Molecular profiling of isolated histological components of Wilms tumor implicates a common role for the Wnt signaling pathway in kidney and tumor development

Wilms tumor (WT), a tumor composed of three histological components - blastema (BL), epithelia and stroma - is considered an appropriate model system to study the biological relationship between differentiation and tumorigenesis. To investigate molecular associations between nephrogenesis and WT, the gene expression pattern of individual cellular components was analyzed, using a customized platform containing 4,608 genes. WT gene expression patterns were compared to genes regulated during kidney differentiation. BL had a closer gene expression pattern to the earliest stage of normal renal development. The BL gene expression pattern was compared to that of fetal kidney (FK) and also between FK and mature kidney, identifying 25 common de-regulated genes supposedly involved in the earliest events of WT onset. Quantitative RT-PCR was performed, confirming the difference in expression levels for 13 of 16 genes (81.2%) in the initial set and 8 of 13 (61.5%) in an independent set of samples. An overrepresentation of genes belonging to the Wnt signaling pathway was identified, namely PLCG2, ROCK2 and adenomatous polyposis coli (APC). Activation of the Wnt pathway was confirmed in WT, using APC at protein level and PLCG2 at mRNA and protein level. APC showed positive nuclear immunostaining for an independent set of WT samples, similarly to the FK in week 11. Lack of PLCG2 expression was confirmed in WT and in FK until week 18. Taken together, these results provided molecular evidence of the recapitulation of the embryonic kidney by WT as well as involvement of the Wnt pathway in the earliest events of WT onset. Copyright (C) 2008 S. Karger AG, Basel.

Activation of the Wnt/Beta-catenin Signaling Pathway during Oral Carcinogenesis Process Is Not Influenced by the Absence of Galectin-3 in Mice

Background/Aim: Galectin-3 has been associated with activated Wnt pathway, translocating beta-catenin into the nucleus. However, it is still unknown whether this lectin drives the Wnt signaling activation in lesions from galectin-3-deficient (Gal3(-/-)) mice. The purpose was to study beta-catenin expression in tongue lesions from Gal3(-/-) and wildtype (Gal3(+/+)) mice and the status of Wnt signaling. Materials and Methods: Twenty Gal3(-/-) and Gal3(+/+) male mice were challenged with 4-nitroquinolin-1-oxide and killed at week 16 and 32. Tongues were processed and stained with H&E to detect dysplasias and carcinomas. An imunohistochemical assay was performed to evaluate beta-catenin expression. Results: Carcinomas were more evident in Gal3(+/+) than Gal3(-/-) mice (55.5% vs. 28.5%, respectively; p>0.05). Elevated expression of non-membranous beta-catenin was observed in dysplasias and carcinomas from both groups (p>0.05). Conclusion: Absence of galectin-3 does not interfere in the pattern of beta-catenin expression and therefore in the mediation of the Wnt signaling pathway.

Repetitive transcranial magnetic stimulation improve tinnitus in normal hearing patients: a double-blind controlled, clinical and neuroimaging outcome study

Background and purpose: Tinnitus is a frequent disorder which is very difficult to treat and there is compelling evidence that tinnitus is associated with functional alterations in the central nervous system. Targeted modulation of tinnitus-related cortical activity has been proposed as a promising new treatment approach. We aimed to investigate both immediate and long-term effects of low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) in patients with tinnitus and normal hearing. Methods: Using a parallel design, 20 patients were randomized to receive either active or placebo stimulation over the left temporoparietal cortex for five consecutive days. Treatment results were assessed by using the Tinnitus Handicap Inventory. Ethyl cysteinate dimmer-single photon emission computed tomography (SPECT) imaging was performed before and 14 days after rTMS. Results: After active rTMS there was significant improvement of the tinnitus score as compared to sham rTMS for up to 6 months after stimulation. SPECT measurements demonstrated a reduction of metabolic activity in the inferior left temporal lobe after active rTMS. Conclusion: These results support the potential of rTMS as a new therapeutic tool for the treatment of chronic tinnitus, by demonstrating a significant reduction of tinnitus complaints over a period of at least 6 months and significant reduction of neural activity in the inferior temporal cortex, despite the stimulation applied on the superior temporal cortex.

