Avenços en l'estudi de la litiasi renal: mètodes de chemical imaging i intel·ligencia artificial (ANN) per la caracterització de càlculs renals

La litiasi urinària és un trastorn que implica la formació de precipitats en qualsevol part del tracte urinari. Aquest és un desordre comú que afecta aproximadament a una desena part de la població de la Unió Europea al llarg de la seva vida. A més, durant els cinc anys posteriors a un episodi litiàsic el percentatge de recurrència dels pacients és del 45 al 75%. Aquest trastorn urinari està influït per una gran quantitat de variables, d’origen fisiològic, psicològic i ambiental. Els episodis litiàsics, es poden solucionar espontàniament, amb l’expulsió del càlcul renal, o bé a través de diverses intervencions mèdiques. Els tractaments mèdics derivats de la litiasi urinària; és a dir, la fragmentació del càlcul, intervencions quirúrgiques i tractaments posteriors generen unes grans despeses als sistemes mèdics. Pels motius exposats, la identificació del desordre que ha originat l’episodi litiàsic és de radical importància, per tal de minimitzar el risc de reincidència. Els mètodes més usuals per determinar les causes que desencadenen la formació del càlcul renal són les anàlisis d’orina i l’estudi del càlcul generat. La correcta descripció de la composició i, especialment, l’estructura del càlcul renal pot aportar informació clau sobre les possibles causes de la seva formació, tant de l’inici de nucleació del càlcul com de les successives etapes de creixement cristal·lí. Tenint en compte aquest darrer aspecte, el present estudi s’ha dirigit a la caracterització de càlculs urinaris mitjançant l’aplicació de metodologies d’imatge química (Hyperspectral Imaging), el que va contribuir a determinar les principals característiques espectrals de cada compost majoritari als càlculs renals. D’altra banda, la utilització de mostres de composició coneguda ha possibilitat la creació d’un model amb Xarxes Neuronals Artificials, que permet la classificació de noves mostres de composició desconeguda, de manera més ràpida que el procediment actual. Aquest treball constitueix una nova contribució a la comprensió de l’estructura de les pedres de ronyó, així com les condicions de la seva formació. Els resultats obtinguts destaquen les possibilitats que presenten les tècniques emprades al camp de la litiasi renal, que permeten complementar els coneixements existents enfocats a millorar la qualitat de vida dels pacients.

Superoxide dismutases and glutaredoxins have a distinct role in the response of Candida albicans to oxidative stress generated by the chemical compounds menadione and diamide

To cope with oxidative stress, Candida albicans possesses several enzymes involved in a number of biological processes, including superoxide dismutases (Sods) and glutaredoxins (Grxs). The resistance of C. albicans to reactive oxygen species is thought to act as a virulence factor. Genes such as SOD1 and GRX2, which encode for a Sod and Grx, respectively, in C. albicans are widely recognised to be important for pathogenesis. We generated a double mutant, Δgrx2/sod1, for both genes. This strain is very defective in hyphae formation and is susceptible to killing by neutrophils. When exposed to two compounds that generate reactive oxygen species, the double null mutant was susceptible to menadione and resistant to diamide. The reintegration of the SOD1 gene in the null mutant led to recovery in resistance to menadione, whereas reintegration of the GRX2 gene made the null mutant sensitive to diamide. Despite having two different roles in the responses to oxidative stress generated by chemical compounds, GRX2 and SOD1 are important for C. albicans pathogenesis because the double mutant Δgrx2/sod1 was very susceptible to neutrophil killing and was defective in hyphae formation in addition to having a lower virulence in an animal model of systemic infection.

La infección por VIH y las intoxicaciones agudas por plaguicidas, incluidas en la lista de enfermedades de declaración obligatoria

Boletín semanal para profesionales sanitarios de la Secretaría General de Salud Pública y Participación Social de la Consejería de Salud

Central nervous system involvement at first relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy without intrathecal prophylaxis.

BACKGROUND The prevalence of and risk factors for central nervous system recurrence in patients with acute promyelocytic leukemia are not well established and remain a controversial matter. DESIGN AND METHODS Between 1996 and 2005, 739 patients with newly diagnosed acute promyelocytic leukemia enrolled in two consecutive trials (PETHEMA LPA96 and LPA99) received induction therapy with all-trans retinoic acid and idarubicin. Consolidation therapy comprised three courses of anthracycline monochemotherapy (LPA96), with all-trans retinoic acid and reinforced doses of idarubicin in patients with an intermediate or high risk of relapse (LPA99). Central nervous system prophylaxis was not given. RESULTS Central nervous system relapse was documented in 11 patients. The 5-year cumulative incidence of central nervous system relapse was 1.7% (LPA96 3.2% and LPA99 1.2%; p=0.09). The cumulative incidence was 0%, 0.8%, and 5.5% in low-, intermediate-, and high-risk patients, respectively. Relapse risk score (p=0.0001) and the occurrence of central nervous system hemorrhage during induction (5-year cumulative incidence 18.7%, p=0.006) were independent risk factors for central nervous system relapse. CONCLUSIONS This study shows a low incidence of central nervous system relapse in patients with acute promyelocytic leukemia following therapy with all-trans retinoic acid and anthracycline without specific central nervous system prophylaxis. Central nervous system relapse was significantly associated with high white blood cell counts and prior central nervous system hemorrhage, which emerged as independent prognostic factors.

