Antithrombins Wibble and Wobble (T85M/K): archetypal conformational diseases with in vivo latent-transition, thrombosis, and heparin activation

The inherent variability of conformational diseases is demonstrated by two families with different mutations of the same conserved aminoacid in antithrombin. Threonine 85 underlies the opening of the main beta-sheet of the molecule and its replacement, by the polar lysine, in antithrombin Wobble, resulted in a plasma deficiency of antithrombin with an uncharacteristically severe onset of thrombosis at 10 years of age, whereas the replacement of the same residue by a nonpolar methionine, antithrombin Wibble, gave near-normal levels of plasma antithrombin and more typical adult thromboembolic disease. Isolated antithrombin Wibble had a decreased thermal stability (Tm 56.2, normal 57.6 degreesC) but was fully stabilized by the heparin pentasaccharide (Tm 71.8, normal 71.0 degreesC), indicating that the prime abnormality is a laxity in the transition of the main sheet of the molecule from the 5- to 6-stranded form, as was confirmed by the ready conversion of antithrombin Wibble to the 6-stranded latent form on incubation. That this transition can occur in vivo was shown by the finding of nearly 10% of the proband's plasma antithrombin in the latent form and also, surprisingly, of small but definitive amounts of latent antithrombin in normal plasma. The latent transition will be predictably accelerated not only by gross mutations, as with antithrombin Wobble, to give severe episodic thrombosis, but also by milder mutations, as with antithrombin Wibble, to trigger thrombosis in the presence of other predisposing factors, including the conformational stress imposed by the raised body temperatures of fevers. Both antithrombin variants had an exceptional (25-fold) increase in heparin affinity and this, together with an increased inhibitory activity against factor Xa, provides evidence of the direct linkage of A-sheet opening to the conformational basis of heparin binding and activation.     

Cost-effectiveness of assertive community treatment teams

The long cane can be used as a mobility aid for visually handicapped people. According to a questionnaire completed by Japanese cane users, it seems they are not always satisfied with using long canes for a variety of reasons. In this study, hand-transmitted vibration from the long cane due to tapping the ground was measured because an exposure to repeated shock-type tapping vibration may affect the hand-arm system. A sighted female wearing a blindfold participated. The measurement was carried out in different conditions with three different ground materials both indoor and outdoors. The vibration at three axes of the cane grip and one axis at the wrist were measured. The pinch forces between an index finger and the grip were also measured using a strain gauge in order to observe how the vibration characteristics depend on the changing forces. Measurement, evaluation and assessment were based on the International Standard (ISO 5349). The estimated daily exposure time and the transmissibility were obtained in order to investigate the severity of the hand-transmitted vibration caused by the long cane. It was found that the characteristics of tapping vibration depend on different measurement conditions and the vibration might be associated with a health risk over a long life span.     

Effective use of ribonucleotide reductase inhibitors (Didox and Trimidox) alone or in combination with didanosine (ddI) to suppress disease progression and increase survival in murine acquired immunodeficiency syndrome (MAIDS)

Ribonucleotide reductase inhibitors (RRIs) have been recently shown to inhibit retroviral replication. We examined a new series of RRIs, 3,4-dihydroxybenzohydroxamic acid (Didox) and 3,4,5-trihydroxybenzohydroxamidoxime (Trimidox) for their ability to alter disease progression in murine acquired immunodeficiency syndrome (MAIDS), both alone and in combination with 2',3'-dideoxyinosine (ddI). MAIDS disease was induced by inoculation of female C57BL/6 mice with the LP-BM5 murine leukemia virus (MuLV) and disease progression characterized by extensive peripheral lymphadenopathy and splenomegaly. Efficacy of treatment with these drugs was based upon their ability to influence survival and disease pathophysiology by monitoring the development of splenomegaly. Toxicity was determined by changes in body weight, total peripheral white blood cell count and hematocrit. Didox or trimidox monotherapy was associated with increased survival and decreased disease pathophysiology, with no apparent toxicity. Combined with ddI, their ability to reduce development of viral induced splenomegaly was enhanced compared to trimidox, didox or ddI alone. These results demonstrate RRIs have potent activity in reversing the disease manifestations characteristic of MAIDS. Further studies are warranted to determine human clinical efficacy.     

Colour flow duplex imaging of occlusive arterial disease of the lower limb

BACKGROUND: The development of duplex ultrasonography and colour flow imaging has greatly extended the scope of non-invasive assessment of lower limb arterial disease. This review questions whether recent advances might allow colour duplex imaging to displace arteriography as the primary imaging modality for native vessel occlusive disease. METHODS: A literature review was carried out based predominantly on a Medline database search of English language publications from 1985 to 1996. RESULTS: Increasing evidence indicates that colour duplex ultrasonography can accurately image the lower limb native arterial tree, and that colour duplex imaging can replace diagnostic arteriography in a large proportion of patients. CONCLUSION: Arteriography should no longer be considered the gold standard of imaging of peripheral arterial occlusive disease. Future studies should concentrate on the efficacy of colour duplex sonography in guiding clinical decision making.     

Assessment of childhood phobias

Childhood phobias can be successfully treated using a variety of behavioral strategies, provided there has been a psychometrically sound assessment. Measures are also important for the evaluation of treatment efficacy and the testing of hypotheses generated by new ideas and theories of children's phobias. This paper outlines broad-based assessment procedures used in the evaluation of children's phobias, including the behavioral or problem-focused interview, the diagnostic interview, self-report inventories, caregiver completed instruments, behavioral observations, self-monitoring and physiological assessment. Reflecting recent theoretical and clinical advances in the study of childhood internalizing disorders, we also explore laboratory-based measures and family assessment measures. Particular attention is given to psychometric issues and developmental sensitivity in our discussion of these assessment procedures.     

