Solid-phase synthesis for thalidomide-based proteolysis-targeting chimeras (PROTAC).

A preloaded resin consisting of a thalidomide moiety and an ethylene-oxy linker allows the simple and fast formation of PROTACs. The feasibility of the procedure was illustrated by conjugating different protein kinase inhibitors. The biological functionality of an ibrutinib-like conjugate was then confirmed by a cellular experiment.

Anti-angiogenic effects of novel cyclin-dependent kinase inhibitors with a pyrazolo[4,3-d]pyrimidine scaffold.

BACKGROUND AND PURPOSE: Cyclin-dependent kinase 5 (CDK5) has recently emerged as an attractive target in several tumour entities. Inhibition of CDK5 has been shown to have anti-angiogenic effects in vitro and in vivo. However, potent inhibitors of CDK5, which can be applied in vivo, are still scarce. We have recently developed a new series of 5-substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines that show a preference for inhibiting CDK5 and tested them in vitro and in vivo in a murine model of hepatocellular carcinoma. EXPERIMENTAL APPROACH: All compounds were initially examined for effects on proliferation of HUVECs. The most potent compounds were then tested on migration, and one of them, LGR2674, was selected for assessing effects on nuclear fragmentation, cell cycle, cell viability and metabolic activity. Furthermore, LGR2674 was tested in a tube formation assay and in vivo in a murine model of hepatocellular carcinoma, induced by s.c. injection of HUH7 cells (measurement of in vivo toxicity, tumour vascularization, tumour cell proliferation and tumour size). KEY RESULTS: LGR2674 showed an EC50 in the low nanomolar range in the proliferation and migration assays. Cytotoxic effects started at 50 nM, a concentration that did not influence the cell cycle. In vivo, LGR2674 was well tolerated and caused a clear reduction in vessel density in the tumours; also tumour cell proliferation was inhibited and tumour growth retarded. CONCLUSIONS AND IMPLICATIONS: Pyrazolo[4,3-d]pyrimidine is a novel scaffold for the development of potent CDK inhibitors with in vivo potential. Such structures are good candidates for broadening our pharmacological arsenal against various tumours.

Reduced retinal nerve fibre layer thickness in children with severe obesity.

BACKGROUND: Some optic nerve diseases are silent and insidious. Recently, reduced thickness of retinal nerve fibre layer (RNFL) has been associated with increasing body mass index in adults. OBJECTIVES: To investigate the association of childhood obesity with RNFL measured by optical coherence tomography imaging. METHODS: Ninety-seven children aged 5-14 years classified according to standard deviation score of body mass index (SDS-BMI) were included. Parameters of metabolic risk, adipocytokines (leptin, adiponectin) and interleukin-6 were analyzed. All subjects underwent a comprehensive ophthalmologic examination with direct ophthalmoscopy. Evaluation of RNFL with optical coherence tomography of the head of the nerve was performed. RESULTS: RNFL thickness on the average and inferior, superior and nasal quadrants were decreased in severely obese children (SDS-BMI > 4) with respect to the other groups. However, no statistically significant association was found between the different groups of children and RNFL thickness in the temporal quadrant. There was a significant inverse correlation of RNFL thickness with adiposity indices (P = 0.016), leptin (P = 0.029) and interleukin-6 (P = 0.030) in overweight and obese children. CONCLUSIONS: These findings suggest that adiposity and obesity-related inflammatory factors may be associated with the loss of retinal ganglion cells in children.

Elevated advanced oxidation protein products (AOPPs) indicate metabolic risk in severely obese children.

