[Core competencies in internal medicine]. / Competencias básicas de la medicina interna.

The working group of the Spanish Society of Internal Medicine (SEMI) on "Competencies of the Internist" has defined the basic medical knowledge, skills and attitudes that all internists in Spain should have. This list of competencies represents the Internal Medicine core curriculum within the context of the future educational framework of medical specialties in Health Sciences.

Prevalence and awareness of cardiovascular risk factors in patients with schizophrenia: a cross-sectional study in a low cardiovascular disease risk geographical area.

OBJECTIVE: Prevalence of cardiovascular disease is high in schizophrenia. Our aim is to estimate the prevalence of cardiovascular risk factors (CVRF) among schizophrenia patients. METHOD: National cross-sectional study in patients diagnosed with schizophrenia under treatment with second generation antipsychotics and admitted to short-stay hospitalisation units. RESULTS: A sample of 733 consecutively admitted patients was enrolled; the most prevalent CVRFs were smoking 71% (95% CI: 67-74%) and hypercholesterolemia 66% (61-70%) followed by hypertriglyceridemia 26% (26-32%), hypertension 18% (15-21%) and diabetes 5% (4-7%). Metabolic syndrome showed 19% (95% CI: 16-23%) prevalence or, according to updated definitions (Clin Cornerstone 7 [2005] 36-45), 24% (95% CI: 20-28%). The rate of patients within the high-risk range of a 10-year fatal cardiovascular event was 6.5%. CVRFs under routine management were diabetes (60%), hypertension (28%) and, to a lesser extent, dyslipemia (14%). Treatment for CVRFs was associated to gender, men for hypertension OR = 25.34, p < 0.03 and women for diabetes OR = 0.02, p < 0.03. CONCLUSION: We found that CVRFs in schizophrenia were prevalent and under-diagnosed, and thus with insufficient therapeutic management.

A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome.

Wolfram syndrome is a progressive neurodegenerative disorder transmitted in an autosomal recessive mode. We report two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The deletions reached percentages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members of the family, the percentages of deleted mitochondrial DNA genomes were only 1-10%. Recently, a Wolfram syndrome gene has been linked to markers on 4p16. In both families linkage between the disease locus and 4p16 markers gave a maximum multipoint lod score of 3.79 at theta = 0 (P<0.03) with respect to D4S431. In these families, the syndrome was caused by mutations in this nucleus-encoded gene which deleteriously interacts with the mitochondrial genome. This is the first evidence of the implication of both genomes in a recessive disease.

Impact of 3-Monthly Vitamin D Supplementation Plus Exercise on Survival after Surgery for Osteoporotic Hip Fracture in Adult Patients over 50 Years: A Pragmatic Randomized, Partially Blinded, Controlled Trial.

OBJECTIVE: To determine whether 3-monthly supplementation of an oral vitamin D widely used in Spain (calcifediol) plus daily exercise could influence survival at one and four years after surgery for osteoporotic hip fracture. DESIGN: A pragmatic, randomized, partially single-blind placebo-controlled study. SETTING: Patients admitted to a tertiary university hospital for acute hip fracture. PARTICIPANTS: 675 healthy adult patients undergoing surgery for osteoporotic hip fracture were recruited from January 2004 to December 2007. INTERVENTION: Patients were randomized to receive either 3-monthly oral doses of 3 mg calcifediol (Hidroferol Choque®) or placebo in the 12 months postsurgery. Patients who received calcifediol were also given an exercise programme. The placebo group received standard health recommendations only. MEASUREMENTS: The primary endpoint was survival at 1 year and at 4 year follow-up. We also recorded new fractures, medical complications and anti-osteoporotic treatment compliance. RESULTS: We included a total of 88 patients, aged 62 to 99 years. Mean age was 82 years and 88.6% were women. At 12 months, 10 (11.3%) patients had died, 9 of them, from the non-intervention group. At 4 years after surgery, 20 (22.7%) had died, 3 (3.4%) from the intervention group and 17 (19.3%) from the non-intervention group. At this time, survival curve analysis showed 93% survival in the intervention group and 62% in the non-intervention group (p=0.001). At 12-month follow up, there were 18 new fractures, 9 in each group. The non-intervention group had more medical complications, with significant differences at visit 2 (p = 0.04) and 3 (p = 0.02) but not at visit 4 (p = 0.18). No significant differences between groups were found regarding treatment compliance. CONCLUSION: 3-monthly, oral supplements of 3 mg calcifediol plus daily exercise improved survival at one-year and four-year follow up after surgery for an osteoporotic hip fracture.

