Simultaneous multislice acquisition using rosette trajectories (SMART): a new imaging method for functional MRI

OBJECTIVES: Despite the recent introduction of new peroral drugs as well as neurosurgical methods for Parkinson's disease, treatment of late stage parkinsonian patients remains difficult and many patients become severely handicapped because of fluctuations in their motor status. Injections and infusions of apomorphine has been suggested as an alternative in the treatment of these patients, but the number of studies describing the effects of such a treatment over longer time periods is still limited. The objective was to investigate the therapeutic response and range of side effects during long term treatment with apomorphine in advanced Parkinson's disease. METHODS: Forty nine patients (30 men, 19 women; age range 42-80 years) with Parkinson's disease were treated for 3 to 66 months with intermittent subcutaneous injections or continuous infusions of apomorphine. RESULTS: Most of the patients experienced a long term symptomatic improvement. The time spent in "off" was significantly reduced from 50 to 29.5% with injections and from 50 to 25% with infusions of apomorphine. The quality of the remaining "off" periods was improved with infusion treatment, but was relatively unaffected by apomorphine injections. The overall frequency and intensity of dyskinesias did not change. The therapeutic effects of apomorphine were stable over time. The most common side effect was local inflammation at the subcutaneous infusion site, whereas the most severe were psychiatric side effects occurring in 44% of the infusion and 12% of the injection treated patients. CONCLUSION: Subcutaneous apomorphine is a highly effective treatment which can substantially improve the symptomatology in patients with advanced stage Parkinson's disease over a prolonged period of time.     

Role of the negative charges in the cytosolic domain of TOM22 in the import of precursor proteins into mitochondria

TOM22 is an essential mitochondrial outer membrane protein required for the import of precursor proteins into the organelles. The amino-terminal 84 amino acids of TOM22 extend into the cytosol and include 19 negatively and 6 positively charged residues. This region of the protein is thought to interact with positively charged presequences on mitochondrial preproteins, presumably via electrostatic interactions. We constructed a series of mutant derivatives of TOM22 in which 2 to 15 of the negatively charged residues in the cytosolic domain were changed to their corresponding amido forms. The mutant constructs were transformed into a sheltered Neurospora crassa heterokaryon bearing a tom22::hygromycin R disruption in one nucleus. All constructs restored viability to the disruption-carrying nucleus and gave rise to homokaryotic strains containing mutant tom22 alleles. Isolated mitochondria from three representative mutant strains, including the mutant carrying 15 neutralized residues (strain 861), imported precursor proteins at efficiencies comparable to those for wild-type organelles. Precursor binding studies with mitochondrial outer membrane vesicles from several of the mutant strains, including strain 861, revealed only slight differences from binding to wild-type vesicles. Deletion mutants lacking portions of the negatively charged region of TOM22 can also restore viability to the disruption-containing nucleus, but mutants lacking the entire region cannot. Taken together, these data suggest that an abundance of negative charges in the cytosolic domain of TOM22 is not essential for the binding or import of mitochondrial precursor proteins; however, other features in the domain are required.     

An import signal in the cytosolic domain of the Neurospora mitochondrial outer membrane protein TOM22

TOM22 is an integral component of the preprotein translocase of the mitochondrial outer membrane (TOM complex). The protein is anchored to the lipid bilayer by a central trans-membrane segment, thereby exposing the amino-terminal domain to the cytosol and the carboxyl-terminal portion to the intermembrane space. Here, we describe the sequence requirements for the targeting and correct insertion of Neurospora TOM22 into the outer membrane. The orientation of the protein is not influenced by the charges flanking its trans-membrane segment, in contrast to observations regarding proteins of other membranes. In vitro import studies utilizing TOM22 preproteins harboring deletions or mutations in the cytosolic domain revealed that the combination of the trans-membrane segment and intermembrane space domain of TOM22 is not sufficient to direct import into the outer membrane. In contrast, a short segment of the cytosolic domain was found to be essential for the import and assembly of TOM22. This sequence, a novel internal import signal for the outer membrane, carries a net positive charge. A mutant TOM22 in which the charge of the import signal was altered to -1 was imported less efficiently than the wild-type protein. Our data indicate that TOM22 contains physically separate import and membrane anchor sequences.     

Identification of a receptor mediating absorption of dietary cholesterol in the intestine

Here we show that scavenger receptor class B type I is present in the small-intestine brush border membrane where it facilitates the uptake of dietary cholesterol from either bile salt micelles or phospholipid vesicles. This receptor can also function as a port for several additional classes of lipids, including cholesteryl esters, triacylglycerols, and phospholipids. It is the first receptor demonstrated to be involved in the absorption of dietary lipids in the intestine. In liver and steroidogenic tissues, the physiological ligand of this receptor is high-density lipoprotein. We show that binding of high-density lipoprotein and apolipoprotein A-I to the brush border membrane-resident receptor inhibits uptake of cholesterol (sterol) into the brush border membrane from lipid donor particles. This finding lends further support to the conclusion that scavenger receptor BI catalyzes intestinal cholesterol uptake. Our findings suggest new therapeutic approaches for limiting the absorption of dietary cholesterol and reducing hypercholesterolemia and the risk of atherosclerosis.     

A new approach for solution of vehicle routing problem with hard time window: an application in a supermarket chain

In this study, a vehicle routing problem with hard time windows (VRPHTW) that appears to meet demands of customers’ service within time intervals in a supermarket chain is solved. In VRPHTW, to reach a solution by an exact method is quite difficult and sometimes impossible if number of constraints is large enough (i.e., NP-hard), and solution time of a VRPHTW grows exponentially. As the size of the problem grows, a near optimal solution can be found using a heuristic method. A hierarchical approach consisting of two stages as “cluster-first route-second” is proposed. In the first stage, customers are assigned to vehicles using three different clustering algorithms (i.e., K-means, K-medoids and DBSCAN). In the second stage, a VRPHTW is solved using a MILP. The main contribution of the article is that the proposed hierarchical approach enables us to deal with a large size real problem and to solve it in a short time using the exact method. Finally, the proposed approach is employed on a supermarket chain. An instance of the algorithm is demonstrated to illustrate the applicability of the proposed approach and the results obtained are highly favourable.     

When people with pre-existing disabilities age in place: implications for social work practice

Dental implants are subject to large and highly complex loads of varying magnitude, duration and vector. Bridge performance is closely related to load transmission both at the bone to implant interface and between components within the implant-abutment-bridge cylinder complex. The design of the interface between components within this complex may have a profound influence on the long term function of the implant supported prosthesis. An in vitro evaluation of implants 3.5 mm in diameter, utilizing an internal conical interface has demonstrated increased resistance to bending moments at the fixture-abutment interface (P = 0.00010) and at the abutment-bridge cylinder interface (P < 0.01), when compared to a standard 3.75 mm implant with a hex mediated, butt joint interface. The relatively small values for coefficient of variance measured in both systems would confirm that whilst the size of data is small, it is nonetheless a reliable indication of the relative strength of these implant designs.