Abstract Background Until now the therapeutic value of lymphadenectomy for renal-cell carcinoma has remained controversial. Several studies attempting to solve this controversy have been published, ...but none of them were set up as prospective randomized trials. Objective To assess whether a complete lymph-node dissection in conjunction with a radical nephrectomy for renal-cell cancer is more effective than a radical nephrectomy alone. Design, setting, and participants In 1988, the European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Group started a randomized phase 3 trial comparing radical nephrectomy with a complete lymphadenectomy to radical nephrectomy alone. After the renal-cell carcinoma was judged to be N0M0 and resectable, patients were randomly selected prior to surgery to undergo either a radical nephrectomy with a complete lymph-node dissection or to undergo a radical nephrectomy alone. Postoperatively all patients were followed for progression of disease and mortality. Intervention All patients underwent a radical nephrectomy with or without a complete lymph-node dissection. Measurements All patients were postoperatively evaluated for time-to-progression, overall survival, and progression-free survival. Time-to-event curves were estimated based on the Kaplan-Meier method and compared using a two-sided log-rank test. Results and limitations Of the 772 patients selected for randomization, 40 were not eligible for the study. 383 patients were randomly selected to receive a complete lymph-node dissection together with a radical nephrectomy, and 389 patients were randomly selected to undergo a radical nephrectomy alone. The complication rate did not differ significantly between the two groups. Complete lymph-node dissections in 346 patients revealed an absence of lymph-node metastases in 332 patients. The study revealed no significant differences in overall survival, time to progression of disease, or progression-free survival between the two study groups. Conclusions This study shows that, after proper preoperative staging, the incidence of unsuspected lymph-node metastases is low (4.0%) and that, notwithstanding a possible relationship to this low incidence rate, no survival advantage of a complete lymph-node dissection in conjunction with a radical nephrectomy could be demonstrated.
Ménière disease is characterized by endolymphatic hydrops, whereas perilymphatic enhancement on MR imaging has been suggested to be of additional value in diagnosing Ménière disease. This study ...evaluates the presence of endolymphatic hydrops and perilymphatic enhancement in patients with Ménière disease and with other vertigo-associated inner ear pathology.
A 3D-FLAIR sequence 4 hours after intravenous gadolinium injection was performed to visualize the endolymph and perilymph in 220 patients suspected of having Ménière disease. Patients' ears were retrospectively categorized as having Ménière disease (probable or definite) or other vertigo-associated inner ear pathology not attributable to Ménière disease. Endolymphatic hydrops was evaluated using a visual classification system, and perilymphatic enhancement was scored both visually and quantitatively.
Endolymphatic hydrops was present in 137 (91.9%) of the definite Ménière disease ears and in 9 (7.0%) of the ears with other vertigo-associated inner ear pathology (
< .001). The combination of endolymphatic hydrops and visually increased perilymphatic enhancement was present in 122 (81.9%) definite Ménière disease ears compared with 4 (3.1%) ears with other vertigo-associated inner ear pathology (
< .001). This combination increases the positive predictive value from 0.94 for endolymphatic hydrops and 0.91 for perilymphatic enhancement to 0.97. The addition of measured perilymphatic enhancement leads to a moderate decrease in sensitivity from 0.92 for endolymphatic hydrops to 0.86.
The combination of perilymphatic enhancement and endolymphatic hydrops in patients suspected of having Ménière disease increases the positive predictive value in the diagnosis of definite Ménière disease.
A healthy dietary pattern defined by international recommendations of the World Health Organisation (WHO) has been shown to reduce overall mortality risk. It is unknown whether this healthy dietary ...pattern is associated with overall cancer incidence.
In total 35,355 men and women within the Dutch European Prospective Investigation into Cancer and Nutrition-cohort were followed for cancer occurrence. Diet was assessed through a validated food-frequency questionnaire. We computed a dietary score for all participants based on the seven WHO dietary guidelines for the prevention of chronic diseases (Healthy Diet Indicator (HDI)). We used the existing HDI score based on the 1990 WHO guidelines, and adapted it to meet with the 2002 WHO guidelines. Multivariate-adjusted Cox proportional hazards analysis was used to examine the association between adherence to the HDI and subsequent overall cancer risk.
