Absence of beta-amyloid deposits after immunization in Alzheimer disease with Lewy body dementia

OBJECTIVE: To describe the neuropathological and biochemical findings of the brain examination of a patient enrolled in the AN-1792(QS-21) trial with an initial clinical diagnosis of Alzheimer disease (AD), in whom Lewy body variant was thereafter clinically diagnosed. DESIGN: A case report. SETTING: University memory clinic. Patient A 74-year-old woman with clinical features of probable AD. Intervention The patient received 2 injections of 225 mug of AN-1792 (beta-amyloid [Abeta]) plus 50 mug of the adjuvant QS-21 at an interval of 4 weeks. The patient was an antibody responder with an IgG anti-AN-1792 antibody titer exceeding 10 000 and an IgM titer exceeding 3500. Maximum serum anti-Abeta titers were reached in 4.7 months. During the 3 following years, while the Mini-Mental State Examination score remained globally stable despite several confusional episodes, she developed clinical features of dementia with Lewy bodies. The patient died 34 months postimmunization. An autopsy was performed. MAIN OUTCOME MEASURES: Neuropathological and biochemical examination of the brain using standardized evaluation for tau, beta-amyloid, and synuclein deposits. RESULTS: Neither neuropathological nor biochemical examinations showed amyloid deposit in the brain of this immunized patient. For tau deposition, Braak stage was IV/VI, and the Western blot analysis score was 9c/10. The neuropathological semiquantitative score for alpha-synuclein aggregation was 4. There was no inflammation. These results were compared with those of an age-matched patient with AD and a control devoid of any neurological disease. CONCLUSION: In this Lewy body variant case, with globally stable functional and cognitive features, Abeta immunization resulted in a significant clearance of amyloid deposits, with remaining tau and synuclein pathological features in the brain. Patients with a Lewy body variant of AD should not be excluded from enrollment in Abeta-immunization trials.     

Effect of selenate on growth and photosynthesis of Chlamydomonas reinhardtii

Algal communities play a crucial role in aquatic food webs by facilitating the transfer of dissolved inorganic selenium (both an essential trace element and a toxic compound for a wide variety of organisms) to higher trophic levels. The dominant inorganic chemical species of selenium in freshwaters are selenite (SeO(3)(2-)) and selenate (SeO(4)(2-)). At environmental concentrations, selenite is not likely to have direct toxic effects on phytoplankton growth [Morlon, H., Fortin, C., Floriani, M., Adam, C., Garnier-Laplace, J., Boudou, A., 2005a. Toxicity of selenite in the unicellular green alga Chlamydomonas reinharditii: comparison between effects at the population and sub-cellular level. Aquat. Toxicol. 73(1), 65-78]. The effects of selenate, on the other hand, are poorly documented. We studied the effects of selenate on Chlamydomonas reinhardtii growth (a common parameter in phytotoxicity tests). Growth inhibition (96-h IC(50)) was observed at 4.5+/-0.2 microM selenate (p<0.001), an effective concentration which is low compared to environmental concentrations. Growth inhibition at high selenium concentrations may result from impaired photosynthesis. This is why we also studied the effects of selenate on the photosynthetic process (not previously assessed in this species to our knowledge) as well as selenate's effects on cell ultrastructure. The observed ultrastructural damage (chloroplast alterations, loss of appressed domains) confirmed that chloroplasts are important targets in the mechanism of selenium toxicity. Furthermore, the inhibition of photosynthetic electron transport evaluated by chlorophyll fluorescence induction confirmed this hypothesis and demonstrated that selenate disrupts the photosynthetic electron chain. Compared to the classical 'growth inhibition' parameter used in phytotoxicity tests, cell diameter and operational photosynthetic yield were more sensitive and may be convenient tools for selenate toxicity assessment in non-target plants.     

