Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR+5

BackgroundHigh-risk medulloblastoma is defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5–19 years with newly diagnosed high-risk medulloblastoma treated according to the phase II trial PNET HR+5.MethodsAll children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m²) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1–3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy).ResultsFifty-one patients (median age, 8 y; range, 5–19) were enrolled. The median follow-up was 7.1 years (range: 3.4–9.0). The 3 and 5-year PFS with their 95% confidence intervals (95% CI) were 78% (65–88) and 76% (63–86), and the 3 and 5-year OS were 84% (72–92) and 76% (63–86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (P-value = 0.039) with large-cell/anaplastic being of worse prognosis, as well as a molecular subgroup (P-value = 0.012) with sonic hedgehog (SHH) and group 3 being of worse prognosis than wingless (WNT) and group 4. Therapy was well tolerated.ConclusionsThis treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.     

Dopaminergic system genes in ADHD: toward a biological hypothesis.

Converging evidence has implicated abnormalities of dopamine neurotransmission to the pathology of attention deficit hyperactivity disorder (ADHD). Several genetic association studies have been published, but so far, no DNA variants have been unequivocally demonstrated as contributing to ADHD susceptibility. Four dopamine related gene loci have been implicated, however: DAT 1, DRD 4, DBH, and DRD 5. Each of these may influence the liability of ADHD to a small degree. Notably, all are involved in signal transduction at the neuronal synapse. In this article, we investigate as candidate genes for ADHD, DNA polymorphisms at dopamine receptors, the dopamine transporter, and genes known to be involved in dopamine synthesis and metabolism. In a recent article, we confirmed the previously reported association of DAT 1 (480 bp allele) with ADHD and identified polymorphisms at two additional loci showing preferential transmission to ADHD children of alleles at DRD 5 (148 bp allele) and at DBH (allele 2, Taq I polymorphism). Increased transmission of the 4 bp deletion in the untranslated exon 1 of the DOPA decarboxylase gene was also observed but was of marginal significance. Nonsignificant trends of association were found for TH (allele 2) and DRD2 (Ser-311). No preferential transmission of alleles to ADHD children was observed for polymorphisms at DRD 1, DRD 2 (Taq I), DRD 3, DRD 4, and COMT. Analyzing the data by sex of transmitting parent showed significant preferential paternal transmission of alleles at TH (allele 2) and a nonsignificant trend for paternal transmission for DRD 2 (Ser-311). We attempt to put these findings together with what is known of the function of the particular proteins, and suggest working hypotheses.     

Stigma in families of individuals in early stages of psychotic illness: family stigma and early psychosis

Aim: Stigma is pervasive among families of individuals with psychotic disorders and includes both general and ‘associative’ stigma – that is, the process by which a person is stigmatized by virtue of association with another stigmatized individual. These forms of stigma may present a barrier to help seeking. However, little is known about stigma in the early stages of evolving psychotic disorder. Methods: Family members of 11 individuals at clinical high risk and of nine patients with recent‐onset psychosis were evaluated for generalized and associative stigma using the Opinions about Mental Illness (modified) and the Family Experiences Interview Schedule. Results: In this small study, the level of stigma was low, as families endorsed many supportive statements, forexample, patients should be encouraged to vote, patients want to work, mental illness should be protected legally as a disability and parity should exist in insurance coverage. Families also endorsed that both talking and a belief in God and prayer can help someone get better. Only ethnic minority families of individuals with recent‐onset psychosis endorsed a sense of shame and need to conceal the patient's illness. Conclusions: This preliminary study suggests that family stigma is low in the early stages of psychotic disorder, a finding that requires further investigation in a larger and more representative sample. This may be an opportune time to engage young people and families, so as to reduce duration of untreated illness. Ethnic differences in stigma, if replicated, highlight the need for cultural sensitivity in engaging individuals and their families in treatment.     