Ocular abnormalities in chronic schizophrenia: clinical implications

Objective: As part of a randomised double-blind study of a new atypical antipsychotic we sought to determine both the levels of visual acuity and the occurrence of toxic side-effects in a group of patients treated for many years on a variety of antipsychotics. Method: Twenty-three inpatients with a DSM-III-R diagnosis of chronic schizophrenia from two separate hospital locations who met the criteria for the double-blind trial were examined for ocular abnormalities at both baseline and at trial completion. Results: At baseline a high prevalence of abnormalities was identified: 19 patients (82.6%) were found to have one or more ocular abnormalities, including lens opacities/cataracts and corneal pigmentation; three patients, with delusions related to the sun, were noted to have solar burns; a high proportion (almost 70%) of patients had untreated visual acuity problems. No further changes were observed at the follow-up examinations. Conclusions: The possible causes of ocular disturbance in schizophrenia and the reasons for the relatively high ocular morbidity in this group are thought to result from both illness-related factors and the effects of antipsychotic medication. Causality is confounded by a number of issues such as the high prevalence of smoking, poor general health and the variety of antipsychotic medications used in the treatment of psychosis as well as substance abuse. The clinical implications are considered in this paper in relation to the move towards community-based psychiatric services.

Peritumoral brain edema in benign meningiomas: correlation with clinical, radiologic, and surgical factors and possible role on recurrence

Background: Approximately 60% of meningiomas are associated with peritumoral edema. Various causative factors have been discussed in the literature. The objective of this study was to investigate the correlation of PTBE with clinical, radiologic, and surgical aspects and recurrence of meningiomas. Methods: Sixty-one patients with benign meningiomas were chosen for surgical treatment by the Group of Brain Tumors and Metastasis of the Department of Neurosurgery. All patients underwent complete surgical resection (Simpson grades I and 2), and those with atypical and malignant histopathologic grades were excluded. Tumors located in the cavernous sinus, tuberculum sellae, foramen magnum, ventricles, and petroclival region were excluded. Results: Edema extension had a positive correlation with the higher recurrence rates (P=.042) and with the presence of irregular margins (P<.011) on bivariate analysis. Meningiomas with larger edema sizes also showed correlation with large meningiomas (P=.035), and the ones with smaller edema sizes correlated with the tentorial location (P=.032). Multivariate analysis showed an association between PTBE and the presence of seizures (odds ratio, 3.469), large meningiomas (odds ratio, 15.977), and for each cubic centimeter added to its size, the risk of edema increased 1.082 times (odds ratio). Conclusion: Peritumoral brain edema may be related to the invading potential of meningiomas and may play a role in the recurrence potential of the tumor. As a consequence, it is reasonable to consider the presence of edema as an additional factor to be taken into account when mapping out strategies for the treatment of meningiomas. (C) 2008 Elsevier Inc. All rights reserved.

Guanosine promotes B16F10 melanoma cell differentiation through PKC-ERK 1/2 pathway