Impact of Laparoscopic Roux-en-Y Gastric Bypass on Metabolic Syndrome, Inflammation, and Insulin Resistance in Super Versus Morbidly Obese Women

Background  Although Roux-en-Y gastric bypass (RYGBP) is one of the preferred bariatric procedures in obese individuals, the efficacy of this procedure in the setting of super-obesity [body mass index (BMI) ≥50] is unclear. The aim of this study was to compare the efficacy of laparoscopic (L) RYGBP to reverse metabolic syndrome, inflammation, and insulin resistance in super-obese women compared to morbidly obese women. Methods  Seventy-three consecutive women were enrolled in this prospective study. Anthropometric, metabolic, and inflammatory biological parameters were assessed in 18 super-obese and 55 morbidly obese women before LRYGBP and 1 year after surgery. Metabolic syndrome was diagnosed according to the International Diabetes Federation definition. Results  Before surgery, super-obese women had a higher BMI, fat mass, blood insulin, and HOMA1-IR than morbidly obese women. Both groups had similar serum levels of C-reactive protein and orosomucoid. The incidence of metabolic syndrome, type 2 diabetes, and increased liver enzymes was comparable in the two groups. One year after LRYGBP, metabolic syndrome, type 2 diabetes, metabolic and inflammatory biological parameters were improved in the whole study population. A similar degree of improvement was observed in super-obese and morbidly obese women, although BMI and fat mass were persistently higher in super-obese patients. Conclusions  One year after surgery, LRYGBP was equally effective at reversing metabolic syndrome, inflammation, and insulin resistance in morbidly obese and super-obese women.     

Oxidative stress and proinflammatory effects of carbon black and titanium dioxide nanoparticles: Role of particle surface area and internalized amount

The ubiquitous presence of nanoparticles (NPs) together with increasing evidence linking them to negative health effects points towards the need to develop the understanding of mechanisms by which they exert toxic effects. This study was designed to investigate the role of surface area and oxidative stress in the cellular effects of two chemically distinct NPs, carbon black (CB) and titanium dioxide (TiO₂), on the bronchial epithelial cell line (16HBE14o-). CB and TiO₂ NPs were taken up by 16HBE cells in a dose-dependent manner and were localized within the endosomes or free in the cytoplasm. Oxidative stress produced inside the cell by NPs was well correlated to the BET surface area and endocytosis of NPs. Contrary to intracellular conditions only CB NPs produced reactive oxygen species (ROS) under abiotic conditions. Exposure of cells to NPs resulted in an increased granulocyte macrophage colony stimulating factor (GM-CSF) mRNA expression and secretion. Inflammatory effects of NPs were dependent on the surface area and were mediated through oxidative stress as they were inhibited by catalase. It can be concluded that NP induced oxidative stress and pro-inflammatory responses are well correlated not only with the BET (Brunauer, Emmett and Teller) surface of the individual NPs but also with the internalized amount of NPs. Differences of even few nanometers in primary particle size lead to significant changes in inflammatory and oxidative stress responses.     

cIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40 ligand

Peripheral blood monocytes are plastic cells that migrate to tissues and differentiate into various cell types, including macrophages, dendritic cells, and osteoclasts. We have described the migration of cellular inhibitor of apoptosis protein 1 (cIAP1), a member of the IAP family of proteins, from the nucleus to the Golgi apparatus in monocytes undergoing differentiation into macrophages. Here we show that, once in the cytoplasm, cIAP1 is involved in the degradation of the adaptor protein tumor necrosis factor receptor-associated factor 2 (TRAF2) by the proteosomal machinery. Inhibition of cIAP1 prevents the decrease in TRAF2 expression that characterizes macrophage formation. We demonstrate that TRAF2 is initially required for macrophage differentiation as its silencing prevents Ikappa-Balpha degradation, nuclear factor-kappaB (NF-kappaB) p65 nuclear translocation, and the differentiation process. Then, we show that cIAP1-mediated degradation of TRAF2 allows the differentiation process to progress. This degradation is required for the macrophages to be fully functional as TRAF2 overexpression in differentiated cells decreases the c-Jun N-terminal kinase-mediated synthesis and the secretion of proinflammatory cytokines, such as interleukin-8 and monocyte chemoattractant protein 1 (MCP-1) in response to CD40 ligand. We conclude that TRAF2 expression and subsequent degradation are required for the differentiation of monocytes into fully functional macrophages.     

