Loss of ability to work and ability to live independently in Parkinson's disease.

OBJECTIVE: Ability to work and live independently is of particular concern for patients with Parkinson's disease (PD). We studied a series of PD patients able to work or live independently at baseline, and evaluated potential risk factors for two separate outcomes: loss of ability to work and loss of ability to live independently. METHODS: The series comprised 495 PD patients followed prospectively. Ability to work and ability to live independently were based on clinical interview and examination. Cox regression models adjusted for age and disease duration were used to evaluate associations of baseline characteristics with loss of ability to work and loss of ability to live independently. RESULTS: Higher UPDRS dyskinesia score, UPDRS instability score, UPDRS total score, Hoehn and Yahr stage, and presence of intellectual impairment at baseline were all associated with increased risk of future loss of ability to work and loss of ability to live independently (P ≤ 0.0033). Five years after initial visit, for patients ≤70 years of age with a disease duration ≤4 years at initial visit, 88% were still able to work and 90% to live independently. These estimates worsened as age and disease duration at initial visit increased; for patients >70 years of age with a disease duration >4 years, estimates at 5 years were 43% able to work and 57% able to live independently. CONCLUSIONS: The information provided in this study can offer useful information for PD patients in preparing for future ability to perform activities of daily living.

Impaired early visual response modulations to spatial information in chronic schizophrenia.

Early visual processing stages have been demonstrated to be impaired in schizophrenia patients and their first-degree relatives. The amplitude and topography of the P1 component of the visual evoked potential (VEP) are both affected; the latter of which indicates alterations in active brain networks between populations. At least two issues remain unresolved. First, the specificity of this deficit (and suitability as an endophenotype) has yet to be established, with evidence for impaired P1 responses in other clinical populations. Second, it remains unknown whether schizophrenia patients exhibit intact functional modulation of the P1 VEP component; an aspect that may assist in distinguishing effects specific to schizophrenia. We applied electrical neuroimaging analyses to VEPs from chronic schizophrenia patients and healthy controls in response to variation in the parafoveal spatial extent of stimuli. Healthy controls demonstrated robust modulation of the VEP strength and topography as a function of the spatial extent of stimuli during the P1 component. By contrast, no such modulations were evident at early latencies in the responses from patients with schizophrenia. Source estimations localized these deficits to the left precuneus and medial inferior parietal cortex. These findings provide insights on potential underlying low-level impairments in schizophrenia.

Impact of clinical practice guidelines on priorisation for intensive care beds allocation in high-risk acute coronary syndrome patients: does age play a role?

QUESTION UNDER STUDY: To assess which high-risk acute coronary syndrome (ACS) patient characteristics played a role in prioritising access to intensive care unit (ICU), and whether introducing clinical practice guidelines (CPG) explicitly stating ICU admission criteria altered this practice. PATIENTS AND METHODS: All consecutive patients with ACS admitted to our medical emergency centre over 3 months before and after CPG implementation were prospectively assessed. The impact of demographic and clinical characteristics (age, gender, cardiovascular risk factors, and clinical parameters upon admission) on ICU hospitalisation of high-risk patients (defined as retrosternal pain of prolonged duration with ECG changes and/or positive troponin blood level) was studied by logistic regression. RESULTS: Before and after CPG implementation, 328 and 364 patients, respectively, were assessed for suspicion of ACS. Before CPG implementation, 36 of the 81 high-risk patients (44.4%) were admitted to ICU. After CPG implementation, 35 of the 90 high-risk patients (38.9%) were admitted to ICU. Male patients were more frequently admitted to ICU before CPG implementation (OR=7.45, 95% CI 2.10-26.44), but not after (OR=0.73, 95% CI 0.20-2.66). Age played a significant role in both periods (OR=1.57, 95% CI 1.24-1.99), both young and advanced ages significantly reducing ICU admission, but to a lesser extent after CPG implementation. CONCLUSION: Prioritisation of access to ICU for high-risk ACS patients was age-dependent, but focused on the cardiovascular risk factor profile. CPG implementation explicitly stating ICU admission criteria decreased discrimination against women, but other factors are likely to play a role in bed allocation.

Molecular pathology of colorectal cancer.