[Analysis of scientific production and bibliometric impact of a group of Spanish clinical researchers]. / Análisis de la producción científica y del impacto bibliométrico en un grupo de investigadores clínicos españoles.

BACKGROUND: To study the behaviour of several indicators of scientific production and repercussion in a group of Spanish clinical researchers and to evaluate their possible utility for interpreting individual or collective scientific pathways. METHOD: We performed a unicentric, ecological pilot study involving a group of physicians with consolidated research experience. From the Science Citation Index Expanded (SCI-Expanded) database, we obtained the number of publications of each author (indicator of production) and the number of citations, impact factor and h index (indicators of repercussion). These indicators were calculated individually for each of the years of research experience and we assessed the relationship between the experience of the researcher and the value of the indicator achieved, the relationship between these indicators themselves, and their temporal evolution, both individually and for the entire group. RESULTS: We analysed 35 researchers with a research experience of 28.4 (9.6) years. The h index showed the lowest coefficient of variance. The relationship between the indicators and research experience was significant, albeit modest (R2 between 0.15-0.22). The 4 indicators showed good correlations. The temporal evolution of the indicators, both individual and collective, adjusted better to a second grade polynomial than a linear function: individually, all the authors obtained R2>0.90 in all the indicators; together the best adjustment was produced with the h index (R2=0.61). Based on the indicator used, substantial variations may be produced in the researchers' ranking. CONCLUSIONS: A model of the temporal evolution of the indicators of production and repercussion can be described in a relatively homogeneous sample of researchers and the h index seems to demonstrate certain advantages compared to the remaining indicators. This type of analysis could become a predictive tool of performance to be achieved not only for a particular researcher, but also for a homogeneous group of resear-chers corresponding to a specific scientific niche.

Consensus document and recommendations on the use of natriuretic peptides in clinical practice. / Documento de consenso y recomendaciones sobre el uso de los péptidos natriuréticos en la práctica clínica.

Natriuretic peptides are a useful laboratory tool for the diagnosis, prognosis and treatment of patients with heart failure. Natriuretic peptides are used in various healthcare settings (consultations, emergency department, hospitalization, laboratory) and by various primary care and specialised professionals. However, their use in clinical practice is still scare and uneven. Properly using and interpreting natriuretic peptides in clinical practice requires a minimum of prelaboratory (pathophysiology), laboratory (methods) and postlaboratory (interpretation and integration of clinical data) expertise. The objective of this consensus document, developed by several scientific societies, is to update the necessary concepts and expertise on natriuretic peptides that enable its application in the diagnosis, prognosis and treatment of heart failure, in various healthcare environments.

Statin-associated autoimmune myopathy: A distinct new IFL pattern can increase the rate of HMGCR antibody detection by clinical laboratories.