Pharmacokinetic fluvoxamine-clomipramine interaction with favorable therapeutic consequences in therapy-resistant depressive patient.

We describe the case of a depressive patient who was a rapid metabolizer of CYP2D6 substrates and a heavy smoker, and who did not respond to several courses of treatment with antidepressants, as a result of unusually low drug-plasma levels. During hospitalization, he did not improve after treatment with clomipramine (150-225 mg/day during three weeks), but showed a response within four days after addition of fluvoxamine (100 mg/day). Plasma levels of clomipramine and desmethylclomipramine changed from 58 ng/ml and 87 ng/ml to 223 ng/ml and 49 ng/ml respectively one week after addition of fluvoxamine. Present knowledge of the role of cytochrome P-450 isozymes, such as CYP1A2, CYP2C19, CYP2D6, and CYP3A4, in the metabolism of psychotropic drugs as well as therapeutic drug-plasma level monitoring may thus help to determine individual treatment.

HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity.

BACKGROUND AND AIM The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. METHODS High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. RESULTS The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07). CONCLUSIONS HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.

Amniotic fluid iodine concentrations do not vary in pregnant women with varying iodine intake.

Iodine deficiency is an important clinical and public health problem. Its prevention begins with an adequate intake of iodine during pregnancy. International agencies recommend at least 200 microg iodine per d for pregnant women. We assessed whether iodine concentrations in the amniotic fluid of healthy pregnant women are independent of iodine intake. This cross-sectional, non-interventional study included 365 consecutive women who underwent amniocentesis to determine the fetal karyotype. The amniocentesis was performed with abdominal antisepsis using chlorhexidine. The iodine concentration was measured in urine and amniotic fluid. The study variables were the intake of iodized salt and multivitamin supplements or the prescription of a KI supplement. The mean level of urinary iodine was 139.0 (SD 94.5) microg/l and of amniotic fluid 15.81 (SD 7.09) microg/l. The women who consumed iodized salt and those who took a KI supplement had significantly higher levels of urinary iodine than those who did not (P = 0.01 and P = 0.004, respectively). The urinary iodine levels were not significantly different in the women who took a multivitamin supplement compared with those who did not take this supplement, independently of iodine concentration or multivitamin supplement. The concentrations of iodine in the amniotic fluid were similar, independent of the dietary iodine intake. Urine and amniotic fluid iodine concentrations were weakly correlated, although the amniotic fluid values were no higher in those women taking a KI supplement. KI prescription at recommended doses increases the iodine levels in the mother without influencing the iodine levels in the amniotic fluid.

Epigenetic regulation of human cancer/testis antigen gene, HAGE, in chronic myeloid leukemia.

BACKGROUND AND OBJECTIVES Cancer testis antigens (CTA) provide attractive targets for cancer-specific immunotherapy. Although CTA genes are expressed in some normal tissues, such as the testis, this immunologically protected site lacks MHC I expression and as such, does not present self antigens to T cells. To date, CTA genes have been shown to be expressed in a range of solid tumors via demethylation of their promoter CpG islands, but rarely in chronic myeloid leukemia (CML) or other hematologic malignancies. DESIGN AND METHODS In this study, the methylation status of the HAGE CTA gene promoter was analyzed by quantitative methylation-specific polymerase chain reaction (MSP) and sequencing in four Philadelphia-positive cell lines (TCC-S, K562, KU812 and KYO-1) and in CML samples taken from patients in chronic phase (CP n=215) or blast crisis (BC n=47). HAGE expression was assessed by quantitative reverse transcriptase-polymerase chain reaction. RESULTS The TCC-S cell line showed demethylation of HAGE that was associated with over-expression of this gene. HAGE hypomethylation was significantly more frequent in BC (46%) than in CP (22%) (p=0.01) and was correlated with high expression levels of HAGE transcripts (p<0.0001). Of note, in CP-CML, extensive HAGE hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (p=0.01) or imatinib (p=0.01), molecular response to imatinib (p=0.003) and progression-free survival (p=0.05). INTERPRETATIONS AND CONCLUSION: The methylation status of the HAGE promoter directly correlates with its expression in both CML cell lines and patients and is associated with advanced disease and poor outcome.