A number of 3,007 new cancers were identified during a mean follow-up of 12.7 years. Adherence to the HDI was not associated with a reduced overall cancer risk. The hazard ratio (HR) of overall cancer associated with a one-point increment of the HDI was 0.96 (95% CI 0.89-1.03) in men, and 1.00 (95% CI 0.96-1.04) in women. Adherence to the HDI was not associated with smoking-related cancer ((HR men: 0.94 (95% CI 0.84-1.04); HR women: 1.00 (95% CI 0.94-1.07)), or alcohol-related cancer ((HR men: 1.02 (95% CI 0.87-1.20); HR women: 1.03 (95% CI 0.98-1.08)).
Greater adherence to the WHO's Healthy Diet Indicator, a dietary pattern for prevention of chronic diseases, was not associated with reduced overall, smoking-related or alcohol-related cancer risk in men or women.
Axonal degeneration is the likely cause of disease progression in multiple sclerosis (MS). Our previous results indicated that neuron-specific N-acetylaspartate (NAA) is a candidate CSF biomarker for ...disease progression in MS. The aim of this study was to explore the potential of NAA as an early biomarker of axonal damage in MS. Next, we wanted to know the additional value of measurement of NAA compared to other candidate markers for axonal damage, such as neurofilament subunits and tau protein.
Levels of NAA, neurofilament light, neurofilament heavy, and tau were determined in CSF of patients with clinically isolated syndrome (CIS, n = 38), relapsing-remitting MS (RRMS, n = 42), secondary progressive MS (SPMS, n = 28), and primary progressive MS (PPMS, n = 6); patients without neurologic disease (ND, n = 28); noninflammatory neurologic controls (n = 18); and inflammatory neurologic controls (n = 39).
CSF NAA levels were decreased in patients with SPMS compared to ND controls, patients with CIS, and patients with RRMS. CSF NAA levels in patients with CIS and RRMS were similar to those in ND subjects. All axonal damage proteins showed specific patterns of changes and relations with disease activity measures. The neurofilament light chain levels were already increased in patients with CIS, especially in patients who converted to MS. The neurofilament heavy chain levels were highest in the patients with SPMS. Tau levels were similar in MS and ND.
CSF N-acetylaspartate (NAA) levels were not different from patients without neurologic disease in early stages of multiple sclerosis, though decreased as the disease progressed. Combining CSF NAA and neurofilament levels yields information on different phases of axonal pathology.
Apomixis, the clonal formation of seeds, is a rare yet widely distributed trait in flowering plants. We have isolated the PARTHENOGENESIS (PAR) gene from apomictic dandelion that triggers embryo ...development in unfertilized egg cells. PAR encodes a K2-2 zinc finger, EAR-domain protein. Unlike the recessive sexual alleles, the dominant PAR allele is expressed in egg cells and has a miniature inverted-repeat transposable element (MITE) transposon insertion in the promoter. The MITE-containing promoter can invoke a homologous gene from sexual lettuce to complement dandelion LOSS OF PARTHENOGENESIS mutants. A similar MITE is also present in the promoter of the PAR gene in apomictic forms of hawkweed, suggesting a case of parallel evolution. Heterologous expression of dandelion PAR in lettuce egg cells induced haploid embryo-like structures in the absence of fertilization. Sexual PAR alleles are expressed in pollen, suggesting that the gene product releases a block on embryogenesis after fertilization in sexual species while in apomictic species PAR expression triggers embryogenesis in the absence of fertilization.
It is generally assumed that floods during the growing season have a strong impact on the distribution of grassland plant species in river floodplains but this proposition has never been tested. We ...examined the survival and growth responses of twenty species, originating from mid- and high-level floodplain grasslands along the River Rhine in the Netherlands, to total submergence for a maximum of two months in an outdoor flooding experiment. Plant survival and biomass reduction with flooding duration was determined as well as biomass recovery after de-submergence. Our results indicate that species survival is the most prominent factor correlated with species distribution in floodplain areas. Relatively flood tolerant species occurred mainly at low elevations along the floodplain while more flood sensitive species were restricted to high parts of the floodplain gradient. Biomass reduction rates during submergence were only marginally significantly correlated with species lower distribution boundaries along the flooding gradient. Biomass recovery rate was significantly correlated with species distribution patterns in the field only after 2 weeks of complete submergence, but not after 4 and 8 weeks. Our results suggest that the more flood tolerant species can have various ways to survive and recover from flooding, ranging from low rates of biomass loss and low recovery to relatively high rates of biomass loss and quick recovery. Our results are consistent with the notion that disturbance by floods during the growing season is an important determinant of species lower distribution boundaries in river floodplains. They also suggest that high survival under flooding may be achieved by different physiological mechanisms. Such mechanisms are discussed in this paper.