BACKGROUND AND AIMS: The assessment of oxidative stress may aid in the identification of subsequent metabolic risk in obese children. The objective of this study was to determine whether the plasma level of advanced oxidation protein products, analyzed with a recently proposed modified assay that involves a delipidation step (mAOPPs), was related to metabolic risk factors (MRFs) in severely obese children. METHODS AND RESULTS: The plasma levels of mAOPPs were determined by spectrophotometry in 54 severely obese and 44 healthy children. We also measured lipid peroxidation biomarkers (thiobarbituric acid-reactive substances, malondialdehyde, and 8-isoprotane F(2α)) and sulfhydryl groups, a marker of antioxidant defense. Protein oxidation and lipid peroxidation markers were higher and sulfhydryl levels were lower in obese children compared with controls. Taking metabolic risk into account, obese children were subdivided according to the cutoff point (53.2 µmol/L) obtained for their mAOPPs values from the ROC curve. Anthropometric measures and the existence of hypertension did not differ between groups. The presence of dyslipidemia and insulin resistance was significantly higher in the group with higher mAOPPs levels. The highest levels of mAOPPs were found in the children with ≥3 MRFs. The level of mAOPPs was positively correlated with triglycerides and negatively correlated with high-density lipoprotein cholesterol. There was no correlation of this marker of protein oxidation with biomarkers of lipid peroxidation. CONCLUSION: The determination of mAOPPs in delipidated plasma is an easy way to evaluate protein oxidation. It may be useful in severely obese children for better cardiovascular risk assessment.

Fungal colonization and/or infection in non-neutropenic critically ill patients: results of the EPCAN observational study.

The purpose of this paper is to determine the incidence of fungal colonization and infection in non-neutropenic critically ill patients and to identify factors favoring infection by Candida spp. A total of 1,655 consecutive patients (>18 years of age) admitted for > or = 7 days to 73 medical-surgical Spanish intensive care units (ICUs) participated in an observational prospective cohort study. Surveillance samples were obtained once a week. One or more fungi were isolated in different samples in 59.2% of patients, 94.2% of which were Candida spp. There were 864 (52.2%) patients with Candida spp. colonization and 92 (5.5%) with proven Candida infection. In the logistic regression analysis risk factors independently associated with Candida spp. infection were sepsis (odds ratio [OR] = 8.29, 95% confidence interval [CI] 5.07-13.6), multifocal colonization (OR = 3.49, 95% CI 1.74-7.00), surgery (OR = 2.04, 95% CI 1.27-3.30), and the use of total parenteral nutrition (OR = 4.37, 95% CI 2.16-8.33). Patients with Candida spp. infection showed significantly higher in-hospital and intra-ICU mortality rates than those colonized or non-colonized non-infected (P < 0.001). Fungal colonization, mainly due to Candida spp., was documented in nearly 60% of non-neutropenic critically ill patients admitted to the ICU for more than 7 days. Proven candidal infection was diagnosed in 5.5% of cases. Risk factors independently associated with Candida spp. infection were sepsis, multifocal colonization, surgery, and the use of total parenteral nutrition.

Antibiotic prescription for community-acquired pneumonia in the intensive care unit: impact of adherence to Infectious Diseases Society of America guidelines on survival.

BACKGROUND: The purpose of our study was to analyze prognostic factors associated with mortality for patients with severe community-acquired pneumonia (CAP). METHODS: We conducted a prospective multicenter study including all patients with CAP admitted to the intensive care unit during a 15-month period in 33 Spanish hospitals. Admission data and data on the evolution of the disease were recorded. Multivariate analysis was performed using the SPSS statistical package (SPSS). RESULTS: A total of 529 patients with severe CAP were enrolled; the mean age (+/-SD) was 59.9+/-16.1 years, and the mean Acute Physiology and Chronic Health Evaluation (APACHE) II score (+/-SD) was 18.9+/-7.4. Overall mortality among patients in the intensive case unit was 27.9% (148 patients). The rate of adherence to Infectious Diseases Society of America (IDSA) guidelines was 57.8%. Significantly higher mortality was documented among patients with nonadherence to treatment (33.2% vs. 24.2%). Multivariate analysis identified age (odds ratio [OR], 1.7), APACHE II score (OR, 4.1), nonadherence to IDSA guidelines (OR, 1.6), and immunocompromise (OR, 1.9) as the variables present at admission to the intensive care unit that were independently associated with death in the intensive care unit. In 15 (75%) of 20 cases of Pseudomonas aeruginosa infection, the antimicrobial treatment at admission was inadequate (including 8 of 15 cases involving patients with adherence to IDSA guidelines). Chronic obstructive pulmonary disease (OR, 17.9), malignancy (OR, 11.0), previous antibiotic exposure (OR, 6.2), and radiographic findings demonstrating rapid spread of disease (OR, 3.9) were associated with P. aeruginosa pneumonia. CONCLUSIONS: Better adherence to IDSA guidelines would help to improve survival among patients with severe CAP. Pseudomonas coverage should be considered for patients with chronic obstructive pulmonary disease, malignancy, or recent antibiotic exposure.

