Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). Normal individuals carry 2–10 hexanucleotide GGGGCC repeats in the C9orf72 gene, while more than a few hundred repeats represent a risk for ALS and FTD. The proposed molecular mechanisms by which C9orf72 repeat expansions induce neurodegenerative changes are C9orf72 loss-of-function through haploinsufficiency, RNA toxic gain-of-function, and gain-of-function through the accumulation of toxic dipeptide repeat proteins. However, many more cellular processes are affected by pathological processes in C9FTD/ALS, including nucleocytoplasmic transport, RNA processing, normal function of nucleolus, formation of membraneless organelles, translation, ubiquitin proteasome system, Notch signalling pathway, granule transport, and normal function of TAR DNA-binding protein 43 (TDP-43). Although the exact molecular mechanisms through which C9orf72 repeat expansions account for neurodegeneration have not been elucidated, some potential therapeutics, such as antisense oligonucleotides targeting hexanucleotide GGGGCC repeats in mRNA, were successful in preclinical trials and are awaiting phase 1 clinical trials. In this review, we critically discuss each proposed mechanism and provide insight into the most recent studies aiming to elucidate the molecular underpinnings of C9FTD/ALS.
Background/Aims: Renal transplant recipients are exposed to immunosuppressive treatment which may increase the risk for developing malignancies. Limited data exists concerning the occurrence of multiple primary malignancies (MPM) in renal transplant patients. Methods: All the patients who received a renal allograft at our institution from 1973 to 2017 were included in this investigation. Data from patients with more MPM were obtained from the charts and medical records. Malignancies were categorized as synchronous if the interval between occurrences was less than or equal to 6 months and metachronous if the interval was more than 6 months. Results: Out of the 1884 patients who received a renal allograft, 164 (8.7%) developed a malignant tumor. Twenty-two patients (13.4%; 6 females, 16 males) developed MPM, 7 synchronous (31.8%) and 15 metachronous types (68.2%). The most common initial primary tumors were skin cancers (8) and kidney cancers (3). Furthermore, skin cancers were the most common second primary malignancies (9). Log-rank analysis revealed significantly better survival in the synchronous group (113.3 months) than in the metachronous group (24.6 months) (p=0.04). Conclusion: MPM are more frequent in renal transplant recipients than in the general population. It is associated with a high mortality rate, especially in the metachronous group. An increased awareness and frequent screening tests are necessary when managing this condition.
Schizophrenia is a complex polygenic disorder of unknown etiology. Over 3,000
candidate genes associated with schizophrenia have been reported, most of which being
mentioned only once. Alterations in cognitive processing - working memory,
metacognition and mentalization - represent a core feature of schizophrenia, which
indicates the involvement of the prefrontal cortex in the pathophysiology of this
disorder. Hence we compared the gene expression in postmortem tissue from the left
and right dorsolateral prefrontal cortex (DLPFC, Brodmann's area 46), and the medial
part of the orbitofrontal cortex (MOFC, Brodmann's area 11/12), in six patients with
schizophrenia and six control brains. Although in the past decade several studies
performed transcriptome profiling in schizophrenia, this is the first study to
investigate both hemispheres, providing new knowledge about possible brain asymmetry
at the level of gene expression and its relation to schizophrenia. We found that in
the left hemisphere, twelve genes from the DLPFC and eight genes from the MOFC were
differentially expressed in patients with schizophrenia compared to controls. In the
right hemisphere there was only one gene differentially expressed in the MOFC. We
reproduce the involvement of previously reported genes TARDBP and HNRNPC in the
pathogenesis of schizophrenia, and report seven novel genes: SART1, KAT7,
C1D, NPM1, EVI2A, XGY2, and TTTY15. As the
differentially expressed genes only partially overlap with previous studies that
analyzed other brain regions, our findings indicate the importance of considering
prefrontal cortical regions, especially those in the left hemisphere, for obtaining
disease-relevant insights.
Background
Risk models play important roles in stratification and decision‐making towards cardiac surgery. Isolated tricuspid valve surgery is a high risk but increasingly performed the operation, however, the performance of risk models has not been externally evaluated in these patients. We compared the prognostic utility of contemporary risk scores for isolated tricuspid valve surgery.
Methods
Consecutive patients undergoing isolated tricuspid valve surgery at Cleveland Clinic during 2004–2018 were evaluated in this cohort study. EuroSCORE II, Society of Thoracic Surgeon's tricuspid (STS‐TVS) score, and the Model for End‐stage Liver Disease (MELD) score were retrospectively calculated, and their performance for predicting operative mortality, postoperative complications, and mortality during follow‐up was assessed.
Results
Amongst 207 patients studied, the mean age was 54.1 ± 17.9 years, 116 (56.0%) were female, 92 (44.4%) had secondary tricuspid regurgitation, and 151 (72.9%) had a surgical repair. Mean EuroSCORE II, STS‐TVS, and MELD scores were 6.3 ± 6.6%, 5.5 ± 6.2%, and 9.8 ± 4.7, respectively. C‐statistics (95% confidence intervals) for operative mortality were 0.83 (0.74–0.93) for EuroSCORE II, 0.60 (0.45–0.75) for STS‐TVS score, and 0.74 (0.58–0.89) for MELD score, while observed/expected ratios were 0.78 and 0.89 for the first two scores. All three scores were associated with mortality during follow‐up and discriminated most postoperative complications.
Conclusion
EuroSCORE II was superior to STS‐tricuspid score for isolated TVS risk assessment. Although surgical risk scores traditionally underestimated operative mortality after isolated tricuspid valve surgery, they did not in our cohort, reflecting the excellent surgical results. The simple MELD score performed similarly to the EuroSCORE II, especially for discriminating morbidities.
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