BACKGROUND AND OBJECTIVE: Statin-associated autoimmune myopathy (SAAM) with anti-HMGCR antibodies has recently been described. Several specific immunoassays are in use to detect HMGCR antibodies. In the course of systematic autoantibody screening we recognized a new distinct IFL staining pattern on rat liver sections that regularly coincided with anti-HMGCR antibodies. In this study we investigated whether this new IFL pattern is specifically associated to statin-associated autoimmune myopathy and corresponds to anti-HMGCR antibodies. PATIENTS AND METHODS: Twenty-three patients positive for anti-HMGCR antibodies (14 diagnosed with SAAM) were investigated for anti-HMGCR antibodies by two ELISA assays and confirmed by immmunoblot. HMGCR associated liver IFL pattern (HALIP) was detected by indirect IFL and the reactivity against HMGCR was confirmed by immunoabsorption using purified human HMGCR antigen. 90 patients with other autoimmune diseases and 45 non-autoimmune statin treated patients were studied as controls. RESULTS: 21 out of 23 (91%) anti-HMGCR positive patients were HALIP positive. The staining was completely and specifically removed by immunoabsorption with human purified HMGCR. None of the control sera from autoimmune patients or non-autoimmune statin treated subjects was positive for HALIP. Statistical concordance between HALIP and anti-HMGCR antibody specific tests was 98.7%, kappa 0.95. CONCLUSIONS: A new and distinct IFL staining pattern (HALIP) is associated to HMGCR associated myopathy. Absorption and concordance studies indicate that the antigen recognized in the liver by HALIP is HMGCR or a closely related protein. Awareness of this new pattern can help to detect HMGCR autoantibodies in statin treated patients tested for autoimmune serology.

Aging is associated with increased lipid peroxidation in human hearts, but not with mitochondrial respiratory chain enzyme defects.

BACKGROUND: Aging is associated with increased oxidative damage at multiple cellular and tissular levels. A decrease in mitochondrial function has repeatedly been advocated as a primary key event, especially on the basis of analysis of skeletal muscle mitochondria. However, some doubts on this issue have arisen when confounding variables (such as physical activity or smoking habit) have been taken into account in the analysis of mitochondrial respiratory chain (MRC) enzyme activities or when additional analytical parameters such as enzyme ratios have been considered. OBJECTIVE: To determine whether oxidative damage and enzyme activities of the MRC are influenced by the aging process in human hearts. PATIENTS AND METHODS: We studied cardiac muscle obtained from 59 organ donors (age: 56+/-12 years, 75% men). Oxidative membrane damage was evaluated through the assessment of lipid peroxidation. Absolute and relative enzyme activities (AEA and REA, respectively) of complex I, II, III and IV of the MRC were spectrophotometrically measured. Stoichiometric relationships among MRC complexes were also assessed through calculating MRC ratios. Linear regression analyses were employed to disclose any potential correlation between mitochondrial dysfunction and aging. RESULTS: We found a progressive, significant increase of heart membrane lipid peroxidation with aging (P<0.05). Conversely, neither AEA nor REA decreased with age (P=n.s. for all complexes). Similarly to observations in other tissues, we found that stoichiometry of the MRC enzymes is maintained within a narrow range in human hearts. When the effects of aging on MRC ratios were explored, we failed again in demonstrating any subtle disarray. CONCLUSION: MRC enzymes remain preserved in heart with aging, and thus they cannot be considered the main cause of the increased oxidative damage associated with aging.

Mitochondrial function in heart muscle from patients with idiopathic dilated cardiomyopathy.

OBJECTIVE: To study the mitochondrial respiratory chain enzyme activities in patients with idiopathic dilated cardiomyopathy (IDC). METHODS: Mitochondrial respiratory chain enzyme activities were assessed spectrophotometrically in left ventricular tissue of 17 patients with IDC undergoing cardiac transplantation, as well as in two groups of controls: a group of six patients suffering from ischemic dilated cardiomyopathy (IC) also undergoing cardiac transplantation, and a group of 17 organ donors considered normal from a cardiac point of view. Cytochrome b gene from three IDC patients whose complex III activity was particularly low and from three controls was also sequenced. RESULTS: We found that complex III enzymatic activity was lower not only in IDC but also in IC patients when compared with normal controls. When analysing cytochrome b gene we only found neutral polymorphisms previously described. CONCLUSIONS: In view of such results, we believe that the decrease of respiratory chain complex III activity found in some cases of IDC is a secondary phenomenon, and not due to a primary mitochondrial disease.