Colorectal cancer (CRC) is one of the most intensively studied cancer types, partly because of its high prevalence but also because of the existence of its precursor lesions, tubular or villous adenomas, and more recently (sessile) serrated adenomas, which can be detected endoscopically and removed. The morphological steps in the adenoma-carcinoma sequence have been elucidated at a molecular level, which has been facilitated by identification of the genes responsible for familial intestinal cancer. However, apart from early detection of familial forms of CRC and its use in genetic counseling, until recently such detailed molecular knowledge has had little impact on clinical management of the disease. This has dramatically changed in the last decade. With drugs specifically targeting the epidermal growth factor receptor (EGFR) having been shown effective in CRC, mechanisms responsible for resistance have been explored. The finding that KRAS mutated cancers do not respond to anti-EGFR treatment has had a profound impact on clinical management and on molecular diagnostics of CRC. Additional genetic tests for mutations in NRAS, BRAF and PIK3CA contribute to determining who to treat, and others will follow. New therapies effective in patients with advanced CRC are under investigation. Remaining burning questions for optimal management are which patients will relapse after resection of the primary tumor and which patients will respond to the standard 5FU-oxaliplatin adjuvant treatment regimen. Predictive tests to address these issues are eagerly awaited. New classifications of CRC, based on molecular parameters, are emerging, and we will be confronted with new subtypes of CRC, for which the definition is based on combinations of gene expression patterns, chromosomal alterations, gene mutations and epigenetic characteristics. This will be instrumental in designing new approaches for therapy but will also be translated into molecular diagnostics. Both will contribute to improved clinical management of CRC.

Controlled study of 50-Hz repetitive transcranial magnetic stimulation for the treatment of Parkinson disease.

OBJECTIVE: To investigate the safety and efficacy of 50-Hz repetitive transcranial magnetic stimulation (rTMS) in the treatment of motor symptoms in Parkinson disease (PD). BACKGROUND: Progression of PD is characterized by the emergence of motor deficits that gradually respond less to dopaminergic therapy. rTMS has shown promising results in improving gait, a major cause of disability, and may provide a therapeutic alternative. Prior controlled studies suggest that an increase in stimulation frequency might enhance therapeutic efficacy. METHODS: In this randomized, double blind, sham-controlled study, the authors investigated the safety and efficacy of 50-Hz rTMS of the motor cortices in 8 sessions over 2 weeks. Assessment of safety and clinical efficacy over a 1-month period included timed tests of gait and bradykinesia, Unified Parkinson's Disease Rating Scale (UPDRS), and additional clinical, neurophysiological, and neuropsychological parameters. In addition, the safety of 50-Hz rTMS was tested with electromyography-electroencephalogram (EMG-EEG) monitoring during and after stimulation. RESULTS: The authors investigated 26 patients with mild to moderate PD: 13 received 50-Hz rTMS and 13 sham stimulation. The 50-Hz rTMS did not improve gait, bradykinesia, and global and motor UPDRS, but there appeared a short-lived "on"-state improvement in activities of daily living (UPDRS II). The 50-Hz rTMS lengthened the cortical silent period, but other neurophysiological and neuropsychological measures remained unchanged. EMG/EEG recorded no pathological increase of cortical excitability or epileptic activity. There were no adverse effects. CONCLUSION: It appears that 50-Hz rTMS of the motor cortices is safe, but it fails to improve motor performance and functional status in PD. Prolonged stimulation or other techniques with rTMS might be more efficacious but need to be established in future research.

Targeting B-cell lymphomas with inhibitors of the MALT1 paracaspase.

The paracaspase MALT1 is an Arg-specific protease that cleaves multiple substrates to promote lymphocyte proliferation and survival. The catalytic activity of MALT1 is normally tightly regulated by antigen receptor triggering, which promotes MALT1 activation by its inducible monoubiquitination-dependent dimerization. Constitutive MALT1 activity is a hallmark of specific subsets of B-cell lymphomas, which are characterized by chromosomal translocations or point mutations that activate MALT1 or its upstream regulators. Recent findings suggest that such lymphomas may be sensitive to treatment with MALT1 inhibitors. Here we review recent progress in the understanding of MALT1 function and regulation, and the development of small molecule MALT1 inhibitors for therapeutic applications.

A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306).

BACKGROUND: Cilengitide is a selective integrin inhibitor that is well tolerated and has demonstrated biologic activity in patients with recurrent malignant glioma. The primary objectives of this randomized phase 2 trial were to determine the safety and efficacy of cilengitide when combined with radiation and temozolomide for patients with newly diagnosed glioblastoma multiforme and to select a dose for comparative clinical testing. METHODS: In total, 112 patients were accrued. Eighteen patients received standard radiation and temozolomide with cilengitide in a safety run-in phase followed by a randomized phase 2 trial with 94 patients assigned to either a 500 mg dose group or 2000 mg dose group. The trial was designed to estimate overall survival benefit compared with a New Approaches to Brain Tumor Therapy (NABTT) Consortium internal historic control and data from the published European Organization for Research and Treatment of Cancer (EORTC) trial EORTC 26981. RESULTS: Cilengitide at all doses studied was well tolerated with radiation and temozolomide. The median survival was 19.7 months for all patients, 17.4 months for the patients in the 500 mg dose group, 20.8 months for patients in the 2000 mg dose group, 30 months for patients who had methylated O6-methylguanine-DNA methyltransferase (MGMT) status, and 17.4 months for patients who had unmethylated MGMT status. For patients aged ≤70 years, the median survival and survival at 24 months was superior to what was observed in the EORTC trial (20.7 months vs 14.6 months and 41% vs 27%, respectively; P = .008). CONCLUSIONS: Cilengitide was well tolerated when combined with standard chemoradiation and may improve survival for patients newly diagnosed with glioblastoma multiforme regardless of MGMT methylation status. The authors concluded that, from an efficacy and safety standpoint, future trials of this agent in this population should use the 2000 mg dose. Cancer 2012. © 2012 American Cancer Society.