Malignant melanoma is one of the most lethal cancers. Nowadays, several anti-melanoma therapies have been employed. However, the poor prognosis and/or the increased toxicity of those treatments clearly demonstrate the requirement of searching for new drugs or novel combined chemotherapeutic protocols, contemplating both effectiveness and low toxicity. Guanosine (Guo) has been used in combination with acriflavina to potentiate the latter`s antitumor activity, through still unknown mechanisms. Here, we show that Guo induces B16F10 melanoma cell differentiation, attested by growth arrest, dendrite-like outgrowth and increased melanogenesis, and also reduced motility. A sustained ERK 1/2 phosphorylation was observed after Guo treatment and ERK inhibition led to blockage of dendritogenesis. Intracellular cyclic AMP was not involved in ERK activation, since its levels remained unchanged. Protein kinase C (PKC), in contrast to phospholipase C (PLC), inhibition completely prevented ERK activation. While the classical melanoma differentiation agent forskolin activates cAMP-PKA-Raf-MEK-ERK pathway in B16F10 cells, here we suggest that a cAMP-independent, PKC-ERK axis is involved in Guo-induced B16F10 differentiation. Altogether, our results show that Guo acts as a differentiating agent, with cytostatic rather than cytotoxic properties, leading to a decreased melanoma malignancy. Thus, we propose that Guo may be envisaged in combination with lower doses of conventional anti-melanoma drugs, in an attempt to prevent or diminish their adverse effects. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

Clinical End Points and Response Criteria in Mycosis Fungoides and Sezary Syndrome: A Consensus Statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer

Mycosis fungoides (MF) and Sezary syndrome (SS), the major forms of cutaneous T-cell lymphoma, have unique characteristics that distinguish them from other types of non-Hodgkin`s lymphomas. Clinical trials in MF/SS have suffered from a lack of standardization in evaluation, staging, assessment, end points, and response criteria. Recently defined criteria for the diagnosis of early MF, guidelines for initial evaluation, and revised staging and classification criteria for MF and SS now offer the potential for uniform staging of patients enrolled in clinical trials for MF/SS. This article presents consensus recommendations for the general conduct of clinical trials of patients with MF/SS as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood, and visceral organs, and definition of end points and response criteria. These guidelines should facilitate collaboration among investigators and collation of data from sponsor-generated or investigator-initiated clinical trials involving patients with MF or SS. J Clin Oncol 29:2598-2607. (C) 2011 by American Society of Clinical Oncology

Clinical and immunopathological evaluation of epidermolysis bullosa acquisita

P>Background. Epidermolysis bullosa acquisita (EBA) is a subepidermal blistering disease with IgG antibodies against collagen VII. The disease is heterogeneous and can lead to significant morbidity. Aim. To characterize the clinical and laboratory profile of patients with EBA from Sao Paulo, Brazil. Methods. In total, 12 patients (mean age 24 years) were analysed for cutaneous and mucosal involvement, laboratory data and response to treatment. Results. Mucosal involvement occurred in 11 of the 12 patients (eyes in 4/12, nose in 4/9, pharynx-larynx in 5/9 and oesophagus in 4/10; 3 patients did not undergo nasopharyngeal examination and 2 paediatric patients did not undergo endoscopy). Using direct immunofluorescence, different patterns of deposits were found at the basement membrane zone: IgG (12/12), IgA (6/12), IgM (4/12), C3 (11/12). Indirect immunofluorescence (IIF) was positive in 6 of 12 patients, and IIF on salt-split skin detected dermal deposition in 10 of 12 patients. Antinuclear antibodies were found in 3 of 12 patients, but none of them fulfilled the criteria for systemic lupus erythematosus. After treatment, total remission was achieved in three patients and partial remission in five (three were maintained on minimal treatment, one on the full treatment and one was able to come off treatment). Two patients were lost to follow-up and the remaining two had disease flares. Complications were mainly mucosal (oesophageal stenosis, laryngeal synechia, symblephara and trichiasis). Conclusions. Mucosal involvement in EBA is a determining factor for disease morbidity. Complete evaluation of the patient, focusing on both cutaneous and extracutaneous sites is essential, as EBA may evolve to refractory disease, severely compromising its outcome.