Double coupling Edman chemistry for high-sensitivity automated protein sequencing

Capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) is a promising new method for the analysis of protein sequencing products. It gives 10 zmol (1 zmol = 10(-21) mol) limits of detection (3 sigma) for fluorescein thiohydantoin (FTH) amino acids. We have developed a separation for the (FTH)-amino acid products generated from 18 of the 20 coded amino acids. The extremely low volume requirement associated with CE-LIF makes it incompatible with commercial sequencers. For this reason, we have also been developing a miniaturized sequencer that can be more easily coupled to our detection system. Both the CE-LIF system and the miniaturized sequencer are described.     

Cancer conferences. Can they be improved?

In a previous study, we showed that overexpression of cyclin D, a G1 cyclin, is frequently associated with keratinocyte carcinogenesis as an early event. Another G1 cyclin, cyclin E, was recently suggested to be a prognostic marker for breast cancer. In order to evaluate the role of cyclin E in human keratinocyte carcinogenesis, we analysed the expression of cyclin E by immunohistochemistry in normal skin, seborrheic keratosis (SK), keratoacanthoma (KA), actinic keratosis (AK), Bowen's disease (BD), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Positive cells were seen rarely in normal epidermis, in 9 of 20 cases of SK, in 5 of 6 cases of KA, in 9 of 13 cases of AK and in all 27 cases of BD. Some of the cases of AK and BD had positive cells in the superficial epidermis, where atypicality is less obvious. In contrast, positive cells were seen in 4 of 25 cases of SCC and none of 15 cases of BCC. These results suggest that expression of cyclin E plays a role in the formation of benign and premalignant keratinocytic tumors, whereas down-regulation of cyclin E expression may be involved in carcinogenesis in human keratinocytes.     

Increased cognitive load leads to impaired mobility decisions in seniors at risk for falls.

Successful mobility requires appropriate decision-making. Seniors with reduced executive functioning—such as senior fallers—may be prone to poor mobility judgments, especially under dual-task conditions. We classified participants as “At-Risk” and “Not-At-Risk” for falls using a validated physiological falls-risk assessment. Dual-task performance was assessed in a virtual reality environment where participants crossed a simulated street by walking on a manual treadmill while listening to music or conversing on a phone. Those “At-Risk” experienced more collisions with oncoming cars and had longer crossing times in the Phone condition compared to controls. We conclude that poor mobility judgments during a dual-task leads to unsafe mobility for those at-risk for falls. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Behavioral and electrophysiological activity of (Z,E)-7,9,11-dodecatrienyl formate,a mimic of the major sex pheromone component of carob moth,Ectomyelois ceratoniae

The behavioral and electrophysiological activity of a mimic [(Z,E)7,9,11-dodecatrienyl formate] of the major sex pheromone component [(Z,E) 9,11,13-tetradecatrienal] of carob moth was assessed. Wind-tunnel bioassays demonstrated that the formate was as effective as natural gland extracts, and significantly more effective than the trienal alone or than the trienal blended with two minor pheromone components, in evoking source contact. Dispensers containing the formate were as effective as trienal-containing blend lures in attracting males when placed at the same dosage in traps in date gardens. Single-cell recordings showed that at least two olfactory neurons, differentiated by spike amplitude, are located in the long trichoid hairs on male carob moth antennae. Dose-response relationships indicated that puffs from cartridges loaded with at least 0.1 g of the formate or of the trienal were necessary to elicit spiking by either the small or the large-spiking cell within a sensillum. Cross-adaptation studies demonstrated that both compounds stimulated the same large-spiking cell. The frequencies of spikes evoked from the large cell when stimulated by emissions from 0.1-g, 1-g, or 10-g cartridges of either the formate or the trienal were not significantly different, suggesting that the formate is an effective mimic of the trienal at the antennal receptor cell level.     

Organoiron Polyelectrolytes: Synthesis and Characterization of Cationic Cyclopentadienyliron Complexes of Polyarylether-Imines

The synthesis of an aromatic ether complex of cyclopentadienyliron containing two terminal aldehyde groups was achieved via metal-mediated nucleophilic aromatic substitution reactions. This dialdehyde monomer was subsequently reacted with a variety of aliphatic and aromatic diamines to produce the corresponding soluble cationic organoiron polyether-imines. These cationic organometallic polymers were characterized using IR, ¹H, and ¹³C NMR, viscosity and thermogravimetric analysis. Viscosity measurements showed that these polymers exhibited polyelectrolyte effects in DMSO solutions. Thermogravimetric analysis showed that decoordination of the iron moieties occurred at about 300°C for polymers with aliphatic spacers in their backbones, while the cyclopentadienyliron moieties were cleaved from the polymers with aromatic spacers in their backbones at about 200°C. Photolytic demetallation of the organoiron polymers resulted in the removal of the pendent cyclopentadienyliron moieties and allowed for the isolation of their organic analogs. While the organoiron polymers were soluble in polar organic solvents, the corresponding organic polymers exhibited very limited solubilities or were insoluble. The organic polymers had glass transition temperatures between 101 and 120°C