Cognitive impairment and resting‐state network connectivity in Parkinson's disease

The purpose of this work was to evaluate changes in the connectivity patterns of a set of cognitively relevant, dynamically interrelated brain networks in association with cognitive deficits in Parkinson's disease (PD) using resting‐state functional MRI. Sixty‐five nondemented PD patients and 36 matched healthy controls were included. Thirty‐four percent of PD patients were classified as having mild cognitive impairment (MCI) based on performance in attention/executive, visuospatial/visuoperceptual (VS/VP) and memory functions. A data‐driven approach using independent component analysis (ICA) was used to identify the default‐mode network (DMN), the dorsal attention network (DAN) and the bilateral frontoparietal networks (FPN), which were compared between groups using a dual‐regression approach controlling for gray matter atrophy. Additional seed‐based analyses using a priori defined regions of interest were used to characterize local changes in intranetwork and internetwork connectivity. Structural group comparisons through voxel‐based morphometry and cortical thickness were additionally performed to assess associated gray matter atrophy. ICA results revealed reduced connectivity between the DAN and right frontoinsular regions in MCI patients, associated with worse performance in attention/executive functions. The DMN displayed increased connectivity with medial and lateral occipito‐parietal regions in MCI patients, associated with worse VS/VP performance, and with occipital reductions in cortical thickness. In line with data‐driven results, seed‐based analyses mainly revealed reduced within‐DAN, within‐DMN and DAN‐FPN connectivity, as well as loss of normal DAN‐DMN anticorrelation in MCI patients. Our findings demonstrate differential connectivity changes affecting the networks evaluated, which we hypothesize to be related to the pathophysiological bases of different types of cognitive impairment in PD. Hum Brain Mapp, 36:199–212, 2015. © 2014 Wiley Periodicals, Inc.     

Prognostic value of complete remission status at end‐of‐treatment FDG‐PET in R‐CHOP‐treated diffuse large B‐cell lymphoma: systematic review and meta‐analysis

This study systematically reviewed and meta‐analysed the prognostic value of complete remission status at end‐of‐treatment ¹⁸F‐fluoro‐2‐deoxy‐d ‐glucose positron emission tomography (FDG‐PET) in diffuse large B‐cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP). The systematic PubMed/MEDLINE search yielded seven suitable studies comprising a total of 737 R‐CHOP‐treated DLBCL patients who were in complete remission at end‐of‐treatment FDG‐PET. Overall, the methodological quality of included studies was reasonable. The disease relapse rate among all patients with complete remission status according to end‐of‐treatment FDG‐PET ranged from 7·0% to 20·0%, with a weighted summary proportion of 13·7%. Five of seven studies reported progression‐free survival (PFS) of these patients at various specific time points, i.e., 2‐year PFS (n = 1), estimated 3‐year PFS (n = 3) and 5‐year PFS (n = 1), which was 83%, 85–86·4% and 75%, respectively. Three of seven studies reported overall survival (OS) of these patients at various specific time points, i.e., estimated 3‐year OS (n = 2) and estimated 5‐year OS (n = 1), which were 90%, 93·6% and 83%, respectively. In conclusion, a non‐negligible proportion of R‐CHOP‐treated DLBCL patients who achieve complete remission according to end‐of‐treatment FDG‐PET experiences disease relapse during follow‐up.     

Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release

Transient receptor potential (TRP) cation channel subfamily M member 3 (TRPM3), a member of the TRP channel superfamily, was recently identified as a nociceptor channel in the somatosensory system, where it is involved in the detection of noxious heat; however, owing to the lack of potent and selective agonists, little is known about other potential physiological consequences of the opening of TRPM3. Here we identify and characterize a synthetic TRPM3 activator, CIM0216, whose potency and apparent affinity greatly exceeds that of the canonical TRPM3 agonist, pregnenolone sulfate (PS). In particular, a single application of CIM0216 causes opening of both the central calcium-conducting pore and the alternative cation permeation pathway in a membrane-delimited manner. CIM0216 evoked robust calcium influx in TRPM3-expressing somatosensory neurons, and intradermal injection of the compound induced a TRPM3-dependent nocifensive behavior. Moreover, CIM0216 elicited the release of the peptides calcitonin gene-related peptide (CGRP) from sensory nerve terminals and insulin from isolated pancreatic islets in a TRPM3-dependent manner. These experiments identify CIM0216 as a powerful tool for use in investigating the physiological roles of TRPM3, and indicate that TRPM3 activation in sensory nerve endings can contribute to neurogenic inflammation.Transient receptor potential (TRP) channels represent a large and diverse family of nonselective cation channels that respond to a wide range of chemical and physical stimuli and biophysical properties (1). TRP cation channel subfamily M member 3 (TRPM3), a calcium-permeable nonselective cation channel (2), is a typical example of a polymodally gated TRP channel, in that it can be activated by ligands, such as pregnenolone sulfate (PS) and nifedipine, as well as by heat and membrane depolarization (3, 4). Interestingly, recent evidence indicates that combined stimulation with PS and clotrimazole (Clt) leads to the activation of two distinct permeation pathways in TRPM3: the central pore, which is Ca²⁺-permeable and carries an outwardly rectifying current, and an alternative ion permeation pathway that mediates an inwardly rectifying monovalent cation current (5).TRPM3 is highly expressed in somatosensory neurons, where it plays decisive roles in the nocifensive response to PS and heat, as well as in the development of heat hyperalgesia during inflammation (3, 6). In these neurons, TRPM3 is frequently coexpressed with TRPA1 and TRPV1, two TRP channels that have emerged as key regulators of neurogenic inflammation by triggering neuropeptide release from sensory nerve endings (7, 8). Whether activation of TRPM3 can also initiate the release of neuropeptides, such as substance P or calcitonin gene-related peptide (CGRP), which elicit vasodilation, vascular leakage, and other responses in peripheral cell types, is unclear, however. In addition, TRPM3 is expressed in pancreatic beta cells, where it is involved in controlling insulin release (4), as well as in various tissues, including brain, pituitary gland, eye, kidney, and adipose tissue (reviewed in ref. 9). The physiological roles of TRPM3 in these tissues remain only poorly understood, owing in part to the lack of potent and specific pharmacologic tools to modulate its action in vitro and in vivo.Here we describe the identification and characterization of a TRPM3 agonist, CIM0216, with a potency that greatly exceeds that of currently used agonists. This compound has the unique property to open both ion permeation pathways of TRPM3 without the requirement of other channel modulators. We further demonstrate that CIM0216 acts in a TRPM3-dependent manner to induce pain and evoke neuropeptide release from sensory nerve terminals in the skin, and also to release insulin from pancreatic islets. Collectively, these findings provide a novel powerful tool for use in further studies of the physiological functions of TRPM3, and identify TRPM3 as a novel player in neurogenic inflammation.     

Exocrine pancreatic cancer,cigarette smoking,and diabetes mellitus: a case-control study in northern Italy

The role of cigarette smoking and diabetes mellitus as risk factors for exocrine pancreatic cancer (PC) was investigated in a hospital based case-control study. Current smokers were at increased risk for PC (OR = 2.36, 95% CI 1.53-3.63): the magnitude of the risk was related to the lifetime amount of smoking (chi2(trend) = 17.00; P < 0.0001). Among former smokers, after 15 years from ceasing smoking, the risk for PC dropped to the level of a lifetime non-smoker, whichever the lifetime smoking amount. Diabetes was associated with a 2.89-fold increased risk for PC (95% CI 1.71-4.86): the risk was 4.76 (95% CI 1.99-11.53) for diabetes diagnosed up to 2 years before the diagnosis of PC and dropped to 2.07 (95% CI 1.02-4.20) for diabetes diagnosed more than 5 years before PC. The risk for PC was estimated according to the treatment used to control diabetes: it was 6.49 (95% CI 2.28-18.48) for insulin treated diabetes and 2.12 (95% CI 1.16-3.87) for diabetes treated with oral hypoglycemic drugs. The risk of PC for diabetes treated for more than 5 years before the diagnosis of PC was 6.21 (95% CI 1.61-23.96) for patients treated with insulin and 1.21 (95% CI 0.50-2.92) for those treated with oral hypoglycemic drugs: the type of treatment needed to control the disease may discriminate between the diabetes that represents a consequence of cancer from the diabetes that could represent an etiological co-factor. More studies are needed to clarify whether long-lasting insulin-treated diabetes is an etiological co-factor in PC.     

Increasing intracellular trehalose is sufficient to confer desiccation tolerance to Saccharomyces cerevisiae

