Sleep and epilepsy in neonates

Background and objectiveIn clinical practice, the association between sleep and epilepsy has been increasingly observed in adults and during childhood. The aim of this article is to verify the relationship between sleep and epilepsy in the neonatal period in order to identify evidence and mechanisms to explain how epilepsy or neonatal seizures might disrupt sleep and how sleep might influence seizure occurrence and epilepsy during this age span.MethodsLiterature review with search of PubMed database using the key words neonatal seizures and sleep.Results and conclusionThe complex processes of cortical maturation are closely related to the regulation of sleep–wakefulness cycles. Sleep regulation in the context of neonatal seizures is frequently abnormal, and these alterations may be a result of the maladaptative plasticity of neuronal networks. Furthermore, in this situation altered connectivity might also be associated with other expressions of neurological dysfunction such as cognitive and behavioral problems. EEG background abnormalities and higher frequency of discharges are often associated with disrupted sleep organization. The outcome of newborns with seizures where sleep organization is undifferentiated seems to be more unfavorable.     

Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel.

Bisphosphonates (BP) prevent, reduce, and delay cancer-related skeletal complications in patients, and have substantially decreased the prevalence of such events since their introduction. Today, a broad range of BP with differences in potency, efficacy, dosing, and administration as well as approved indications is available. In addition, results of clinical trials investigating the efficacy of BP in cancer treatment-induced bone loss (CTIBL) have been recently published. The purpose of this paper is to review the current evidence on the use of BP in solid tumours and provide clinical recommendations. An interdisciplinary expert panel of clinical oncologists and of specialists in metabolic bone diseases assessed the widespread evidence and information on the efficacy of BP in the metastatic and nonmetastatic setting, as well as ongoing research on the adjuvant use of BP. Based on available evidence, the panel recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for patients with other solid tumours as primary disease. Dosing of BP should follow approved indications with adjustments if necessary. While i.v. administration is most often preferable, oral administration (clodronate, IBA) may be considered for breast cancer patients who cannot or do not need to attend regular hospital care. Early-stage cancer patients at risk of developing CTIBL should be considered for preventative BP treatment. The strongest evidence in this setting is now available for ZOL. Overall, BP are well-tolerated, and most common adverse events are influenza-like syndrome, arthralgia, and when used orally, gastrointestinal symptoms. The dose of BP may need to be adapted to renal function and initial creatinine clearance calculation is mandatory according to the panel for use of any BP. Subsequent monitoring is recommended for ZOL and PAM, as described by the regulatory authority guidelines. Patients scheduled to receive BP (mainly every 3-4 weeks i.v.) should have a dental examination and be advised on appropriate measures for reducing the risk of jaw osteonecrosis. BP are well established as supportive therapy to reduce the frequency and severity of skeletal complications in patients with bone metastases from different cancers.     

Secondary infections after pacemaker implantation

INTRODUCTION: Infectious complications following pacemaker implantation are not common but may be particularly severe. Localized wound infections at the site of implantation have been reported in 0.5% of the cases in the most recent series, with an average of about 2%. The incidence of septicemia and infectious endocarditis is lower, about 0.5% of the cases. The operator's experience, the duration of the procedure and repeat procedures are considered to be predisposing factors. CURRENT KNOWLEDGE AND KEY POINTS: The main cause of these infections has been recently demonstrated to be local contamination during implantation. The commonest causal organism is Staphylococcus (75 to 92% of the cases), Staphylococcus aureus being the cause of acute infections (less than 6 weeks), whereas Staphylococcus epidermidis is associated with cases of secondary infection (more than 2 months). The usual clinical presentation is infection at the site of the pacemaker but other forms such as abscess, endocarditis, rejection of the implanted material, septic emboli or phlebitis have been described. The diagnosis is confirmed by local and systemic biological investigations and by echocardiography (especially transesophageal echocardiography) in cases of right heart endocarditis. There are two axes of treatment: bactericidal double antibiotherapy and surgical ablation of the infected material either percutaneously or by cardiotomy. FUTURE PROSPECTS AND PROJECTS: A recent meta-analysis supported the role of systematic, preoperative, prophylactic antibiotic therapy in the prevention of these complications. These data should be confirmed by suitably powered clinical trials.     

Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors

Background  

Aberrant promoter hypermethylation of cancer-associated genes occurs frequently during carcinogenesis and may serve as a cancer biomarker. In this study we aimed at defining a quantitative gene promoter methylation panel that might identify the most prevalent types of renal cell tumors.     

High promoter methylation levels of APC predict poor prognosis in sextant biopsies from prostate cancer patients.

PURPOSE: Prostate cancer is a highly prevalent malignancy and constitutes a major cause of cancer-related morbidity and mortality. Owing to the limitations of current clinical, serologic, and pathologic parameters in predicting disease progression, we sought to investigate the prognostic value of promoter methylation of a small panel of genes by quantitative methylation-specific PCR (QMSP) in prostate biopsies. EXPERIMENTAL DESIGN: Promoter methylation levels of APC, CCND2, GSTP1, RARB2, and RASSF1A were determined by QMSP in a prospective series of 83 prostate cancer patients submitted to sextant biopsy. Clinicopathologic data [age, serum prostate-specific antigen (PSA), stage, and Gleason score] and time to progression and/or death from prostate cancer were correlated with methylation findings. Log-rank test and Cox regression model were used to identify which epigenetic markers were independent predictors of prognosis. RESULTS: At a median follow-up time of 45 months, 15 (18%) patients died from prostate cancer, and 37 (45%) patients had recurrent disease. In univariate analysis, stage and hypermethylation of APC were significantly associated with worse disease-specific survival, whereas stage, Gleason score, high diagnostic serum PSA levels, and hypermethylation of APC, GSTP1, and RASSF1A were significantly associated with poor disease-free survival. However, in the final multivariate analysis, only clinical stage and high methylation of APC were significantly and independently associated with unfavorable prognosis, i.e., decreased disease-free and disease-specific survival. CONCLUSIONS: High-level APC promoter methylation is an independent predictor of poor prognosis in prostate biopsy samples and might provide relevant prognostic information for patient management.     