Guías para el manejo de la neumonía comunitaria del adulto que precisa ingreso en el hospital / Guidelines for the management of community pneumonia in adult who needs hospitalization

La neumonía adquirida en la comunidad (NAC) sigue siendo un problema sanitario de primer orden. En España, la incidencia de este tipo de infección es de 162 casos por cada 100.000 habitantes, lo que supone 53.000 hospitalizaciones al año y un coste de 115 millones de euros. Además, en los últimos años se han producido avances significativos en el conocimiento de la etiología y el diagnóstico de la enfermedad. Al mismo tiempo se está consiguiendo una mejor comprensión del problema derivado del aumento de las resistencias bacterianas, y han aparecido nuevas alternativas terapéuticas para el manejo de esta enfermedad. Por todo ello, un grupo de expertos pertenecientes a tres sociedades científicas de nuestro país (Sociedad Española de Medicina Intensiva, Crítica y Unidades Coronarias - SEMICYUC; Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica - SEIMC; Sociedad Española de Neumología y Cirugía Torácica - SEPAR) se han reunido para, tras una revisión crítica de la literatura, elaborar las presentes Guías para el manejo de la NAC. En ellas se abordan aspectos de epidemiología, índices pronósticos, etiología, diagnóstico, tratamiento y prevención de la enfermedad. El objetivo que se persigue es ayudar a los clínicos en la toma de decisiones, sin olvidar destacar la importancia que tiene el conocer las características particulares de la NAC en cada zona

Community acquired pneumonia is still an important health problem. In Spain the year incidence is 162 cases per 100,000 inhabitants with 53,000 hospital admission costing 115 millions of euros per year. In the last years there have been significant advances in the knowledge of: aetiology, diagnostic tools, treatment alternatives and antibiotic resistance. The Spanish Societies of Intensive and Critical Care (SEMICYUC), Infectious Diseases and Clinical Microbiology (SEIMC) and Pulmonology and Thoracic Surgery (SEPAR) have produced these evidence-based Guidelines for the management of community acquired pneumonia in Adults. The main objective is to help physicians to make decisions about this disease. The different points that have been developed are: aetiology, diagnosis, treatment and prevention

[Guidelines for the management of community pneumonia in adult who needs hospitalization]. / Guías para el manejo de la neumonía comunitaria del adulto que precisa ingreso en el hospital.

Community acquired pneumonia is still an important health problem. In Spain the year incidence is 162 cases per 100,000 inhabitants with 53,000 hospital admission costing 115 millions of euros per year. In the last years there have been significant advances in the knowledge of: aetiology, diagnostic tools, treatment alternatives and antibiotic resistance. The Spanish Societies of Intensive and Critical Care (SEMICYUC), Infectious Diseases and Clinical Microbiology (SEIMC) and Pulmonology and Thoracic Surgery (SEPAR) have produced these evidence-based Guidelines for the management of community acquired pneumonia in Adults. The main objective is to help physicians to make decisions about this disease. The different points that have been developed are: aetiology, diagnosis, treatment and prevention.

Economic impact of Candida colonization and Candida infection in the critically ill patient.

The objective of the study presented here was to assess the economic impact of Candida colonization and Candida infection in critically ill patients admitted to intensive care units (ICUs). For this purpose, a prospective, cohort, observational, and multicenter study was designed. A total of 1,765 patients over the age of 18 years who were admitted for at least 7 days to 73 medical-surgical ICUs in 70 Spanish hospitals between May 1998 and January 1999 were studied. From day 7 of ICU admission to ICU discharge, samples of tracheal aspirates, pharyngeal exudates, gastric aspirates and urine were collected every week for culture. Prolonged length of stay was associated with severity of illness, Candida colonization or infection, infection by other fungi, antifungal therapy, treatment with more than one antifungal agent, and toxicity associated with this therapy. Compared to non-colonized, non-infected patients (n=720), patients with Candida colonization (n=880) had an extended ICU stay of 6.2 days (OR, 1.69; 95%CI, 1.53-1.87; P<0.001) and an extended hospital stay of 8.6 days (OR, 1.27; 95%CI, 1.16-1.40; P<0.001). The corresponding figures for patients with Candida infection (n=105) were 12.7 days for ICU stay (OR, 2.13; 95%CI, 1.72-2.64; P<0.001) and 15.5 days for hospital stay (OR, 1.23; 95%CI, 0.99-1.52; P=0.060). Candida colonization resulted in an additional 8,000 EUR in direct costs and Candida infection almost 16,000 EUR. Both Candida colonization and Candida infection had an important economic impact in terms of cost increases due to longer stays in both the ICU and in the hospital.