Scientific production and bibliometric impact of a representative group of Spanish internists with established research careers. / Producción científica e impacto bibliométrico de un grupo representativo de internistas españoles con trayectoria investigadora consolidada.

OBJECTIVE: To study the temporal evolution of the bibliometric indices of internists with established research experience in order to predict the future behavior of researchers and to assess whether output focused on a specific area of internal medicine helps obtain greater visibility than in general internal medicine. MATERIAL AND METHOD: We analyzed a representative group of members of the Spanish Society of Internal Medicine (SEMI) based on data obtained from the Web of Science. As an indicator of productivity, we analyzed the number of articles published. As impact indicators, we studied the impact factor (IF), the number of citations and the h-index. RESULTS: We analyzed 42 internists, with a mean experience of 30 years and a total of 6655 publications. The mean (SD) number of studies was 158 (96), the number of citations was 2,850 (2,865), the IF was 711 (549) and the h-index was 25 (11). These figures were higher for the specialist internists than for the general internists. There was a good relationship between the impact and productivity indicators (R(2)=.61-.89) and a poor relationship between these indicators and the years of experience (R(2)=.13-.19). The temporal evolution of these indicators for each individual researcher and for all researchers as a whole was adjusted to a second-degree polynomial model, with the h-index having the highest R(2) values. CONCLUSIONS: The h-index is the factor that had the best adjustment and least variability and could therefore help predict the future scientific output and impact of internists. The specialist researchers achieved greater visibility than the general internists.

Mitochondrial involvement in antiretroviral therapy-related lipodystrophy.

OBJECTIVES: The management of HIV infection has greatly improved during recent years essentially because of the appearance of new antiretroviral drugs. Highly active antiretroviral therapy (HAART) has achieved important reductions of viraemia and significant recoveries of CD4(+) cell counts in HIV-infected patients. Nonetheless, cases of HIV-infected individuals experiencing lipodystrophy (LD) are being increasingly reported. The purpose of this work was to analyse whether the presence of mitochondrial abnormalities is a frequent feature in LD, since we previously detected mitochondrial abnormalities in an HIV-patient. The second main objective was to study whether LD could be associated with a specific drug. DESIGN: Seven HIV patients presenting LD and five HIV non-LD controls participated in the study. LD patients met the following criteria: (1) LD was their only clinical abnormality, (2) LD was clinically relevant, (3) compliance with antiretroviral treatment was higher than 90% and (4) patients did not have personal or familial history suggestive of mitochondrial disease or neuromuscular disorder. METHODS: Histological stainings, histo-enzymatic reactions, enzymatic and respiratory activities of mitochondrial respiratory chain complexes, and mitochondrial DNA (mtDNA) depletion and rearrangements were examined on muscle mitochondria. RESULTS: Structural muscle abnormalities, mitochondrial respiratory chain dysfunction or mtDNA deletions were detected in all HIV lipodystrophic patients. CONCLUSIONS: The mitochondrial abnormalities found suggest that mitochondrial dysfunction could play a role in the development of antiretroviral therapy-related lipodystrophy.

Vacuolation of muscle fibers near sarcolemmal breaks represents T-tubule dilatation secondary to enhanced sodium pump activity.

