Active angiogenesis in metastatic renal cell carcinoma predicts clinical benefit to sunitinib-based therapy.

BACKGROUND: Sunitinib represents a widely used therapy for metastatic renal cell carcinoma patients. Even so, there is a group of patients who show toxicity without clinical benefit. In this work, we have analysed pivotal molecular targets involved in angiogenesis (vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (KDR), phosphorylated (p)KDR and microvascular density (MVD)) to test their potential value as predictive biomarkers of clinical benefit in sunitinib-treated renal cell carcinoma patients. METHODS: Vascular endothelial growth factor-A, KDR and pKDR-Y1775 expression as well as CD31, for MVD visualisation, were determined by immunohistochemistry in 48 renal cell carcinoma patients, including 23 metastatic cases treated with sunitinib. Threshold was defined for each biomarker, and univariate and multivariate analyses for progression-free survival (PFS) and overall survival (OS) were carried out. RESULTS: The HistoScore mean value obtained for VEGF-A was 121.6 (range, 10-300); for KDR 258.5 (range, 150-300); for pKDR-Y1775 10.8 (range, 0-65) and the mean value of CD31-positive structures for MVD visualisation was 49 (range, 10-126). Statistical differences for PFS (P=0.01) and OS (P=0.007) were observed for pKDR-Y1775 in sunitinib-treated patients. Importantly, pKDR-Y1775 expression remained significant after multivariate Cox analysis for PFS (P=0.01; HR: 5.35, 95% CI, 1.49-19.13) and for OS (P=0.02; HR: 5.13, 95% CI, 1.25-21.05). CONCLUSIONS: Our results suggest that the expression of phosphorylated (i.e., activated) KDR in tumour stroma might be used as predictive biomarker for the clinical outcome in renal cell carcinoma first-line sunitinib-treated patients.

Trastornos del sueño en el paciente adulto hospitalizado / Disorders of sleep in the hospitalized adult patient

Hospitalized adult patients frequently have sleep complaints. The majority of studies have principally focused in ICU patients. However, many medical and surgical disorders can disrupt the normal sleep architecture. Sleep disorders in hospitalized patients are susceptible to be successfully treated with hypnotics and control of ambient factors. We reviewed papers published in the Medline between 1997 – 2012, those considered relevant are be discussed in this review.

[Silent celiac disease among 21 patients with cryptogenic epilepsy]. / Enfermedad celíaca silente en epilepsia criptogénica del adulto.

BACKGROUND: Celiac disease (CD) is predominant in women and young people. Atypical, non-enteric symptoms are more common among adults. There is also an association between CD and neurological disorders, especially with cerebellar ataxia, polyneuropathy and epilepsy. AIM: To study the frequency of CD in a group of adults with cryptogenic epilepsy. MATERIAL AND METHODS: Twenty one patients with cryptogenic epilepsy, aged 20 to 65 years (14 women) were studied, measuring IgA-anti transglutaminase antibodies and deamidated gliadin peptide (DGP) IgG and IgA antibodies. RESULTS: One patient had elevated titers of both types of antibodies. Small bowel biopsy showed villous atrophy and lymphocytic infiltration compatible with CD. CONCLUSIONS: One of 21 adult patients with cryptogenic epilepsy had a silent CD.

Enfermedad celíaca silente en epilepsia criptogénica del adulto / Silent celiac disease among 21 patients with cryptogenic epilepsy

Background: Celiac disease (CD) is predominant in women and young people. Atypical, non-enteric symptoms are more common among adults. There is also an association between CD and neurological disorders, especially with cerebellar ataxia, polyneuropathy and epilepsy. Aim: To study the frequency of CD in a group of adults with cryptogenic epilepsy. Material and Methods: Twenty one patients with cryptogenic epilepsy, aged 20 to 65years (14 women) were studied, measuring IgA-anti transglutaminase antibodies and deamidated gliadin peptide (DGP) IgG and IgA antibodies. Results: One patient had elevated titers of both types of antibodies. Small bowel biopsy showed villous atrophy and lymphocytic infiltration compatible with CD. Conclusions: One of 21 adult patients with cryptogenic epilepsy had a silent CD.

'Loss of pigment epithelium-derived factor enables migration, invasion and metastatic spread of human melanoma'.

Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein that displays broad anti-tumor activity based on dual targeting of the tumor microenvironment (anti-angiogenic action) and the tumor cells (direct anti-tumor action). Here, we show that PEDF expression is high in melanocytes, but it is lost during malignant progression of human melanoma. Using a high-throughput analysis of the data from microarray studies of molecular profiling of human melanoma, we found that PEDF expression is lost in highly invasive melanomas. In paired cell lines established from the same lesion but representing the high and low extremes of malignant potential, abundant PEDF expression was restricted to the poorly aggressive counterparts. We used RNA interference to directly address the functional consequences of PEDF silencing. PEDF knockdown in poorly aggressive melanoma cell lines augmented migration, invasion and vasculogenic mimicry, which translated into an increased in vivo metastatic potential. PEDF interference also significantly enhanced the migratory and invasive capability of normal melanocytes and moderately increased their proliferative potential. Our results show that loss of PEDF enables melanoma cells to acquire an invasive phenotype and, therefore, modulation of this multifunctional factor could be critical for the malignant progression of human melanoma.

Topiramato oral en status epiléptico refractario: revisión bibliográfica y experiencia local / Oral topiramate in refractory status epilepticus: bibliographic revision and local experience

Aim. To assess the efficiency of topiramate (TPM), an antiepileptic medication which possesses multiple mechanisms of action, a wide therapeutic spectrum and good pharmacokinetics in the management of status epilepticus (SE), especially in refractory. Several reports have shown that TPM presents different efficacy in the management of different types of refractory status epilepticus, both adults and children. Also present our experience with two patients with SE who responded early without TPM oral complications. Conclusions. TPM oral as drug associated, is an antiepileptic medication that has shown therapeuticefficacy in cases reports and observational studies the management SE of different types and nature. This efficacy has not been contrasted with randomized controlled trials and prospective studies, therefore, future studies with larger numbers of patients are needed to confirm published reports.

Síndrome de Kleine-Levin: caso clínico y revisión del tema / Kleine-Levin Syndrome: clinical case and revision

Episodic hypersomnia, compulsive excessive eating and erotic behaviour, with schizophreniclike mental symptoms are the hallmarks of the rare Kleine–Levin syndrome. Many patients may not necessarily fulfill minimum criteria described for diagnosis. We report a 19 years young man with incomplete presentation the Kleine–Levin syndrome and briefly reviewed the most relevantaspects of this disorder, its epidemiology, clinical symptoms and complementary diagnostic examinations. Known therapeutic options and prognosis are also discussed.

Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer.

Colorectal cancer is a major cause of cancer death worldwide. A number of key oncogenes and tumor suppressor genes have been proposed to drive progression from healthy colonic epithelia to malignant tumors, including members of the Wnt/beta-catenin pathway. Recently, CpG island promoter hypermethylation was shown to cause inactivation of two extracellular Wnt inhibitors in colon cancer: secreted frizzled-related proteins (sFRPs) and Wnt inhibitory factor-1 (WIF-1). Here, we show for the first time that another extracellular Wnt inhibitor, the DICKKOPF-1 (DKK-1) gene, is transcriptionally silenced by CpG island promoter hypermethylation in colon cancer cell lines (n=9), whereas treatment with the DNA-demethylating agent 5-aza-2-deoxycytidine restored DKK-1 expression. Restoration of DKK-1 function in non-expressing cells bearing a truncated APC (Adenomatous Polyposis Coli) gene had no effect on beta-catenin/T-cell factor-dependent transcription, but induced tumor suppressor-like features such as reduced colony formation density and tumor growth inhibition in nude mice. These results suggest additional functions for DKK-1 other than inhibiting canonical Wnt signaling. In primary colorectal tumors, DKK-1 was found hypermethylated in 17% (nine of 54) of cases. Furthermore, while for both SFRP-1 and WIF-1 methylation-associated silencing occurred across the whole spectrum of colorectal tumorigenesis, DKK-1 promoter was selectively hypermethylated in advanced colorectal neoplasms (Duke's C and D tumors).