A three-year aeropalynological study in Estepona (southern Spain).

An aeropalynological study was carried out in the atmosphere of Estepona, a very popular tourist resort situated in the "Costa del Sol", (southern Spain) based on the data obtained during a three year air-monitoring programme (March 1995 to March 1998) using a volumetric pollen trap. The 34 taxa that reached a 10-day mean air pollen concentration equal to or greater than 1 grain of pollen/m(3) of air are reflected in the calendar. The first 10 taxa, in order of abundance, were: Cupressaceae, Olea europaea, Quercus, Poaceae, Urticaceae, Plantago, Pinus, Chenopodiaceae-Amaranthaceae, Ericaceae and Castanea, the first 3 of which accounted for approximately 56 % of the annual total pollen count. The greatest diversity of pollen type occurred during spring, while the highest pollen concentrations were reached from February-June, when approximately more than 80 % of the annual total pollen was registered. The lowest concentrations were obtaining during January, August and September. The annual quantity of pollen collected, the intensity and the dates on which the maximum peaks were recorded differed for the 3 years studied, which can be explained by reference to various meteorological parameters, especially rainfall and temperature. The pollen calendar spectrum is typically Mediterranean and similar to those of nearby localities, in which many pollen types are represented and the long tails indicating long flowering periods.

The diamine oxidase gene is associated with hypersensitivity response to non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity drug reactions. Histamine is released in the allergic response to NSAIDs and is responsible for some of the clinical symptoms. The aim of this study is to analyze clinical association of functional polymorphisms in the genes coding for enzymes involved in histamine homeostasis with hypersensitivity response to NSAIDs. We studied a cohort of 442 unrelated Caucasian patients with hypersensitivity to NSAIDs. Patients who experienced three or more episodes with two or more different NSAIDs were included. If this requirement was not met diagnosis was established by challenge. A total of 414 healthy unrelated controls ethnically matched with patients and from the same geographic area were recruited. Analyses of the SNPs rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742 and rs1049793 in the HDC, HNMT and DAO genes were carried out by means of TaqMan assays. The detrimental DAO 16 Met allele (rs10156191), which causes decreased metabolic capacity, is overrepresented among patients with crossed-hypersensitivity to NSAIDs with an OR  = 1.7 (95% CI  = 1.3-2.1; Pc  = 0.0003) with a gene-dose effect (P = 0.0001). The association was replicated in two populations from different geographic areas (Pc  = 0.008 and Pc  = 0.004, respectively). CONCLUSIONS AND IMPLICATIONS: The DAO polymorphism rs10156191 which causes impaired metabolism of circulating histamine is associated with the clinical response in crossed-hypersensitivity to NSAIDs and could be used as a biomarker of response.

Trends in yearly prevalence of third-generation cephalosporin and fluoroquinolone resistant Enterobacteriaceae infections and antimicrobial use in Spanish hospitals, Spain, 1999 to 2010.

Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp. are a major cause of infections in hospitalised patients. The aim of our study was to evaluate rates and trends of resistance to third-generation cephalosporins and fluoroquinolones in infected patients, the trends in use for these antimicrobials, and to assess the potential correlation between both trends. The database of national point prevalence study series of infections and antimicrobial use among patients hospitalised in Spain over the period from 1999 to 2010 was analysed. On average 265 hospitals and 60,000 patients were surveyed per year yielding a total of 19,801 E. coli, 3,004 K. pneumoniae and 3,205 Enterobacter isolates. During the twelve years period, we observed significant increases for the use of fluoroquinolones (5.8%-10.2%, p<0.001), but not for third-generation cephalosporins (6.4%-5.9%, p=NS). Resistance to third-generation cephalosporins increased significantly for E. coli (5%-15%, p<0.01) and for K. pneumoniae infections (4%-21%, p<0.01) but not for Enterobacter spp. (24%). Resistance to fluoroquinolones increased significantly for E. coli (16%30%, p<0.01), for K. pneumoniae (5%-22%, p<0.01), and for Enterobacter spp. (6%-15%, p<0.01). We found strong correlations between the rate of fluoroquinolone use and the resistance to fluoroquinolones, third-generation cephalosporins, or co-resistance to both, for E. coli (R=0.97, p<0.01, R=0.94, p<0.01, and R=0.96, p<0.01, respectively), and for K. pneumoniae (R=0.92, p<0.01, R=0.91, p<0.01, and R=0.92, p<0.01, respectively). No correlation could be found between the use of third-generation cephalosporins and resistance to any of the latter antimicrobials. No significant correlations could be found for Enterobacter spp.. Knowledge of the trends in antimicrobial resistance and use of antimicrobials in the hospitalised population at the national level can help to develop prevention strategies.