Reflexiones terapéuticas / Therapeutic considerations

No disponible

Coma metabólico secundario a sertralina / Sertraline-induced metabolic coma

La sertralina es un fármaco inhibidor de la recaptación de serotonina en el sistema nervioso central que se utiliza como antidepresivo. Entre sus efectos secundarios se ha descrito la presentación de síndrome de secreción inadecuada de ADH, especialmente en individuos de edad avanzada. En la mayoría de los pacientes afectados, los síntomas revistieron escasa gravedad y pudieron ser rápidamente revertidos. Presentamos los casos de 2 mujeres de mediana edad que desarrollaron SSIADH e hiponatremia severa después de haber seguido tratamiento con sertralina. Ambas ingresaron en nuestra unidad de cuidados intensivos en estado de coma inferior o igual a 8 puntos en la escala de Glasgow y necesitaron ventilación mecánica invasiva (AU)

Incidence of gastroesophageal reflux and aspiration in mechanically ventilated patients using small-bore nasogastric tubes.

BACKGROUND: Use of a large-bore nasogastric tube (NGT) and patient position are considered key factors in promoting gastroesophageal reflux (GER) and pulmonary aspiration in critically ill patients. The objective of this study was to determine the incidence of GER and pulmonary aspiration of gastric contents in mechanically ventilated (MV) patients using small-bore NGTs. METHODS: We studied 30 patients on mechanical ventilation for acute respiratory failure who tolerated enteral nutrition through a small-bore NGT. Patients were randomly assigned to a group with (n = 16) or without (n = 14) a small-bore NGT and were maintained in a semirecumbent position during the study. GER and aspiration of gastric contents were assessed by a radioisotopic technique. Scans were done 24 hours after technetium-99m administration (n = 30). In 9 patients a dynamic scintigraphy was performed immediately after colloid administration, and samples of blood and tracheal and oropharyngeal secretions were obtained basally, 30 minutes, and 24 hours after technetium administration and analyzed for radioactivity using a gamma counter. RESULTS: Both groups were similar in age, underlying diagnosis, number of days of mechanical ventilation at the day of study, and mortality. There were no GER reaching the oropharynx and aspiration of gastric contents in both groups. CONCLUSIONS: GER and aspiration of gastric contents were not detected in MV patients using small-bore NGTs and may be a simple measure to prevent ventilator-associated pneumonia.

Serum protein binding of itraconazole and fluconazole in patients with diabetes mellitus.

The protein binding of itraconazole and fluconazole in the serum of patients with insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus was investigated in vitro. The unbound percentage of itraconazole in patients with IDDM and NIDDM was significantly higher than that in healthy volunteers. In contrast, there were no significant differences in fluconazole protein binding. A negative correlation was established between itraconazole protein binding and albumin concentration, and a positive correlation with free fatty acid concentration. The existence of a larger percentage of unbound itraconazole in diabetes patients could imply a change in drug disposition and an alteration in the effect of the drug. This should be taken into consideration in long duration treatment, especially in view of the non-linear kinetics of itraconazole.

[Intercostal neurofibroma in a patient with von Recklinghausen's disease. Diagnostic utility of helical CT and nuclear magnetic resonance]. / Neurofibroma intercostal en paciente con enfermedad de Von Recklinghausen. Utilidad diagnóstica de la TC helicoidal y la RNM.