Diverse organisms capable of surviving desiccation, termed anhydrobiotes, include species from bacteria, yeast, plants, and invertebrates. However, most organisms are sensitive to desiccation, likely due to an assortment of different stresses such as protein misfolding and aggregation, hyperosmotic stress, membrane fracturing, and changes in cell volume and shape leading to an overcrowded cytoplasm and metabolic arrest. The exact stress(es) that cause lethality in desiccation-sensitive organisms and how the lethal stresses are mitigated in desiccation-tolerant organisms remain poorly understood. The presence of trehalose in anhydrobiotes has been strongly correlated with desiccation tolerance. In the yeast Saccharomyces cerevisiae, trehalose is essential for survival after long-term desiccation. Here, we establish that the elevation of intracellular trehalose in dividing yeast by its import from the media converts yeast from extreme desiccation sensitivity to a high level of desiccation tolerance. This trehalose-induced tolerance is independent of utilization of trehalose as an energy source, de novo synthesis of other stress effectors, or the metabolic effects of trehalose biosynthetic intermediates, indicating that a chemical property of trehalose is directly responsible for desiccation tolerance. Finally, we demonstrate that elevated intracellular maltose can also make dividing yeast tolerant to short-term desiccation, indicating that other disaccharides have stress effector activity. However, trehalose is much more effective than maltose at conferring tolerance to long-term desiccation. The effectiveness and sufficiency of trehalose as an antagonizer of desiccation-induced damage in yeast emphasizes its potential to confer desiccation tolerance to otherwise sensitive organisms.Water is an essential molecule whose absence can lead to a variety of detrimental and often lethal effects on cells and organisms (1–3). Severe water removal, termed desiccation, has been proposed to lead a variety of detrimental stresses (3). Which of these stresses leads to lethality in desiccation-sensitive organisms is unclear. Organisms capable of surviving desiccation, commonly termed anhydrobiotes, are found among bacteria, fungi, plants, and invertebrates (1, 3). Anhydrobiotes harbor stress effectors that are known or postulated to mitigate the different stresses associated with desiccation (2, 4). These stress effectors include osmolytes, heat shock proteins, redox balancing enzymes, nonreducing disaccharides (trehalose, sucrose), and hydrophilins (short unstructured hydrophilic proteins—also known as LEAs) (1). A reasonable assumption might be that many if not all of these stress effectors are necessary for desiccation tolerance given the multitude of stresses imposed by desiccation. However, this assumption is challenged by the uncertainty in the number and degree of lethal stresses generated by desiccation and the versatility and coordination/cooperation of multiple stress effectors in ameliorating such lethal stresses. Thus, a critical question in the anhydrobiosis field is whether a single stress effector is sufficient to promote desiccation tolerance.One of the most studied desiccation-associated stress effectors is the simple nonreducing disaccharide, trehalose (α,α-1,1-glucoside) (5). It is found in extremely high concentrations in most anhydrobiotes, including in the model organism Saccharomyces cerevisiae (6, 7). In this yeast, exponentially dividing cells have very low levels of trehalose and are extremely desiccation sensitive (8). However, in saturated cultures, yeast cells accumulate high levels of a number of stress effectors, including extremely high levels of trehalose (up to 15% of dry cell mass) (6, 7). We recently showed that high levels of trehalose are necessary for yeast cells in saturated cultures to survive weeks to months of desiccation (long term), but not a few days (short term) (9). Trehalose dispensability during short-term desiccation is due in part to overlapping functions with the heat shock factor Hsp104. This overlap led us to discover that trehalose functions as a chemical chaperone capable of preventing the aggregation of both membrane and cytoplasmic proteins (9). Work in the nematode Caenorhabditis elegans demonstrated that worms unable to synthesize trehalose display hallmarks of membrane damage, consistent with trehalose playing a role in preserving membrane structure (10). Indeed, trehalose has been found to be lipidated in nematodes and these “maradolipids” are required for efficient desiccation tolerance (11). Due to the different and versatile mechanisms by which trehalose confers desiccation tolerance in anhydrobiotes, we hypothesize that trehalose, in the absence of other stress effectors, will be sufficient in conferring desiccation tolerance.A simple way to address this hypothesis is to increase the intracellular levels of trehalose in desiccation/dehydration-sensitive cells or organisms then assess whether they acquire desiccation tolerance. Two strategies for increasing intracellular trehalose have been previously used. These were engineering high level expression of trehalose biosynthetic enzymes or importing extracellular trehalose via fusion with lipid vesicles (12–16). Both methods only generated small increases in trehalose levels and minor increases in dehydration but not desiccation tolerance. This weak effect could reflect the need for additional stress effectors. Alternatively, trehalose alone could indeed be sufficient for desiccation tolerance but was missed for two reasons. First, high physiological levels of trehalose observed in desiccation-tolerant organisms were not reached so a potential critical threshold level of trehalose was not met. Second, the biosynthetic strategy not only increased trehalose but also trehalose-6-phosphate, a potent regulator of glucose metabolism that has deleterious effects on cell and organism fitness. Thus, it remains untested whether trehalose alone is sufficient for generating desiccation tolerance.The correlative evidence for trehalose being sufficient for desiccation tolerance was provided from our previous study comparing desiccation sensitivity of saturated and exponentially dividing cultures of yeast (8). Cells in a saturated culture rapidly lose desiccation tolerance when they divide upon dilution into fresh media. Shortly, after dilution, the levels of many stress factors, including trehalose, diminish. Trehalose levels drop as a consequence of activation of two intracellular trehalases, NTH1 and NTH2, and the inhibition of the trehalose biosynthetic enzyme Tps1 (6, 7). The diluted cells retained their desiccation tolerance significantly longer when trehalose depletion was slowed by inactivation of the trehalases (9). This result is consistent with the notion that sustaining high trehalose levels, while reducing the levels of other stress effectors, is sufficient to promote desiccation tolerance. Encouraged by this result, we decided to investigate further the potential sufficiency of trehalose for desiccation tolerance, exploiting the ability of the AGT1 sugar transporter to import extracellular trehalose (17). Here, we show that when AGT1 overexpressing cells are grown in the presence of trehalose, they acquire high levels of intracellular trehalose and desiccation tolerance similar to that of saturated cultures. We characterize this novel acquisition of desiccation tolerance and provide important insights into the roles of trehalose concentration and trehalose structure in both short- and long-term desiccation tolerance.     