Glutathione levels modulate domoic acid induced apoptosis in mouse cerebellar granule cells.

Exposure of mouse cerebellar granule neurons (CGNs) to domoic acid induced cell death, either by apoptosis or by necrosis, depending on its concentration. Necrotic damage predominated in response to domoic acid above 0.1 microM. In contrast, cell injury with apoptotic features (assessed by Hoechst staining and DNA laddering assay) was evident after exposure to lower concentrations of domoic acid (< or = 0.1 microM). The AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptor antagonist 2,3-dihydroxy-6-nitro-sulfamoylbenzo [f] quinoxaline, but not the N-methyl-D-aspartate receptor antagonist MK-801, prevented domoic acid-induced apoptosis. To evaluate the role of oxidative stress in domoic acid-induced apoptosis, experiments were carried out in CGNs isolated from wild-type mice (Gclm (+/+)) and mice lacking the modifier subunit of glutamate-cysteine ligase, the first and rate-limiting step of glutathione (GSH) biosynthesis (Gclm (-/-)). CGNs from Gclm (-/-) mice have very low levels of GSH and were more sensitive to domoic acid-induced apoptosis and necrosis than Gclm (+/+) CGNs. The antioxidant melatonin (200 microM) and the membrane-permeant GSH delivery agent GSH ethyl ester (2.5 mM) prevented domoic acid-induced apoptosis. Domoic acid increased formation of reactive oxygen species but did not affect intracellular GSH levels. Domoic acid also increased cytosolic and mitochondrial calcium levels, increased oxidative stress in mitochondria, and altered mitochondrial membrane potential, which ultimately caused cytochrome c release, activation of caspase-3, and degradation of poly (ADP-ribose) polymerase. These results indicate that low concentrations of domoic acid cause apoptotic neuronal cell death mediated by oxidative stress.     

Panretinal photocoagulation versus PRP plus intravitreal bevacizumab for high‐risk proliferative diabetic retinopathy (IBeHi study)

Purpose: To evaluate the effects of panretinal photocoagulation (PRP) compared with PRP plus intravitreal bevacizumab on best corrected visual acuity (BCVA) and total area of fluorescein leakage from active new vessels (NVs) in patients with high‐risk proliferative diabetic retinopathy (PDR). Methods: We carried out a prospective study of patients with high‐risk PDR and no prior laser treatment who were randomly assigned to receive PRP (PRP group) or PRP plus intravitreal injection of 1.5 mg of bevacizumab (PRP‐plus group). In all patients, the PRP was administered at two time‐points (weeks 1 and 3), with the intravitreal bevacizumab delivered at the end of the second laser episode in the PRP‐plus group. Standardized ophthalmic evaluation including Early Treatment Diabetic Retinopathy Study BCVA as well as stereoscopic fundus photography and fluorescein angiography were performed at baseline and at weeks 4, 9 (± 1) and 16 (± 2). Main outcome measures included changes in BCVA and in total area of fluorescein leakage from active NVs. Results: Twenty‐two (n = 30 eyes) consecutive patients completed the 16‐week follow‐up. There was no significant difference between the PRP and PRP‐plus groups with respect to age, gender, type or duration of diabetes, area of fluorescein leakage from active NVs or BCVA. No significant difference in BCVA was observed between the groups throughout the study period. However, the total area of actively leaking NVs was significantly reduced in the PRP‐plus group compared with the PRP group at weeks 4, 9 and 16 (p < 0.001). No major adverse events were identified. Conclusions: In the short‐term, the adjunctive use of intravitreal bevacizumab with PRP was associated with a greater reduction in the area of active leaking NVs than PRP alone in patients with high‐risk PDR.     

Multiple mechanisms of telomere maintenance exist and differentially affect clinical outcome in diffuse malignant peritoneal mesothelioma

PURPOSE: This study aims to investigate the prevalence of the two known telomere maintenance mechanisms, telomerase activity (TA) and alternative lengthening of telomeres (ALT), and to assess their prognostic relevance in diffuse malignant peritoneal mesothelioma (DMPM). EXPERIMENTAL DESIGN: In 44 DMPM specimens obtained from 38 patients, TA was determined using the telomeric repeat amplification protocol and ALT was detected by assaying ALT-associated promyelocytic leukemia nuclear bodies. The prognostic significance of telomere maintenance mechanisms was analyzed by Cox regression in the overall series and in a subset of 29 patients who underwent a uniform treatment regimen consisting of cytoreductive surgery and hyperthermic i.p. chemotherapy. RESULTS: Telomere maintenance mechanisms were detectable in 86.4% of DMPM: ALT or TA alone was found in 18.2% or 63.6% of lesions, respectively, whereas two cases (4.6%) were ALT+/TA+. TA and ALT proved to be inversely associated (P = 0.002). In the overall series, TA was prognostic for 4-year relapse (TA+ versus TA-, hazard ratio, 3.30; 95% confidence interval, 1.23-8.86; P = 0.018) and cancer-related death (TA+ versus TA-, hazard ratio, 3.56; 95% confidence interval, 1.03-12.51; P = 0.045), whereas ALT failed to significantly affect clinical outcome. These results held true also in the subset of patients submitted to uniform treatment with cytoreductive surgery and hyperthermic i.p. chemotherapy. CONCLUSIONS: Our results indicate that both known telomere maintenance mechanisms, TA and ALT, are present in DMPM and differentially affect patient prognosis.