Person-centredness: conceptual and historical perspectives

PURPOSE: The definition and aims of rehabilitation are both topics of frequent debate. Recently several authors have suggested defining rehabilitation and its goals in terms of 'person-centredness'. However such attempts to define rehabilitation in this way have not occurred without running into their own difficulties and criticisms. Consequently, one may question whether person-centredness is a good candidate to characterize and define rehabilitation. The purpose of this article is to reflect upon the historical background and conceptual underpinnings of this term and their relevance for understanding contemporary person-centred rehabilitation. METHOD: We conducted a conceptual and historical analysis of the notion of person-centredness in relation to rehabilitation. We ask first whether person-centredness has a consistent and fixed definition and meaning? Secondly, where does person-centredness come from, what is its conceptual history and does an historical approach enable us to identify a unique source for person-centredness? RESULTS: In the context of rehabilitation, we have identified four main understandings or interpretations of the term person-centredness, each of which denotes several ideas that can be, in turn, interpreted in quite different ways. Thus the concept of person-centredness in rehabilitation has multiple meanings. The conceptual history indicates that person-centredness has diverse meanings and that it has been used in a variety of contexts somewhat unrelated to disability and rehabilitation. Moreover, there does not seem to be any strict relationship between person-centredness as it is used in the context of rehabilitation and these prior uses and meanings. CONCLUSION: Person-centredness has an ancient pedigree, but its application in the field of rehabilitation raises both practical and theoretical difficulties. It may be that rehabilitation might get a better sense of what it should be and should do by focusing less on the rhetoric of person-centredness and by putting more emphasis on the investigation and operationalization of its key conceptual components.     

Perceived exertion and rehabilitation with arm crank in elderly patients after total hip arthroplasty: a preliminary study

This preliminary study examined, in a restricted randomized trial, the effects of a 6-week arm-crank rehabilitation training program in elderly osteoarthrosis patients after total hip arthroplasty, first on physiological and perceptual responses and second on physical function. Two groups of patients were studied: a training group (N = 7, mean age = 74.9 yr, standard deviation [SD] = 5.0 yr) who followed a training program in addition to traditional rehabilitation, and a control group who followed traditional rehabilitation only (N = 7 mean age = 75.4 yr, SD = 5.1 yr). At the beginning of the training program, the heart rate and the perceived exertion were not significantly correlated during the exercise session. However, at the end of the training program, five patients had a significant heart rate/perceived exertion relationship (p < 0.05). Furthermore, positive effects of the arm-crank rehabilitation training program were observed on cardioventilatory and functional responses in the training group compared with the control group. These results suggest that after an habituation period, most of our elderly osteoarthrosis patients experienced physical sensations that were connected to physiological responses. Therefore, perceived exertion could be useful in these patients to regulate exercise intensity, especially at the end of and after the rehabilitation period.     

Revascularization of the superficial femoral artery with paclitaxel-coated balloon for claudication

Background: Percutaneous angioplasty of the superficial femoral artery (SFA) with paclitaxel-coated balloon, intended to reduce restenosis, has been proven safe and effective in recent randomized controlled trials.

Objective: To assess outcome results of angioplasty of the SFA with paclitaxel-coated balloon in claudicants in real-world practice of a single center.

Material &; Methods: A continuous prospective cohort study of 53 claudicants (62 lower limbs) from January 2015 to December 2016. Study end points include primary patency, freedom from clinically driven target-lesion revascularization and symptom relief.

Results: It concerns 17 women (32%) and 36 men (68%) with a mean age of 67.8 years, suffering life-style-limiting claudication. Only short to intermediate-length stenoses or occlusions (30.6%), with a mean length of 59.6?mm were selected for percutaneous angioplasty with a paclitaxel-coated balloon. Technical success was 100%. At 16 months, primary patency attained 92.0% (3 early occlusions, 2 restenoses). There were two re-interventions at 6 and 9 months, resulting in a clinically driven target lesion revascularization rate of 3.2%. At the end of the follow-up of 16 months, all but two patients (96.2%) remained symptom-free. Two patients died during follow-up (no procedure-related deaths).

Conclusion: Paclitaxel-coated balloon angioplasty of the SFA gives in routine clinical practice excellent midterm results, with a restenosis rate of 6.5% at 1 year. This procedure has authors’ preference as first-choice technique for correction of short- and intermediate-length symptomatic stenoses of the SFA.     

The kinase domain of mitochondrial PINK1 faces the cytoplasm

Mutations in PTEN-induced putative kinase 1 (PINK1) are a cause of autosomal recessive familial Parkinson's disease (PD). Efforts in deducing the PINK1 signaling pathway have been hindered by controversy around its subcellular and submitochondrial localization and the authenticity of its reported substrates. We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. Although deletion of the transmembrane domain disrupts this topology, common PD-linked PINK1 mutations do not. These results are critical in rectifying the location and orientation of PINK1 in mitochondria, and they should help decipher its normal physiological function and potential pathogenic role in PD.