Panencefalitis esclerosante subaguda de inicio en edad adulta: presentación atípica en 2 pacientes / Adult onset subacute sclerosing panencephalitis: atypical presentation in 2 cases

Subacute sclerosing panencephalitis is an infrequent central nervous system viral disease and is a late manifestation of persistent infection by a mutant form of measles virus. Since it affects mainly children and teenagers, the diagnosis in older ages is difficult. Its main clinical symptoms are cognitive impairment, behavioral disturbances and myoclonia. We report two males, aged 21 and 22 years old, presenting with the disease with atypical manifestations. One had a catatonic syndrome and the other, amaurosis. The recognition of the different presentation forms of the disease, endemic in developing countries, allows an earlier diagnosis and a more efficient treatment, when available

La epilepsia refractaria del adulto y los antiepilépticos nóveles: el rol de la gabapentina / Refractary epilepsy in adults and new antiepileptic drugs: role of gabapentin

The features of refractory epilepsies and the role of functional surgery and new antiepileptic drugs is reviewed. Among the latter, gabapentin, a drug with peculiar pharmacokinetic properties, is highlighted as a therapeutic alternative in refractory epilepsies and eventually for epileptic patients without previous treatment. A new type of relationship between the pharmaceutical industry and physicians, that privileges clinical research is discussed

Partition of rose bengal anion from aqueous medium into a lipophilic environment in the cell envelope of Salmonella typhimurium: implications for cell-type targeting in photodynamic therapy.

Photodynamic therapy employs photosensitizers for the selective destruction of tumor tissue while sparing the surrounding healthy tissue. Photosensitization may also be applied to the selective eradication of microorganisms. Photosensitized inactivation requires that the sensitizer bind to the target and therefore the factors that determine photosensitizer binding are critical to photosensitization selectivity. This paper reports the determination of some features of the binding site of the potent photosensitizer, Rose Bengal, in Salmonella bacteria and describes some of the factors that affect this binding. The shift in the wavelength of maximum fluorescence and experiments with the fluorescence quencher TNBS indicate that Rose Bengal is located in a non-aqueous compartment such as the outer membrane. The dye does not seem to significantly accumulate inside the cell, but rather to accumulate in the outer membrane. Time-dependent changes in sensitizer localization in two strains of Salmonella typhimurium that differ in cell wall formation, LT-2 and TA1975, correspond to their differences in susceptibility to photosensitized killing. Therefore these results provide clues to the factors that determine photosensitization selectivity. Understanding this phenomenon is essential for the efficient design of selective photosensitizers and for optimizing antitumor and antiviral photodynamic therapy.

Carbamazepina: consideraciones prácticas / Carbamazepine: practical considerations

Se revisan las características farmacológicas clínicas de la Carbamazepina y se hace hincapié en las dificultades de índole práctica que ocasiona el uso de este fármaco antiepiléptico

Phototoxicity mechanism of a kryptocyanine dye in human red cell membranes and isolated murine mitochondria.

The phototoxicity mechanism of a kryptocyanine dye, N,N'-bis(2-ethyl-1,3-dioxolane)kryptocyanine (EDKC+), has been studied in RBC membranes and isolated mitochondria. Lipophilic, positively charged dyes, such as EDKC+, may be useful as tumor-cell-selective, light-activated cytotoxic agents. Exposure of the RBC membranes to 700-nm light and EDKC+ inhibited membrane acetylcholinesterase and photodecomposed EDKC+ in air-purged but not argon-purged samples. Photoinactivation of acetylcholinesterase was the same in D2O as in H2O and was not quenched by superoxide dismutase. Ascorbate and azide (10 mM) quenched or slightly enhanced, respectively, the inactivation. In argon-purged samples containing methyl viologen, EDKC+ photodecomposed, but acetylcholinesterase activity was unaffected. The mechanism may involve electron transfer to oxygen and subsequent formation of toxic photoproducts from EDKC+. In contrast, exposure of murine mitochondria to EDKC+ and 700-nm light caused inhibition of mitochondrial respiration in both the presence and absence of oxygen. The photodecomposition of EDKC+ correlated with inhibition of respiration. Thus, the phototoxicity of EDKC+ in mitochondria may be due to electron transfer from photoexcited EDKC+ to oxygen and electron acceptors in the membrane. These studies indicate that dyes such as EDKC+ may be useful for photochemotherapy of hypoxic regions in tumors.