Transsected rat soleus muscles incubated in oxygenated Krebs solution in vitro at 37 degrees C develop prominent vacuolation in the vicinity of the cut ends of muscle fibers which extends further along the fiber with increasing time of incubation. Electron microscopy shows that the vacuoles represent dilated segments of T-tubules. Their formation is prevented if the muscle is not cut, or in the following situations: omission of Na+ from the medium, incubation at 10 degrees C, or in media containing either 2,4-dinitrophenol or ouabain. Vacuole formation is considerably reduced by substituting Cl- with organic anions or by adding 9-anthracene carboxylic acid to the medium. These results suggest that a massive influx of sodium into the muscle fibers through their cut ends results in maximal stimulation of the Na+-K+-ATPase of the T-tubular membrane leading to increasing Na+ concentration in the lumen of T-tubules followed by influx of Cl- to maintain the electrical gradient. The accumulation of these ions leads to the entry of water from either the extracellular space or the sarcoplasm and consequent dilatation of T-tubules. Rapid incorporation of lipids into T-tubular membrane to increase its surface is presumably necessary for this to occur. Similar T-tubular dilatation appears to occur in vivo in surviving portions of muscle fibers adjacent to segmental necrosis.

Is mitochondrial DNA depletion involved in Alzheimer's disease?

Several studies have suggested that mitochondrial metabolism disturbances and mitochondrial DNA (mtDNA) abnormalities may contribute to the progression of the pathology of Alzheimer's disease (AD). In this study we have investigated whether the amount of mtDNA is modified in different brain regions (cerebellum, hippocampus and frontal cortex) of confirmed AD necropsies and in blood of living AD patients. We used a real-time PCR method to analyse the mtDNA relative abundance in brain regions from 12 AD and seven controls and from a group of blood samples (17 living AD patients and 11 controls). MtDNA from blood samples together with hippocampus and cerebellum brain areas did not show differences between controls and AD. However, AD patients showed a 28% decrease in the amount of mtDNA in the frontal cortex when compared to controls for this specific area. Since frontal cortex is a severely affected region in AD, our results support the hypothesis that mitochondrial defects may play a role in the pathogenesis of AD.

Streptococcal myositis as a complication of juvenile dermatomyositis.

The infection of muscle is an infrequent condition. We report on a patient with a juvenile form of dermatomyositis who developed infectious myositis caused by Streptococcus pyogenes. The inflammatory myopathy probably favoured the colonization of muscle during a bacteremia related to the skin lesions. The main forms of streptococcal myositis, which can currently be differentiated by means of imaging techniques, are discussed in addition to its treatment and prognosis.

Muscle involvement in rheumatoid arthritis: clinicopathological study of 21 symptomatic cases.

The aim of the current study was to analyze the frequency and characteristics of symptomatic myopathies occurring in rheumatoid arthritis (RA) patients, to correlate these findings with clinical data, and to evaluate their therapeutic implications. All RA patients from a cohort of 350 RA patients from a single institution who developed muscular symptomatology during an 8-year period were included in the study (n = 21). Clinical and laboratory data and electromyographic results were recorded in all cases, and an open muscle biopsy was performed. Weakness and muscle atrophy were the most common symptoms. Serum creatine kinase was increased in 8 cases (38%). Histopathologic study showed type 2 atrophy in 12 cases. In 13 cases, a treatable disease was diagnosed: dermatomyositis (n = 2), d-penicillamine-related dermatomyositis (n = 2), polymyositis (n = 1), muscular mononuclear cell infiltration (n = 3), polyarteritis nodosa (n = 1), glucocorticoid myopathy (n = 3), and toxic chloroquine myopathy (n = 1). In all but 1 patient, muscular clinical response to new therapy and/or drug withdrawal was satisfactory. Although symptomatic muscular involvement in RA is low (6% in the current series), we have found that nearly two thirds of cases were caused by potentially treatable conditions, mainly myositis or toxic myopathies.

Microvascular changes in skeletal muscle in idiopathic inflammatory myopathy.