Predictors of Conversion from Radial Into Femoral Access in Cardiac Catheterization

Background

Fewer bleeding complications and early ambulation make radial access a privileged route for cardiac catheterization. However, transradial (TR) approach is not always successful, requiring its conversion into femoral access.

Objectives

To evaluate the rate of conversion from radial into femoral access in cardiac catheterization and to identify its predictors.

Methods

Prospective dual-center registry, including 7632 consecutive patients undergoing catheterization via the radial access between Jan/2009 and Oct/2012. We evaluated the incidence of conversion into femoral access and its predictors by logistic regression analysis.

Results

The patients’ mean age was 66 ± 11 years, and 32% were women. A total of 2969 procedures (38.4%) were percutaneous coronary interventions (PCI), and the most used first intention arterial access was the right radial artery (97.6%). Radial access failure rate was 5.8%. Independent predictors of conversion from radial into femoral access were the use of short introducer sheaths (OR 3.047, CI: 2.380-3.902; p < 0.001), PCI (OR 1.729, CI: 1.375-2.173; p < 0.001), female sex (OR 1.569, CI: 1.234-1.996; p < 0.001), multivessel disease (OR 1.457, CI: 1.167-1.819; p = 0.001), body surface area (BSA) ≤ 1.938 (OR 1.448, CI: 1.120-1.871; p = 0.005) and age > 66 years (OR 1.354, CI: 1.088-1.684; p = 0.007).

Conclusion

Transradial approach for cardiac catheterization has a high success rate and the need for its conversion into femoral access in this cohort was low. Female sex, older age, smaller BSA, the use of short introducer sheaths, multivessel disease and PCI were independent predictors of conversion into femoral access.     

New insights into the genetics of glioblastoma multiforme by familial exome sequencing

Glioblastoma multiforme (GBM) is the most aggressive and malignant subtype of human brain tumors. While a family clustering of GBM has long been acknowledged, relevant hereditary factors still remained elusive. Exome sequencing of families offers the option to discover respective genetic factors.We sequenced blood samples of one of the rare affected families: while both parents were healthy, both children were diagnosed with GBM. We report 85 homozygous non-synonymous single nucleotide variations (SNVs) in both siblings that were heterozygous in the parents. Beyond known key players for GBM such as ERBB2, PMS2, or CHI3L1, we identified over 50 genes that have not been associated to GBM so far. We also discovered three accumulative effects potentially adding to the tumorigenesis in the siblings: a clustering of multiple variants in single genes (e.g. PTPRB, CROCC), the aggregation of affected genes on specific molecular pathways (e.g. Focal adhesion or ECM receptor interaction) and genomic proximity (e.g. chr22.q12.2, chr1.p36.33). We found a striking accumulation of SNVs in specific genes for the daughter, who developed not only a GBM at the age of 12 years but was subsequently diagnosed with a pilocytic astrocytoma, a common acute lymphatic leukemia and a diffuse pontine glioma.The reported variants underline the relevance of genetic predisposition and cancer development in this family and demonstrate that GBM has a complex and heterogeneous genetic background. Sequencing of other affected families will help to further narrow down the driving genetic causes for this disease.     

Gas gangrene in the deep spaces of the head and neck visualized on computed tomography images

Cellulitis accompanied by gas gangrene is a rapidly-spreading and potentially fatal infection. Here, we present a case of gas gangrene in the deep spaces of the head and neck in an elderly woman, diagnosed by computed tomography (CT). An 86-year-old woman with Alzheimer’s disease, hypertension, hyperlipidemia, and osteoporosis was referred to our institute by her local dentist. The patient exhibited trismus caused by severe swelling in the left submandibular area. CT images of the head and neck area showed swelling of the cervical tissue with air in the parapharyngeal and masticator spaces. She was treated with antibiotics, followed by drainage. Although the therapy was continued, the patient died from a cardiac complication on hospital day 42. Our case highlights the usefulness of CT for diagnosing gas gangrene in the deep spaces of the head and neck in a woman with Alzheimer’s disease.