High systemic cholesterol levels have been associated with osteoarthritis (OA) development. Therefore, cholesterol lowering by statins has been suggested as a potential treatment for OA. We ...investigated whether therapeutic high-intensive cholesterol-lowering attenuated OA development in dyslipidemic APOE∗3Leiden.CETP mice.
Female mice (n = 13–16 per group) were fed a Western-type diet (WTD) for 38 weeks. After 13 weeks, mice were divided into a baseline group and five groups receiving WTD alone or with treatment: atorvastatin alone, combined with PCSK9 inhibitor alirocumab and/or ANGPTL3 inhibitor evinacumab. Knee joints were analysed for cartilage degradation, synovial inflammation and ectopic bone formation using histology. Aggrecanase activity in articular cartilage and synovial S100A8 expression were determined as markers of cartilage degradation/regeneration and inflammation.
Cartilage degradation and active repair were significantly increased in WTD-fed mice, but cholesterol-lowering strategies did not ameliorate cartilage destruction. This was supported by comparable aggrecanase activity and S100A8 expression in all treatment groups. Ectopic bone formation was comparable between groups and independent of cholesterol levels.
Intensive therapeutic cholesterol lowering per se did not attenuate progression of cartilage degradation in dyslipidemic APOE∗3Leiden.CETP mice, with minor joint inflammation. We propose that inflammation is a key feature in the disease and therapeutic cholesterol-lowering strategies may still be promising for OA patients presenting both dyslipidemia and inflammation.
Both systemic inflammation and dyslipidemia contribute to osteoarthritis (OA) development and have been suggested as a possible link between metabolic disease and OA development. Recently, the CANTOS ...trial showed a reduction in knee and hip replacements after inhibition of IL-1β in patients with a history of cardiovascular disease and high inflammatory risk. In this light, we investigated whether inhibition of IL-1β combined with cholesterol-lowering therapies can reduce OA development in dyslipidemic APOE∗3Leiden mice under pro-inflammatory dietary conditions.
Female ApoE3∗Leiden mice were fed a cholesterol-supplemented Western-Type diet (WTD) for 38 weeks. After 14 weeks, cholesterol-lowering and anti-inflammatory treatments were started. Treatments included atorvastatin alone or with an anti-IL1β antibody, and atorvastatin combined with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor alirocumab without or with the anti-IL1β antibody. Knee joints were analyzed for cartilage degradation, synovial inflammation and ectopic bone formation using histology at end point.
Cholesterol-lowering treatment successfully decreased systemic inflammation in dyslipidemic mice, which was not further affected by inhibition of IL-1β. Synovial thickening and cartilage degeneration were significantly decreased in mice that received cholesterol-lowering treatment combined with inhibition of IL-1β (P < 0.01, P < 0.05, respectively) compared to mice fed a WTD alone. Ectopic bone formation was comparable between all groups.
These results indicate that inhibition of IL-1β combined with cholesterol-lowering therapy diminishes synovial thickening and cartilage degeneration in mice and may imply that this combination therapy could be beneficial in patients with metabolic inflammation.
Abstract
The plasma-induced charge of non-spherical microparticles is a crucial parameter in complex plasma physics, aerosol science and astrophysics. Yet, the literature describes this charge by two ...competing models, neither of which has been experimentally verified or refuted. Here we offer experimental proof that the charge on a two-particle cluster (doublet) in the spatial afterglow of a low-pressure plasma equals the charge that would be obtained by the smallest enclosing sphere and that it should therefore not be based on its geometrical capacitance but rather on the capacitance of its smallest enclosing sphere. To support this conclusion, the size, mass and charge of single particles (singlets) and doublets are measured with high precision. The measured ratio between the plasma-afterglow-induced charges on doublets and singlets is compared to both models and shows perfect agreement with the predicted ratio using the capacitance of the smallest enclosing sphere, while being significantly dissimilar to the predicted ratio based on the particle’s geometrical capacitance.
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