Effectiveness of Pregabalin as Monotherapy or Combination Therapy for Neuropathic Pain in Patients Unresponsive to Previous Treatments in a Spanish Primary Care Setting

BACKGROUND AND OBJECTIVE Patients from a previous study of neuropathic pain (NP) in the Spanish primary care setting still had symptoms despite treatment. Subsequently, patients were treated as prescribed by their physician and followed up for 3 months. Since pregabalin has been shown to be effective in NP, including refractory cases, the objective of this study was to assess the effectiveness of pregabalin therapy in patients with NP refractory to previous treatments. METHODS This was a post hoc analysis of pregabalin-naïve NP patients treated with pregabalin in a 3-month follow-up observational multicenter study to assess symptoms and satisfaction with treatment. Patients were evaluated with the Douleur Neuropathique en 4 questions (DN4), the Brief Pain Inventory (BPI) and the Treatment Satisfaction for Medication Questionnaire (SATMED-Q) overall satisfaction domain. RESULTS 1,670 patients (mean age 58 years, 59 % women), previously untreated or treated with ≥1 drug other than pregabalin, were treated with pregabalin (37 % on monotherapy). At 3 months, pain intensity and its interference with activities decreased by half (p < 0.0001), while the number of days with no or mild pain increased by a mean of 4.5 days (p < 0.0001). Treatment satisfaction increased twofold (p < 0.0001). Patients with a shorter history of pain and those with neuralgia and peripheral nerve compression syndrome (PCS) as etiologies had the highest proportion on monotherapy and showed the greatest improvements in pain-related parameters in their respective group categories. CONCLUSION Treatment with pregabalin (as monotherapy or combination therapy) provides benefits in pain and treatment satisfaction in patients with NP, including refractory cases. Shorter disease progression and neuralgia and PCS etiologies are favorable factors for pregabalin treatment response.

Planifier un sevrage aux glucocorticoïdes: stratégie diagnostique et thérapeutique [How to plan glucocorticoid withdrawal: diagnostic and therapeutic strategies]

Glucocorticoïds are widely used in medicine and associated with numerous complications. Whenever possible, dosage reduction or treatment withdrawal should be considered as soon as possible depending on the underlying disease being treated. Administration of glucocorticoids induces a physiologic negative feed-back on the hypothalamic-pituitary-adrenal (HPA) axis and three clinical situations can be distinguished during treatment withdrawal: reactivation of the disease for which the glucocorticoids were prescribed, acute adrenal insufficiency and steroid withdrawal syndrome. Acute adrenal insufficiency is a feared complication but probably rare. It is usually seen during stress situations and can be observed long after steroid withdrawal. There is no good predictive marker to anticipate acute adrenal insufficiency and clinical evaluation of the patient remains a key element in its diagnosis. If adrenal insufficiency is suspected, HPA suppression can be assessed with dynamic tests. During stress situation, steroid administration is then recommended depending on the severity of the stress.

Efficacy of two educational interventions about inhalation techniques in patients with chronic obstructive pulmonary disease (COPD). TECEPOC: study protocol for a partially randomized controlled trial (preference trial).

BACKGROUND Drugs for inhalation are the cornerstone of therapy in obstructive lung disease. We have observed that up to 75 % of patients do not perform a correct inhalation technique. The inability of patients to correctly use their inhaler device may be a direct consequence of insufficient or poor inhaler technique instruction. The objective of this study is to test the efficacy of two educational interventions to improve the inhalation techniques in patients with Chronic Obstructive Pulmonary Disease (COPD). METHODS This study uses both a multicenter patients´ preference trial and a comprehensive cohort design with 495 COPD-diagnosed patients selected by a non-probabilistic method of sampling from seven Primary Care Centers. The participants will be divided into two groups and five arms. The two groups are: 1) the patients´ preference group with two arms and 2) the randomized group with three arms. In the preference group, the two arms correspond to the two educational interventions (Intervention A and Intervention B) designed for this study. In the randomized group the three arms comprise: intervention A, intervention B and a control arm. Intervention A is written information (a leaflet describing the correct inhalation techniques). Intervention B is written information about inhalation techniques plus training by an instructor. Every patient in each group will be visited six times during the year of the study at health care center. DISCUSSION Our hypothesis is that the application of two educational interventions in patients with COPD who are treated with inhaled therapy will increase the number of patients who perform a correct inhalation technique by at least 25 %. We will evaluate the effectiveness of these interventions on patient inhalation technique improvement, considering that it will be adequate and feasible within the context of clinical practice.

Listado de verificación de procedimientos invasivos en nefrología: catéter peritoneal, catéter venoso central temporal para hemodiálisis y biopsia renal percutánea

Sección "Buenas prácticas en gestión clínica"