Major depression in males: effects of age, severity and adaptation on sleep variables

Sleep abnormalities have been repeatedly demonstrated in major depression. However, the respective influences of age, severity, adaptation and gender have never been clearly disentangled. In a retrospective study, full polysomnograms of 67 male depressive patients and 67 carefully age-matched male healthy control subjects were analyzed. The usual differences associated with the sleep of depressed patients were observed. However, in contrast to most reports, REMS was also found to be reduced; although no comparisons between sexes can be made in this all-male study, one interpretation of this finding is that reduction of REMS is a marker of male depression. Age was found to influence most sleep variables, but not the order of their association with depression. Depression severity was found to be associated with Wake After Sleep Onset (WASO), REMS, and Non-REMS (NREMS). No residual adaptation effect was observed. One of the main markers of depression was in fact the absence of sleep, whether observed as long delays prior to entering sleep, or excessive intermittent awakenings. This sleep reduction affected both REMS and NREMS, in comparable percentages. This supports the hypothesis of a hyperarousal possibly linked to stress.     

Decreasing rate and extent of lymph node staging in patients undergoing radical prostatectomy may undermine the rate of diagnosis of lymph node metastases in prostate cancer

Background

At radical prostatectomy (RP), pelvic lymph node dissection (PLND) represents the most accurate staging procedure for the presence of lymph node (LN) metastases.

Objective

We evaluated the rate of PLND use and its lymph node count (LNC) over the last two decades. We also tested the relationship between LNC and the rate of pN1 stage.

Design, setting, and participants

Between 1988 and 2006, 130 080 RPs were recorded in 17 Surveillance Epidemiology and End Results registries.

Measurements

The statistical significance of temporal trends was evaluated with the chi-square trend test. Separate univariable and multivariable regression analyses tested the relationship between predictors and two end points: (1) lack of LN staging (pNx) and (2) presence of LN metastases (pN1).

Results and limitations

Stage pNx was recorded in 25.9% of patients, and pNx rate was higher in more contemporary years (30.1% in 2000–2006 vs 20.8% in 1988–1993; multivariable p < 0.001). When PLND was performed, an average of 7.4 LNs (median: 6) were removed. The average LNC decreased from 12.0 nodes (median: 12) in 1988 to 6.0 nodes (median: 4) in 2006. Overall pN1 rate was 3.4% and decreased from 10.7% to 3.1% between 1988 and 2006 (p < 0.001). LNC was an independent predictor of pN1 stage (multivariable p < 0.001).

Conclusions

An increasingly larger proportion of prostate cancer patients remain without LN staging at RP. Fewer LNs were removed at PLND over time, resulting in fewer patients diagnosed with pN1 stage at RP. The impact of this phenomenon on cancer control outcomes is still to be verified.     

Treatment with sunitinib enabled complete resection of massive lymphadenopathy not previously amenable to excision in a patient with renal cell carcinoma

We present a case of previously unresectable lymphadenopathy in a patient with renal cell carcinoma treated with sunitinib. Complete resection of a 15-cm left renal cell carcinoma was initially impossible due to massive retroperitoneal disease and encasement of the great vessels and mesenteric vessels. Residual retroperitoneal disease from a radical nephrectomy was treated with the oral, multitargeted receptor tyrosine kinase inhibitor, sunitinib. Tumour shrinkage following five cycles of treatment allowed uncomplicated complete resection of the lymphadenopathy. Follow-up after 6 mo showed no evidence of disease recurrence.