Objectives
To assess survival of patients with muscle-invasive bladder cancer (MIBC) who underwent radical cystectomy (RC) with or without neo-adjuvant chemotherapy (NAC) according to the ...pathological response at RC.
Methods
965 patients with MIBC (cT2-4aN0M0) who underwent RC with or without NAC were analyzed. Among the collected data were comorbidity, clinical and pathological tumor stage, tumor grade, nodal status (y)pN, and OS. Case–control matching of 412 patients was performed to compare oncological outcomes. Kaplan–Meier curves were created to estimate OS for patients who underwent RC with or without NAC, and for those with complete response (pCR), partial response (pPR), or residual or progressive disease (PD).
Results
Patients with a pCR or pPR at RC, with or without NAC, had better OS than patients who had PD (both
p
values < 0.001). Moreover, the incidence of pCR was significantly higher in patients receiving NAC prior to RC than in patients undergoing RC only (31% versus 15%, respectively;
p
< 0.001). Case–control matching displayed better OS of patients who underwent RC with NAC, median survival not reached, than of those who underwent RC only, median 4.5 years (
p
= 0.023).
Conclusions
This study showed that patients with MIBC who underwent NAC with RC had a significant better OS than those who underwent RC only. The proportion of patients with a pCR was higher in those who received NAC and RC than in those who were treated by RC only. The favorable OS rate in the NAC and RC cohort was probably attributed to the higher observed pCR rate.
Summary Introduction Because of a steady decline in the number of autopsies following death due to traumatic injuries, valuable information concerning possible missed injuries and potential ...improvements in management is lost. This retrospective study describes current practice in the Amsterdam region of the Netherlands regarding such autopsies, and their rates. Method The current protocols for autopsies were reviewed. Data from government databases and hospitals for the year 2005 were collected. For all patients included that died an unnatural death due to traumatic injury, causes of death and recommendations for autopsy were reviewed. The number of clinical and medico-legal autopsies was determined. Results Of 872 registered unnatural deaths, 414 were due to traumatic injuries; 63% of these died before reaching hospital and 37% died in hospital. There were more male deaths, and average age was 54 years. In 23% an autopsy was advised by the medical examiners, more often for pre-hospital deaths. The rate of autopsies was 46% when advice was given for a medico-legal autopsy. Conclusion The rates of both medico-legal and clinically desirable autopsies are very low. Currently, the system in Amsterdam focuses mainly on the former, and the latter with its attendant educational aspects is largely ignored. The role of the government should be expanded to optimise the autopsy system in unnatural deaths following traumatic injuries.
Genetic variation in the cholinergic muscarinic-2 (M(2)) receptor gene (CHRM2) has been associated with the risk for developing depression. We previously reported that M(2)-receptor distribution ...volume (V(T)) was reduced in depressed subjects with bipolar disorder (BD) relative to depressed subjects with major depressive disorder (MDD) and healthy controls (HCs). In this study, we investigated the effects of six single-nucleotide polymorphisms (SNPs) for CHRM2 on M(2)-receptor binding to test the hypotheses that genetic variation in CHRM2 influences M(2)-receptor binding and that a CHRM2 polymorphism underlies the deficits in M(2)-receptor V(T) observed in BD. The M(2)-receptor V(T) was measured using positron emission tomography and (18)FFP-TZTP in unmedicated, depressed subjects with BD (n=16) or MDD (n=24) and HCs (n=25), and the effect of genotype on V(T) was assessed. In the controls, one SNP (with identifier rs324650, in which the ancestral allele adenine (A) is replaced with one or two copies of thymine (T), showed a significant allelic effect on V(T) in the pregenual and subgenual anterior cingulate cortices in the direction AA<AT<TT. In contrast, in BD subjects with the TT genotype, V(T) was significantly lower than in BD subjects with the AT genotype in these regions. The BD subjects homozygous for the T -allele also showed markedly lower V(T) (by 27 to 37% across regions) than HCs of the same genotype. Post hoc analyses suggested that T homozygosity was associated with a more severe illness course, as manifested by lower socioeconomic function, poorer spatial recognition memory and a greater likelihood of having attempted suicide. These data represent novel preliminary evidence that reduced M(2)-receptor V(T) in BD is associated with genetic variation within CHRM2. The differential impact of the M(2)-receptor polymorphism at rs324650 in the BD and HC samples suggests interactive effects with an unidentified vulnerability factor for BD.
There is an urgency to find new treatment strategies that could prevent or delay the onset or progression of AMD. Different classes of lipids and lipoproteins metabolism genes have been associated ...with AMD in a multiple ways, but despite the ever-increasing knowledge base, we still do not understand fully how circulating lipids or local lipid metabolism contribute to AMD. It is essential to clarify whether dietary lipids, systemic or local lipoprotein metabolismtrafficking of lipids in the retina should be targeted in the disease. In this article, we critically evaluate what has been reported in the literature and identify new directions needed to bring about a significant advance in our understanding of the role for lipids in AMD. This may help to develop potential new treatment strategies through targeting the lipid homeostasis.