Study of direct immunofluorescence, immunofluorescence mapping and light microscopy in porphyria cutanea tarda

BACKGROUND: Even though porphyria cutanea tarda is the most frequent type of porphyria, there are few studies about its cutaneous physiopathology. OBJECTIVE: To evaluate skin changes in porphyria cutanea tarda using light microscopy and direct immunofluorescence before and after treatment with chloroquine. To perform antigen immunomapping of bullae to study their level of cleavage. METHODS: Light microscopy and direct immunofluorescence of 28 patients are reported in three different phases: 23 patients with active porphyria before treatment (Phase A), 7 patients with clinical remission during treatment (Phase B), and 8 patients with biochemical remission (Phase C). Immunomapping was performed on 7 patients. RESULTS: In active porphyria, direct immunofluorescence showed homogenous and intense fluorescence on the inside and on the walls of blood vessels as well as in the dermal-epidermal junction. In clinical remission (Phase B) and biochemical remission (Phase C), the deposit of immunoglobulins was maintained, but the deposit of complement was reduced in most cases. Immunomapping revealed no standard cleavage plane. CONCLUSION: No correlation was observed between clinical response and immunoglobulin deposits. The reduction of complement favors the hypothesis that activation of the complement cascade represents an additional pathway that leads to endothelial damage.

Clinical, dermoscopic and histopathological evaluation of the Meyerson nevus - Case report

Meyerson nevi occur whenever a rare focal and transitory eczematous eruption arises around melanocytic lesions. The same phenomenon has also been observed in non-melanocytic lesions as well. Herein we report the case of a 25 year old, male patient, who had noticed, two months before, the arising of a pruriginous and erithematous halo around two nevi localized on his abdomen. The lesions were found to be atypical on dermoscopic examination and he was submitted to surgical excision of both nevi. Histopathological examination revealed displastic compound melanocytic nevi, surrounded by intraepidermical vesicles and spongiosis. Present report suggests that Meyerson phenomenon does not seem to alter dermoscopic features of nevi.

Effects of Aerobic Training on Psychosocial Morbidity and Symptoms in Patients With Asthma A Randomized Clinical Trial

Background: Asthma symptoms reduce patients daily activities, impair their health-related quality of life (HRQoL), and increase their reports of anxiety and depress, all of which seem to be related to a decrease in asthma control. Aerobic exercise training is known to improve aerobic fitness and reduce dyspnea in asthmatics; however, its effect in reducing psychologic distress and symptoms remains poorly understood. We evaluated the role of an aerobic training program in improving HRQoL (primary aim) and reducing psychologic distress and asthma symptoms (secondary aims) for patients with moderate or severe persistent asthma. Methods: A total of 101 patients were randomly assigned to either a control group or an aerobic training group and studied during the period between medical consultations. Control group patients (educational program plus breathing exercises) (n = 51) and training group patients (educational program plus breathing exercises plus aerobic training) (n = 50) were followed twice a week during a 3-month period. HRQoL and levels of anxiety and depression were quantified before and after treatment. Asthma symptoms were evaluated monthly. Results: At 3 months, the domains (physical limitations, frequency of symptoms, and psychosocial) and total scores of HRQoL, significantly improved only in the training group patients (P < .001); the number of asthma-symptom-free days and anxiety and depression levels also significantly improved in this group (P < .001). In addition, a linear relationship between improvement in aerobic capacity and the days without asthma symptoms was observed (r = 0.47; P < .01). Conclusions: Our results suggest that aerobic training can play an important role in the clinical management of patients with persistent asthma. Further, they may be especially useful for patients with higher degrees of psychosocial distress.

Experimental models of sepsis and their clinical relevance

Sepsis remains a major cause of morbidity and mortality mainly because of sepsis-induced multiple organ dysfunction. In contrast to preclinical studies, most clinical trials of promising new treatment strategies for sepsis have failed to demonstrate efficacy. Although many reasons could account for this discrepancy, the misinterpretation of preclinical data obtained from experimental studies and especially the use of animal models that do not adequately mimic human sepsis may have been contributing factors. In this review, the potentials and limitations of various animal models of sepsis are discussed to clarify to which extent these findings are relevant to human sepsis. Such models include intravascular infusion of endotoxin or live bacteria, bacterial peritonitis, cecal ligation and perforation, soft tissue infection, pneumonia or meningitis models using different animal species including rats, mice, rabbits, dogs, pigs, sheep, and nonhuman primates. Despite several limitations, animal models remain essential in the development of all new therapies for sepsis and septic shock because they provide fundamental information about the pharmacokinetics, toxicity, and mechanism of drug action that cannot be replaced by other methods. New therapeutic agents should be studied in infection models, even after the initiation of the septic process. Furthermore, debility conditions need to be reproduced to avoid the exclusive use of healthy animals, which often do not represent the human septic patient.

