300 married couples (50% Spanish and 50% Dominicans). Data were gathered by means of an interview with the 10-item scale on Marital Satisfaction and a 7-item scale on Status. Results suggest that spouses are matched by similarity in their health and education and by the perception of similarity in intelligence and the financial advantages of staying together. Dominican couples experienced higher marital satisfaction than Spanish couples. Findings on hypergamy reveals the persistence of some traditional roles' distribution among Spanish speaking cultures. The association between status and marital satisfaction revealed that heterogamy rather than homogamy is associated to such satisfaction. These results stress the relevance of taking into account social and cultural differences, beyond biological and psychological factors, to fully understand couples' satisfaction.

Resumen El matrimonio es una institución apreciada a nivel mundial, pese a que casi la mitad de los primeros matrimonios terminan en divorcio. De ahí la importancia de comprender cómo las personas eligen a sus parejas y qué factores contribuyen a predecir una relación satisfactoria. Más concretamente, en busca de datos que ofrezcan apoyo a los enfoques de semejanza o de complementariedad en su relación con la satisfacción marital, el presente estudio analiza diferentes alternativas de emparejamiento selectivo (homogamia y heterogamia) y su relación con dicha satisfacción marital en parejas españolas y dominicanas. Para llevar a cabo el estudio se ha empleado un muestreo estratificado por cuotas compuesto por un total de 600 participantes, que se corresponden con 300 parejas casadas (un 50% procedente de España y el otro 50% procedente de República Dominicana). Los datos se recogieron a través de entrevista la escala de 10 ítems de Satisfacción Marital y la escala de 7 ítems de Status. Los resultados sugieren que los emparejamientos se caracterizan por la semejanza en salud, formación, inteligencia, y por la percepción compartida de las ventajas económicas asociadas a su permanencia. Las parejas dominicanas experimentan una mayor satisfacción marital que las españolas. Los resultados obtenidos sobre hipergamia revelan la persistencia de una distribución de roles tradicional en países de habla hispana. La asociación entre estatus y satisfacción marital indicaron que la heterogamia más que la homogamia, se asocia a tal satisfacción. Todos estos resultados subrayan la importancia de tener en cuenta diferencias sociales y culturales, además de factores biológicos y psicológicos, para comprender plenamente la satisfacción en las parejas.

Decisions at the end of life made by relatives of institutionalized patients with dementia.

BACKGROUND: The wishes and preferences of patients with dementia should inform the decisions made about their future care. However, the decision-making that occurs at the end of life is a difficult experience for the families of patients. With regard to decision-making in the terminal stages, few studies have explored the experiences and feelings of caregivers of persons with dementia who are institutionalized. AIM: To describe the processes of decision-making used by families regarding treatments at the end of life of institutionalized patients with advanced stages of dementia. METHODS: Five focus groups were conducted in five nursing homes in Spain, representing a total of 84 familiars. RESULTS: Five categories that describe the context for decision-making were identified: the emotional effect, the "living death," the two faces of death, the values and objectives regarding treatments at the end of life, and the lack of knowledge about the progression of dementia. CONCLUSIONS: The participants have unresolved emotional needs resulting from both the disease and the institutionalization of a member of their family. The participants were unprepared to make end-of-life treatment decisions, and they lacked a consistent healthcare provider to provide informational and emotional support that would have helped with decision-making. The carers' own wishes and preferences were shaped by their perceptions and experiences of the dementia illness.

New Copper, Palladium and Nickel Catalytic Systems: An Evolution towards More Efficient Procedures.

Metal-catalysed reactions are a fundamental tool in synthetic chemistry. Increasingly challenging transformations can be accomplished only by means of certain metal catalysts. However, there still remains the need for a substantial decrease of the amount of catalyst, for better reuse or recycling of such active species, and for the avoidance of relatively toxic solvents in favour of environmentally friendly media. These facts apply to copper-, palladium-, and nickel-catalysed cross-coupling reactions, direct arylations, and oxidative processes. This account summarises our research on the last reactions, featuring an evolution towards more sustainable procedures in this field.

The incidence and prognostic implications of dysphagia in elderly patients institutionalized: A multicenter study in Spain.