•High dietary intake of omega-3 is consistently associated with decreased risk of AMD.•HDL-C levels are elevated and triglycerides are decreased in AMD patients.•Composition and activity of HDL particles might be relevant for AMD.•Genes involved in cholesterol transport associate with both AMD and lipid levels.•AMD pathogenesis may be related to circulating lipids, local lipid transport, or both.
Non-syndromic retinitis pigmentosa Verbakel, Sanne K.; van Huet, Ramon A.C.; Boon, Camiel J.F. ...
Progress in retinal and eye research,
September 2018, 2018-09-00, 20180901, Letnik:
66
Journal Article
Recenzirano
Odprti dostop
Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, ...with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20–30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options.
Genetic variants identified through population-based genome-wide studies are generally of high frequency, exerting their action in the central part of the refractive error spectrum. However, the ...power to identify associations with variants of lower minor allele frequency is greatly reduced, requiring considerable sample sizes. Here we aim to assess the impact of rare variants on genetic variation of refractive errors in a very large general population cohort.
Genetic association analyses of non-cyclopaedic autorefraction calculated as mean spherical equivalent (SPHE) used whole-exome sequence genotypic information from 50,893 unrelated participants in the UK Biobank of European ancestry. Gene-based analyses tested for association with SPHE using an optimised SNP-set kernel association test (SKAT-O) restricted to rare variants (minor allele frequency < 1%) within protein-coding regions of the genome. All models were adjusted for age, sex and common lead variants within the same locus reported by previous genome-wide association studies. Potentially causal markers driving association at significant loci were elucidated using sensitivity analyses by sequentially dropping the most associated variants from gene-based analyses.
We found strong statistical evidence for association of SPHE with the SIX6 (p-value = 2.15 x 10-10, or Bonferroni-Corrected p = 4.41x10-06) and the CRX gene (p-value = 6.65 x 10-08, or Bonferroni-Corrected p = 0.001). The SIX6 gene codes for a transcription factor believed to be critical to the eye, retina and optic disc development and morphology, while CRX regulates photoreceptor specification and expression of over 700 genes in the retina. These novel associations suggest an important role of genes involved in eye morphogenesis in refractive error.
The results of our study support previous research highlighting the importance of rare variants to the genetic risk of refractive error. We explain some of the origins of the genetic signals seen in GWAS but also report for the first time a completely novel association with the CRX gene.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal ...eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.
Cone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of ...autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes for these disorders by genome-wide homozygosity mapping. We investigated 75 ACHM, 97 arCD, and 20 early-onset arCD probands and excluded the involvement of known genes for ACHM and arCD. Subsequently, we performed high-resolution SNP analysis and identified large homozygous regions spanning the PDE6C gene in one sibling pair with early-onset arCD and one sibling pair with incomplete ACHM. The PDE6C gene encodes the cone α subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5′-GMP, and thereby plays an essential role in cone phototransduction. Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs. Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families. One patient had a frameshift mutation and a splice defect; the other two had a splice defect and a missense variant (p.M455V). Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD. Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes.
In the last few years, several ground-based and airborne field campaigns have allowed the exploration of the properties and impacts of mineral dust in western Africa, one of the major emission and ...transport areas worldwide. In this paper, we explore the synthesis of these observations to provide a large-scale quantitative view of the mineralogical composition and its variability according to source region and time after transport. This work reveals that mineral dust in western Africa is a mixture of clays, quartz, iron and titanium oxides, representing at least 92% of the dust mass. Calcite ranged between 0.3 and 8.4% of the dust mass, depending on the origin. Our data do not show a systematic dependence of the dust mineralogical composition on origin; this is to be the case as, in most of the instances, the data represent the composition of the atmospheric burden after 1–2 days after emission, when air masses mix and give rise to a more uniform dust load. This has implications for the representation of the mineral dust composition in regional and global circulation models and in satellite retrievals. Iron oxides account for 58 ± 7% of the mass of elemental Fe and for between 2 and 5% of the dust mass. Most of them are composed of goethite, representing between 52 and 78% of the iron oxide mass. We estimate that titanium oxides account for 1–2% of the dust mass, depending on whether the dust is of Saharan or Sahelian origin. The mineralogical composition is a critical parameter for estimating the radiative and biogeochemical impact of mineral dust. The results regarding dust composition have been used to estimate the optical properties as well as the iron fractional solubility of Saharan and Sahelian dust. Data presented in this paper are provided in numerical form upon email request while they are being turned into a public database, the Dust-Mapped Archived Properties (DUST-MAP), which is an open repository for compositional data from other source regions in Africa and worldwide.
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