Open deltoid muscle biopsy specimens from patients with idiopathic adult dermatomyositis, paraneoplastic dermatomyositis, childhood dermatomyositis, and idiopathic polymyositis, and from control patients were studied. Qualitative and morphometric capillary analysis by phase and electron microscopy was carried out. In the morphologic analysis the most striking difference was the presence of capillary damage and a higher capillary depletion in dermatomyositis as well as a higher capillary density in polymyositis. By electron microscopy, capillaries from patients with dermatomyositis showed mainly microtubuloreticular structures, loss of endothelial plasma membranes, and the appearance of abnormal cytoplasmic organelles. In contrast, capillaries from patients with polymyositis exhibited only minimal changes. By morphometric analysis, muscle capillaries in dermatomyositis had a significantly higher mean endothelial thickness than those in polymyositis. Finally, a significant topographic association between capillary damage and muscle fiber changes was observed only in patients with dermatomyositis. On the other hand, paraneoplastic dermatomyositis showed fewer structural and morphometric capillary changes than the other forms of dermatomyositis. We conclude that dermatomyositis is characterized by microvascular alterations that are absent in polymyositis. The topographic proximity of capillary changes to muscle fiber injury suggests that capillary damage may play a role in the pathogenesis of the muscle lesions observed in patients with dermatomyositis.

Reduced steady-state levels of mitochondrial RNA and increased mitochondrial DNA amount in human brain with aging.

The contribution of the mitochondrial genetic system in the degenerative processes of senescence remains unclear. This study deals with age-related changes in brain mtDNA expression in humans. Brain tissue from the frontal lobe cortex was obtained from autopsy of 13 humans aged between 21 and 84 years. No structural changes were detected in mtDNA, increased mtDNA content and reduced steady-state level of mitochondrial transcripts and transcription ratio (mtRNA/mtDNA) were associated with aging. These findings suggest that the increase of the mtDNA levels could be considered as an inefficient compensatory mechanism to maintain the normal levels of mtRNA transcripts. This unbalanced mitochondrial condition could play a role in the process of senescence in human brain.

Myasthenia gravis after allogeneic bone marrow transplantation: report of a new case and pathogenetic considerations.

A 21-year-old caucasian man with T acute lymphoblastic leukemia underwent a bone marrow transplantation (BMT) and developed classic myasthenia gravis (MG) 46 months later. The association of almost all published cases with HLA B35 is discussed, as are the clinical aspects suggesting that BMT survivors are at risk for developing MG as part of the spectrum of chronic graft-versus-host disease.

Respiratory chain activity and mitochondrial DNA content of nonpurified and purified pancreatic islet cells.

Considerable interest has recently focused on the possible role of alterations in mitochondrial activity and mutations in the mitochondrial genome for the development of non-insulin-dependent diabetes. Our study aimed at investigating the normal mitochondrial respiratory chain activity of nonpurified and purified islet cells to further explore whether some diabetic states are associated with alterations of mitochondrial oxidative processes. For this purpose, pancreatic islets were isolated from Wistar rats. Unpurified islet cells were obtained in the presence of trypsin and DNAse, and purified beta and non-beta cells were prepared by autofluorescence-activated sorting using a flowcytometer. Intact cell respiration and substrate oxidation in digitonin-permeabilized cells were measured polarographically with a Clark oxygen electrode in a micro-water-jacketed cell. Specific activity of the individual complexes of the respiratory chain was determined spectrophotometrically in unpurified islet cells. The relative amount of mitochondrial (mtDNA) and nuclear (nDNA) DNA in all three cell populations and in rat brain and skeletal muscle was estimated by dot blotting. The intact cell respiration of unpurified islet cells corresponds to the mean of values obtained for beta and non-beta islet cells. Oxidation rates of different substrates by permeabilized beta cells were lower than those for unpurified and non-beta cells. The amount of mtDNA relative to nDNA was similar in all three groups of cells, and was also similar to that obtained from brain and skeletal muscle. In summary, we have described mitochondrial respiratory chain activity in unpurified, beta, and non-beta islet cells. Our results represent an initial step in investigating the potential pathogenic role that alterations in oxidative phosphorylation could play in some diabetic states.