AIM: Determine the incidence of dysphagia, identify its consequences and objectify related complications and mortality associated with pneumonia, in the institutionalized elderly. METHODS: A prospective observational and multicenter study with a 3-year follow-up period was designed in a cohort of 12 nursing homes within 6 cities in Spain. A total of 2384 patient records were studied. Demographic and clinical data (dementia, cerebrovascular disease), as well as an evaluation of the Barthel Index, dysphagia and aspiration, and mortality at 30 days and 1 year after pneumonia in patients with dysphagia were collected. RESULTS: Of the 2384 patients, 69.6% presented clinical signs of oropharyngeal dysphagia. Patients with dysphagia were older and showed lower functional status and higher prevalence of comorbidities. They had higher mortality as well. CONCLUSIONS: Oropharyngeal dysphagia is a highly prevalent clinical finding in elderly institutionalized patients. Among this population, there is also a higher prevalence of pneumonia, dementia, and cerebrovascular disease and pneumonia is an indicator of mortality.

Synthesis, structure, and catalytic applications for ortho- and meta-carboranyl based NBN pincer-Pd complexes.

o- and m-Carborane-based NBN pincer palladium complexes (oCB-L1)Pd, (oCB-L2)Pd, and (mCB-L1)Pd are synthesized in two steps from commercially available starting materials. The pincer complexes were prepared by the reaction of bis-[R(hydroxy)methyl]-1,2-dicarba-closo-dodecaborane (R = 2-pyridyl oCB-L1, 6-methyl-2-pyridyl oCB-L2) or bis-[2-pyridyl (hydroxy)methyl]-1,2-dicarba-meta-dodecaborane (mCB-L1) with [PdCl2(MeCN)2] under mild conditions. The X-ray structure determination of all carboranyl pincer complexes shows unambiguously B-H activation of the carborane cages. The results agree with the Pd-B bonds in all complexes exhibiting strong σ-electron donation. Theoretical calculations reveal the importance of considering the solid state intermolecular hydrogen bonding when investigating the trans influence in organometallic chemistry. A localized orbitals approach has also been applied to analyze the metal oxidation state in the carboranyl pincer complexes. Catalytic applications of (oCB-L1)Pd and (mCB-L1)Pd have shown the complexes are good catalyst precursors in Suzuki coupling in water and with very low amounts of catalyst loadings.

Prioritization of therapy uncertainties in Dystrophic Epidermolysis Bullosa: where should research direct to? an example of priority setting partnership in very rare disorders.

BACKGROUND: Dystrophic Epidermolysis Bullosa (DEB) is a rare genodermatosis (7 cases per million) that causes blisters and erosions with minor trauma in skin and mucosa, and other systemic complications. A recently updated systematic review showed that the research evidence about DEB therapies is poor. As new trials in DEB are difficult and expensive, it is important to prioritizise research that patients and clinicians consider more relevant. OBJECTIVES: To describe and prioritize the most important uncertainties about DEB treatment shared by patients, carers and health care professionals (HCPs) in order to promote research in those areas. METHODS: A DEB Priority Setting Partnership (PSP) was established, including patients, carers and HCPs. DBE uncertainties were gathered from patients and clinicians, and prioritized in a transparent process, using the methodology advocated by the James Lind Alliance. RESULTS: In the consultation stage, 323 uncertainties were submitted by 58 participants. Once the duplicated and non-treatment uncertainties were removed, the remainder were reduced to a list of 24 most voted questions. These 24 uncertainties were prioritized in a final workshop where a balanced number of patients, carers and HCPs selected the top 10 therapy uncertainties. The final list includes interventions in wound care, itch and pain management, treatment and prevention of syndactyly, cancer prevention and future promising therapies. CONCLUSIONS: The final list of the top 10 treatment uncertainties on the management of DEB provides guidance for researchers and funding bodies, to ensure that future research answers questions that are important to both clinicians and patients. The method proposed by the James Lind Alliance is feasible for very rare disorders.

Application of FISH 7q in MDS patients without monosomy 7 or 7q deletion by conventional G-banding cytogenetics: does -7/7q- detection by FISH have prognostic value?

Chromosomal abnormalities are detected in 40-60% of patients with de novo myelodysplastic syndromes (MDS). This study used the FISH technique in 773 patients with de novo MDS without evidence of monosomy 7 (-7) or 7q deletion (7q-) by conventional G-banding cytogenetics (CC) to analyze their prognostic impact by FISH alone. FISH detected -7/7q- in 5.2% of patients. Presence of -7/7q- was associated with shorter overall survival than absence of such aberrations. Our results suggest that FISH 7q could be beneficial in patients with intermediate WHO morphologic risk stratification and no evidence of -7/7q- by CC.