Factors affecting management decisions in rectal cancer in clinical practice: results from a national survey

Management of rectal cancer has become increasingly complex and a multidisciplinary approach is considered of key importance for improving outcomes. A national survey among specialists involved in this multidisciplinary setting was performed. A web-based survey containing 11 questions regarding rectal cancer management was sent to surgeons and medical oncologists registered by their corresponding societies as members. Statistical analysis was performed using the chi-square and Fisher`s exact tests for all categorical variables according to response to individual questions. Multivariate analysis was performed using Cox`s logistic regression. Overall, 418 email recipients responded the survey. Local staging was performed without either magnetic resonance imaging or endorectal ultrasound by 64% of responders. Seventy-two percent considered that final management decision should be made after neoadjuvant chemoradiation therapy. Additionally, 46% considered that an alternative procedure (local excision or observation) was appropriate in a patient with a complete clinical response. Colorectal surgeons were more frequently in favor of longer intervals after completion of chemoradiation therapy (P = 0.001) and of alternative management procedures after a complete clinical response (P = 0.02). After multivariate analysis, the choice of a watch and wait approach after a complete clinical response following neoadjuvant chemoradiation therapy was significantly more frequent among surgeons (OR 3.5, 95% CI 1.8-7.1). Surgeons seem to be more in favor of tailoring management of rectal cancer according to tumor response after neoadjuvant chemoradiation therapy, with longer intervals after chemoradiation therapy, decisions about treatment strategy being made after chemoradiation therapy instead of before, and the use of alternative surgical procedures after a complete clinical response following neoadjuvant therapy.

Safety of oral glutamine in the abbreviation of preoperative fasting; a double-blind, controlled, randomized clinical trial

Introduction: No study so far has tested a beverage containing glutamine 2 h before anesthesia in patients undergoing surgery. Objectives: The aim of the study was to investigate: 1) the safety of the abbreviation of preoperative fasting to 2 h with a carbohydrate-L-glutamine-rich drink; and 2) the residual gastric volume (RGV) measured after the induction of anesthesia for laparoscopic cholecystectomies. Methods: Randomized controlled trial with 56 women (42 (17-65) years-old) submitted to elective laparoscopic cholecystectomy. Patients were randomized to receive either conventional preoperative fasting of 8 hours (fasted group, n = 12) or one of three different beverages drunk in the evening before surgery (400 mL) and 2 hours before the initiation of anesthesia (200 mL). The beverages were water (placebo group, n = 12), 12.5% (240 mOsm/L) maltodextrine (carbohydrate group, n = 12) or the latter in addition to 50 g (40 g in the evening drink and 10g in the morning drink) of L-glutamine (glutamine group, n = 14). A 20 F nasogastric tube was inserted immediately after the induction of general anesthesia to aspirate and measure the RGV. Results: Fifty patients completed the study. None of the patients had either regurgitation during the induction of anesthesia or postoperative complications. The median (range) of RGV was 6 (0-80) mL. The RGV was similar (p = 0.29) between glutamine group (4.5 [0-15] mL), carbohydrate group (7.0 [0-80] mL), placebo group (8.5 [0-50] mL), and fasted group (5.0 [0-50] mL). Conclusion: The abbreviation of preoperative fasting to 2 h with carbohydrate and L-glutamine is safe and does not increase the RGV during induction of anesthesia. (Nutr Hosp. 2011;26:86-90) DOI:10.3305/nh.2011.26.1.4993