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AbstractBackground/Aims: Pimagedine inhibits the formation of advanced glycation end products and slows the progression of diabetic complications in experimental models. This study was undertaken to determine if pimagedine ameliorates nephropathy in type 1 (insulin-dependent) diabetes mellitus. Methods: This was a randomized, double-masked, placebo-controlled study performed in 690 patients with type 1 diabetes mellitus, nephropathy, and retinopathy. The patients received twice daily dosing with placebo, pimagedine 150 mg, or pimagedine 300 mg for 2–4 years. The primary end point was the time to doubling of serum creatinine; the secondary end points included evaluations of proteinuria, kidney function, and retinopathy. Results: Serum creatinine doubled in 26% (61/236) of the placebo-treated patients and in 20% (91/454) of those who received pimagedine (p = 0.099). The estimated glomerular filtration rate decreased more slowly in the pimagedine-treated patients with a 36-month decrease from baseline of 6.26 ml/min/1.73 m2 as compared with 9.80 ml/min/1.73 m2 in the placebo-treated patients (p = 0.05), and pimagedine reduced the 24-hour total urinary proteinuria. (The mean reduction from baseline at month 36 was 732 mg/24 h at the low dose and 329 mg/24 h at the high dose as compared with 35 mg/24 h in the placebo group; p ≤ 0.001.) Fewer pimagedine-treated patients with baseline and end point evaluations (31/324; 10%) as compared with those receiving placebo (16%; 28/179) experienced a three-step or greater progression of the retinopathy (Early Treatment of Diabetic Retinopathy Study) score (p = 0.030). Three patients receiving high-dose pimagedine but none receiving low-dose treatment developed glomerulonephritis. Conclusions: While this study did not demonstrate a statistically significant beneficial effect of pimagedine on the progression of overt nephropathy resulting from type 1 diabetes, it is noteworthy in providing the first clinical proof of the concept that inhibiting advanced glycation end product formation can result in a clinically important attenuation of the serious complications of type 1 diabetes mellitus.Copyright © 2004 S. Karger AG, Basel

The Osmington Mills Ironstone Member, a Corallian hiatal-condensed bed, contains a varied, mainly in situfauna. It developed over a relatively short time (<0.33 Ma) and is part of a transgressive systems tract. A sharp deepening in sea-level, which has not been previously identified, marks its base; its top, the Oxfordian-Kimmeridge boundary, is a recognized maximum flooding surface.

Shallow-marine sandstone and berthierinic, ooidal, sandy limestone form the Hackness Rock Member (HRM), a Callovian-age hiatal-condensed bed in NE England. The HRM was deposited in response to a rise in relative sea-level. Apart from the major hiatal surfaces represented by two significant non-sequences, it contains a number of other hiatal surfaces representing shorter periods of time. Although the HRM has its own distinctive bioclastic concentrations, early diagenetic mineral assemblages and specific types and degrees of bioturbation, the expression of this bed is variable even over short distances. Variations in the topography of the sea floor produced local hollows and highs, which account for the lateral variability of the HRM and controlled where berthierine ooids formed. Hollows created ‘clastic/colloidal’ traps where finer-grained sediment accumulated and had low physical mobility; these conditions favoured intra-sedimentary growth of berthierine ooids in an early (sub-oxic) diagenetic environment. In contrast, highs were more susceptible to storm reworking and material was more mobile; these conditions resulted in a lower overall rate of accumulation and a lower degree of shallow, sub-surface diagenesis. Copyright © 2002 John Wiley & Sons, Ltd.

We have cloned two splice variants of the human homolog of the α1A subunit of voltage-gated Ca2+ channels. The sequences of human α1A-1 and α1A-2 code for proteins of 2510 and 2662 amino acids, respectively. Human α1A-2α2bδβ1b Ca2+ channels expressed in HEK293 cells activate rapidly (τ+10mV=2.2ms), deactivate rapidly (τ–90mV=148μs), inactivate slowly (τ+10mV=690ms), and have peak currents at a potential of +10mV with 15mM Ba2+ as charge carrier. In HEK293 cells transient expression of Ca2+ channels containing α1A/B(f), an α1A subunit containing a 112 amino acid segment of α1B-1 sequence in the IVS3-IVSS1 region, resulted in Ba2+ currents that were 30-fold larger compared to wild-type (wt) α1A-2-containing Ca2+ channels, and had inactivation kinetics similar to those of α1B-1-containing Ca2+ channels. Cells transiently transfected with α1A/B(f)α2bδβ1b expressed higher levels of the α1, α2bδ, and β1b subunit polypeptides as detected by immunoblot analysis. By mutation analysis we identified two locations in domain IV within the extracellular loops S3-S4 (N1655P1656) and S5-SS1 (E1740) that influence the biophysical properties of α1A. α1AE1740R resulted in a threefold increase in current magnitude, a −10mV shift in steady-state inactivation, and an altered Ba2+ current inactivation, but did not affect ion selectivity. The deletion mutant α1AΔNP shifted steady-state inactivation by −20mV and increased the fast component of current inactivation twofold. The potency and rate of block by ω-Aga IVA was increased with α1AΔNP. These results demonstrate that the IVS3-S4 and IVS5-SS1 linkers play an essential role in determining multiple biophysical and pharmacological properties of α1A-containing Ca2+ channels.

Previous studies on the fertilization rates in externally fertilizing marine invertebrates have been concerned principally with free spawning epifaunal organisms (e.g., Babcock et al., 1992). A technique has been developed to investigate fertilization success in the intertidal infaunal polychaete Arenicola marina. The spawning period at the East Sands, St Andrews, is predictable from previous data, and this facilitates the study of spawning behaviour. Female worms spawn within their burrows, where the eggs may remain for several days. Male worms release sperm puddles on to the surface of the sediment at low water. The sperm is carried on the incoming tide over the surface of the sediment where it is actively drawn into female burrows by pumping. The decrease in sperm concentration as the tide comes in has been measured, and it is estimated that there are typically about 106 sperm.ml-1 in the water column and available to the female at 1 min after covering by the incoming tide. By placing the worms into artificial plastic burrows with removable stoppers, they can be transplanted into the field prior to spawning, and removed afterwards whilst retaining all the contents of the tube (worms, gametes, sediment and water).Preliminary data on the fertilization success suggests that it is highly variable (between 0% and 90%), with typical values of 40-60% for Arenicola marina. Laboratory assays investigating fertilization rate with varying sperm concentration have shown that there is a marked increase in success at 104 and 105 sperm per ml, with values of 30-70%. The field data therefore appear to be consistent with laboratory studies.

Approximately 70% of centrocytic (mantlecell) lymphomas have the chromosomal translocation t(11;14) (ql3; q32) and associated rearrangements at the bcl-1 breakpoint locus and at the cyclin Dl (PRAD1, CCND1) gene, thus implicating this gene in the pathogenesis of centrocytic lymphoma. In order to determine cyclin D1 expression in hematopoietic neoplasms with and without bcl-1 or cyclin D1 rearrangements, northern blot analysis was performed.

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Profiles Judy Denson and Beverly Smallwood and their company called KidSpiration LLC. Inspiration for the`Kidspiration' books series; Solicitation of children's stories; Encouragement to parents to record precious childhood moments.

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Provides a backgrounder into the formation of KidSpiration LLC, a limited liability company based in Hattiesburg, Mississippi, in 1995. Creation by Mississippi entrepreneurs Judy Denson and Beverly Smallwood; Plan to write a book relating children's perspective on the world; Response to the project.