A 44 year-old man with a type I Neurofibromatosis (NFI) and an intercostal mass is presented. By means of percutaneous fine needle aspiration punction under CT control, this tumor could be diagnosed of neurofibroma. It is important to remark not only the role of helical CT with anatomical reconstruction in the diagnosis of intercostal tumors, but also that intercostal location of neurofibromas has been rarely reported in the literature. Because of frequent association between NFI and neoplasms, it is always necessary to perform histological study of every new tumor that appears in the course of this entity.

[Prognostic factors and etiology in patients with severe community-acquired pneumonia admitted at the ICU. Spanish multicenter study. Study Group on Severe Community-Acquired Pneumonia in Spain]. / Factores pronósticos y etiología de los pacientes con neumonía comunitaria grave ingresados en UCI. Estudio multicéntrico español. Grupo de Estudio de Neumonía Comunitaria Grave en Espanña.

OBJECTIVE: To determine the techniques used for the etiological diagnosis of community-acquired pneumonia in patients admitted to the intensive care unit (ICU) and to describe the predominant causative organisms as well as prognostic factors of ICU mortality. PATIENTS AND METHODS: A total of 262 patients with community-acquired pneumonia admitted to 26 ICUs between 1 November of 1991 and 31 October of 1992 were included in a prospective, open, multicenter study. RESULTS: The diagnostic techniques most frequently used were blood culture (243 cases) and simple tracheal aspirate (166 cases). Simple tracheal aspirate (58.4%), bronchoalveolar lavage (47.7%), and protected-specimen brush (44.2%) were the techniques that showed the highest diagnostic reliability. In 220 cases, techniques considered of high diagnostic probability were employed. With the use of these procedures, the most frequent causative pathogens were Streptococcus pneumoniae (13.6%) and Legionella pneumophila (9.5%). In 100 cases (45.5%), no pathogen was isolated. A total of 88 patients (33.6%) died during the ICU stay. Predictive variables of poor outcome selected by means of a multivariate analysis were as follows: multisystemic failure (OR = 28.6; 95% CI: 12.8-65.1; p = 0.0001), APACHE II at the time of ICU admission (OR = 5.3; 95% CI: 2.5-11.3; p = 0.0001), progression and/or spread of lung infection (OR = 4.5; 95% CI: 2.4-8.4; p = 0.0001), and shock on admission (OR = 8.48; 95% CI: 4.5-15.9; p = 0.0001). CONCLUSIONS: In 45.5% of patients with community-acquired pneumonia admitted to ICU, no causative pathogen was identified. The prognosis of these patients was influenced by the severity of disease assessed by APACHE II score and presence of multisystemic failure and shock at the time of ICU admission.

Effects of N-acetylcysteine on tissue oxygenation in patients with multiple organ failure and evidence of tissue hypoxia.

Covert tissue hypoxia, particularly of the splanchnic region, appears important in the pathogenesis of multiple organ failure (MOF). This investigation evaluates the effects of N-acetylcysteine (NAC) upon several measures of tissue oxygenation in 10 patients with severe MOF and evidence of splanchnic hypoxia (as suggested by a pathologically low value (< 7.32) of the pH of the gastric mucosa (pHi)). Patients were studied following a prospective, randomized, placebo-controlled, cross-over design. Measurements included pulmonary and systemic haemodynamics, cardiac output by thermodilution, arterial and mixed venous blood gas values, blood lactate concentration, whole-body oxygen uptake by analysis of the expired gases, and pHi by tonometry. A complete set of measurements was obtained before and 45 min after the infusion of NAC (150 mg.kg-1 in 250 mL of saline) and, also, before and 45 min after the infusion of an equivalent volume of saline. NAC increased the cardiac index and vasodilated the systemic circulation (p < 0.01). However, O2 delivery to the tissues did not increase because the arterial oxygen content fell after NAC (p < 0.01). Mean O2 extraction or lactate concentration did not change after NAC, and pHi fell slightly (from 7.11 +/- 0.21 to 7.07 +/- 0.21; p < 0.05). The infusion of saline did not modify any variable significantly. The O2 extraction fraction increased exponentially in those patients with reduced O2 transport to the tissues. These results argue against a beneficial effect of N-acetylcysteine upon tissue oxygenation in patients with severe multiple organ failure and evidence of splanchnic hypoxia. Furthermore, they suggest that the mechanisms controlling the extraction of oxygen by the peripheral tissues in these patients were not impaired.