Oligodendroglia metabolically support axons and contribute to neurodegeneration.

Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.

Biologics in rheumatoid arthritis - recommendations for Swiss practice.

The new paradigm of therapy in rheumatoid arthritis is to aim toward early and complete remission, using a larger use of conventional DMARDs and biologic agents. The present recommendations were established through a consensus to help practitioners in their daily use of those agents, to reflect the current "best practice" in Switzerland.

TAT-RasGAP317-326-mediated tumor cell death sensitization can occur independently of Bax and Bak.

The increase of cancer specificity and efficacy of anti-tumoral agents are prime strategies to overcome the deleterious side effects associated with anti-cancer treatments. We described earlier a cell-permeable protease-resistant peptide derived from the p120 RasGAP protein, called TAT-RasGAP317-326, as being an efficient tumor-specific sensitizer to apoptosis induced by genotoxins in vitro and in vivo. Bcl-2 family members regulate the intrinsic apoptotic response and as such could be targeted by TAT-RasGAP317-326. Our results indicate that the RasGAP-derived peptide increases cisplatin-induced Bax activation. We found no evidence, using in particular knock-out cells, of an involvement of other Bcl-2 family proteins in the tumor-specific sensitization activity of TAT-RasGAP317-326. The absence of Bax and Bak in mouse embryonic fibroblasts rendered them resistant to cisplatin-induced apoptosis and consequently to the sensitizing action of the RasGAP-derived peptide. Surprisingly, in the HCT116 colon carcinoma cell line, the absence of Bax and Bak did not prevent cisplatin-induced apoptosis and the ability of TAT-RasGAP317-326 to augment this response. Our study also revealed that p53, while required for an efficient genotoxin-induced apoptotic response, is dispensable for the ability of the RasGAP-derived peptide to improve the capacity of genotoxins to decrease long-term survival of cancer cells. Hence, even though genotoxin-induced Bax activity can be increased by TAT-RasGAP317-326, the sensitizing activity of the RasGAP-derived peptide can operate in the absence of a functional mitochondrial intrinsic death pathway.

Caspase-8 and c-FLIPL associate in lipid rafts with NF-kappaB adaptors during T cell activation.

Humans and mice lacking functional caspase-8 in T cells manifest a profound immunodeficiency syndrome due to defective T cell antigen receptor (TCR)-induced NF-kappaB signaling and proliferation. It is unknown how caspase-8 is activated following T cell stimulation, and what is the caspase-8 substrate(s) that is necessary to initiate T cell cycling. We observe that following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR. The lack of caspase-8 results in the absence of MALT1 and Bcl-10 in the active caspase complex. Consistent with this observation, inhibition of caspase activity attenuates NF-kappaB activation. The current findings define a link among TCR, caspases, and the NF-kappaB pathway that occurs in a sequestered lipid raft environment in T cells.

Selected polymorphisms in sex hormone-related genes, circulating sex hormones and risk of endometrial cancer.

BACKGROUND: The role of estrogen and progesterone in the development of endometrial cancer is well documented. Few studies have examined the association of genetic variants in sex hormone-related genes with endometrial cancer risk. METHODS: We conducted a case-control study nested within three cohorts to examine the association of endometrial cancer risk with polymorphisms in hormone-related genes among 391 cases (92% postmenopausal at diagnosis) and 712 individually-matched controls. We also examined the association of these polymorphisms with circulating levels of sex hormones and SHBG in a cross-sectional analysis including 596 healthy postmenopausal women at blood donation (controls from this nested case-control study and from a nested case-control study of breast cancer in one of the three cohorts). RESULTS: Adjusting for endometrial cancer risk factors, the A allele of rs4775936 in CYP19 was significantly associated (OR(per allele)=1.22, 95% CI=1.01-1.47, p(trend)=0.04), while the T allele of rs10046 was marginally associated with increased risk of endometrial cancer (OR(per allele)=1.20, 95% CI=0.99-1.45, p(trend)=0.06). PGR rs1042838 was also marginally associated with risk (OR(per allele)=1.25, 95% CI=0.96-1.61, p(trend)=0.09). No significant association was found for the other polymorphisms, i.e. CYP1B1 rs1800440 and rs1056836, UGT1A1 rs8175347, SHBG rs6259 and ESR1 rs2234693. Rs8175347 was significantly associated with postmenopausal levels of estradiol, free estradiol and estrone and rs6259 with SHBG and estradiol. CONCLUSION: Our findings support an association between genetic variants in CYP19, and possibly PGR, and risk of endometrial cancer.