[Colonic conduit: an alternative to the treatment of urinary incontinence]. / Conducto colónico: alternativa en el tratamiento de la incontinencia urinaria.

We report on 9 patients where on a colon conduit has been constructed. Seven of them suffered from a bladder etrophy, one had a sacral teratoma and the remaining one a vesical rhabdomyoma. The latter two had undergone total cystectomy. This technique involves creation of a conduit with isolation of 10-15 cm of a loop of sigmoid colon. One of its ends is sutured and both ureters become reimplanted with an antireflux procedure. The other end is exteriorized through the skin. Thereafter, once any reflux or uretero-colonic stenosis has been ruled out, the cutaneous stoma is detached and anastomose to the sigmoid colon. Complete technique has been used on six patients. Three of them were operated on two stages with no complications. One patient received one uretero-ureteral anastomosis. Another one had an antireflux technique together with anastomosis between the colon conduit and the sigmoid colon in a one-stage procedure. This same patient had a continent reservoir created with a portion of stomach and the colon conduit. In three cases only the first stage of this operation has been performed and the skin stoma has not been closed because of persisting faecal incontinence. Currently 6 patients are continent (2 of them remain with occasional nocturnal incontinence). The remainder have still an open stoma. Renal function and acid-base balance are normal in all of these patients. Three of them are on bicarbonate support therapy.

[Treatment of ureterocele by endoscopic puncture]. / Tratamiento del ureterocele mediante punción endoscópica.

Ureterocele is a congenital cystic dilatation of the intravesical segment of the ureter. As a consequence, the proximal ureter and renal pelvis become dilated and that results in renal-parenchymal pathological involvement. Management of this anomaly is still controversial. Among the therapeutical options there is a place for endoscopic punction. Our experience with 11 patients undergoing this treatment modality is reported. In all these cases endoscopic punction was the initial treatment. In 7 patients this technique was all that was needed. The technique of intravesical punction is described and its results are specified.

Altered methadone analgesia due to changes in plasma protein binding: role of the route of administration.

1. The effect of experimental inflammation on methadone analgesia was evaluated in rats, by the tail-flick test, after single intravenous (0.35 mg/kg) and subcutaneous (3 mg/kg) doses. 2. After i.v. administration a significant decrease (P < 0.05) in the area under the methadone time-response curve was seen in rats with experimental inflammation, when compared with control. However, no differences in the analgesic response to methadone were detected between control rats and rats with inflammation when the drug was administered by s.c. injection. 3. Plasma mucoprotein levels were significantly increased (P < 0.001) and methadone free fraction was significantly decreased in rats with inflammation (P < 0.05). In addition, after i.v. methadone a decrease in brain uptake in rats with inflammation was detected. A significant correlation between brain uptake index and plasma free fraction was also observed. 4. These results suggest that a decreased immediate response to i.v. methadone may occur in circumstances in which there is an increase in alpha 1 acid glycoprotein, but that this is not likely to be observed when the absorption is not instantaneous.

Protein binding of itraconazole and fluconazole in patients with cancer.

The serum protein binding of itraconazole and fluconazole, new azole antifungal agents, has been investigated in vitro, in serum from healthy volunteers and from patients with cancer. Protein binding was determined by ultrafiltration. Concentrations of both alpha 1-acid glycoprotein (AAG) and albumin (HSA) were measured in all serum samples. The serum protein binding of itraconazole was reduced in patients (96.02 +/- 1.41% vs 97.25 +/- 0.54%; p < 0.01) with respect to healthy volunteers. In contrast, fluconazole protein binding was increased in the same group of patients (22.96 +/- 3.60% vs 13.30 +/- 2.58%; p < 0.01). HSA levels in cancer patients were significantly decreased (p < 0.01) and AAG levels were found to be significantly elevated in patients with respect to control subjects (p < 0.05). A significant linear relationship between the bound/unbound concentration ratio of itraconazole and HSA (r2 = 0.3340; p < 0.01) was found. Similarly, a significant relation was established between the bound/unbound concentration ratio of fluconazole and AAG levels (r2 = 0.2235; p < 0.05). Thus, a weak association between the binding of these drugs and serum protein levels has been observed. It is concluded that both antifungal drugs show different protein binding behaviour in cancer patients.