New interventions in cerebrovascular disease: the role of thrombolytic therapy and balloon angioplasty

The use of thrombolytic agents (plasminogen activators) in the early moments of ischemic stroke to achieve recanalization and potential neurologic improvement has been actively studied over the past 10 years. In the same period, endovascular techniques for cerebral revascularization have evolved significantly. Recent phase III studies, following angiography-based phase I and II studies of plasminogen activators in stroke, have described evidence of clinical benefit and contributors to morbidity (i.e., symptomatic hemorrhage) and mortality that limit the applicability of this approach. The limited formalized experience with percutaneous transluminal balloon angioplasty and stent placement in the carotid artery and cerebral circulation has given rise to concerns about the safety and appropriateness of the procedures in this territory. However, several prospective series support the feasibility of well-designed clinical trials.     

Risk factors associated with incisor injury in elementary school children

This study examined risk factors associated with incisor injury in 3396 third and fourth grade school children in Alachua County, Florida. One of six orthodontists completed a standardized examination form for each child to assess severity of incisor injury, gender, age, race, skeletal relationships, morphologic malocclusion, incisor exposure, interlabial gap, TMJ sounds, chin trauma, and history of lower facial trauma. One in five (19.2%) exhibited some degree of incisor injury. This was limited to a single tooth in 73.1% of those with injury, while enamel injury predominated (89.4%). The majority of the injuries (75.4%) were localized in the maxillary arch, with central incisors the most frequently traumatized. Chi-square tests of association indicated that gender, race, school, orthodontist, history of lower facial trauma, chin trauma, profile, and maxillary and mandibular horizontal positions were associated with incisor injury (P < 0.05). Wilcoxon rank sum tests identified differences in age, overjet, time of screening, and interlabial gap between those with and without injury (P < 0.05). Results of logistic regression analyses indicated risk of incisor injury was greater for children who had a prognathic maxilla, a history of trauma, were older, were male, and had greater overjet and mandibular anterior spacing.     

Agenesis of the corpus callosum in a mother and son

Most reported familial cases of agenesis of the corpus callosum have followed either an autosomal recessive or an X-linked recessive pattern of inheritance. To the best of our knowledge, there is only one previous report of a family showing clear-cut autosomal dominant inheritance. We present the second such family, among whom a mother and her son had moderately severe coordination problems and low-normal intelligence. We suggest that agenesis of the corpus callosum, when transmitted as an autosomal dominant trait, is clinically characterized by a relatively milder phenotype than that occurring when inheritance is either autosomal or X-linked recessive and may be more common than has been thought.     

Eucapnic voluntary hyperventilation as a bronchoprovocation technique: development of a standarized dosing schedule in asthmatics

A variety of dosing schedules have been reported for the hyperventilation method of broncho-provocation testing. To evaluate the effect of challenge technique on the bronchoconstrictive response, we had 16 subjects perform eucapnic voluntary hyperventilation (EVH) with dry, room temperature gas using four different dosing schedules. The hyperventilation challenge dosages included the following: (1) a target minute ventilation (VE) of 20 x FEV1 for 6 min; (2) a target VE of 15 x FEV1 for 12 min; (3) an interrupted challenge with a target VE of 30 x FEV1 for 2 min repeated 3 times; and (4) a target VE of 30 x FEV1 for 6 min. Challenges 2, 3, and 4 gave identical absolute ventilatory challenges (identical factor FEV1 x minutes) but at different VE dosages or time. Challenges 1 and 4 were of identical length, but different target VE. The mean postchallenge fall in FEV1 was 16.6 +/- 10.9%, 11.0 +/- 8.1%, 19.6 +/- 9.9%, and 26.7 +/- 11.3% for challenges 1, 2, 3, and 4, respectively. The response to an identical EVH challenge (FEV1 x 30 for 6 min) was reproducible when performed on separate days. We conclude that the challenge technique used for hyperventilation testing will have a significant impact on the bronchoconstrictive response and must be taken into account when interpreting study results. Tests may be quantitatively comparable over a narrow range of challenge time and VE. We recommend that a 6-min uninterrupted EVH challenge using dry, room temperature gas at a target VE of 30 x FEV1 be adopted as the "standard" challenge.     

The tomato DWARF enzyme catalyses C-6 oxidation in brassinosteroid biosynthesis

Brassinosteroids (BRs) are steroidal plant hormones essential for normal plant growth and development. Mutants in the biosynthesis or perception of BRs are usually dwarf. The tomato Dwarf gene (D), which was predicted to encode a cytochrome P450 enzyme (P450) with homology to other P450s involved in BR biosynthesis, was cloned previously. Here, we show that DWARF catalyses the C-6 oxidation of 6-deoxocastasterone (6-deoxoCS) to castasterone (CS), the immediate precursor of brassinolide. To do this, we first confirmed that the D cDNA complemented the mutant light- and dark-grown phenotypes of the extreme dwarf (dx) allele of tomato. To identify a substrate for the DWARF enzyme, exogenous application of BR intermediates to dx plants was carried out. C-6 oxoBR intermediates enhanced hypocotyl elongation whereas the C-6 deoxoBR, 6-deoxoCS, had little effect. Quantitative analysis of endogenous BR levels in tomato showed mainly the presence of 6-deoxoBRs. Furthermore, dx plants were found to lack CS and had a high level of 6-deoxoCS in comparison to D plants that had CS and a lower level of 6-deoxoCS. Confirmation that DWARF catalyzed the C-6 oxidation of 6-deoxoCS to CS was obtained by functional expression of DWARF in yeast. In these experiments, the intermediate 6alpha-hydroxycastasterone was identified, indicating that DWARF catalyzes two steps in BR biosynthesis. These data show that DWARF is involved in the C-6 oxidation in BR biosynthesis.     

Macrophage and myofibroblast involvement in ischemic acute renal failure is attenuated by endothelin receptor antagonists

BACKGROUND: Endothelin (ET) may be a mediator of injury following ischemia-induced acute renal failure (ARF). ET receptor (ETR) antagonists have been reported to increase survival rates and lower serum creatinines when administered postrenal ischemia-reperfusion injury in the rat. Renal cellular and extracellular matrix responses to this therapy have not been addressed. METHODS: We investigated the use of ETR antagonists, PD 156707 (ETA) and SB 209670 (ETA and ETB) in the treatment of sublethal postischemic ARF. The right kidney of female Sprague-Dawley rats weighing approximately 200 g was removed. After five days, the left renal pedicle was occluded for 45 minutes. Twenty-four hours after renal ischemia, one of two ETR antagonists, PD 156707 (N = 7) or SB 209670 (N = 8), was administered. Experimental animals were compared with an ischemic group receiving only saline (N = 9). Three nephrectomized groups that did not undergo ischemia but that received infusions of saline (N = 6), PD 156707 (N = 6), and SB 209670 (N = 6), respectively, were also studied. Animals were sacrificed one week postischemia. Quantitation of monocytes and macrophages (Mo/Mphi), alpha-smooth muscle actin-positive myofibroblasts, and collagens type III and IV was performed by immunohistochemical staining. Cell kinetics were examined by staining for apoptosis with terminal deoxyuridine triphosphate (dUTP) nick end labeling and for proliferation with proliferating cell nuclear antigen. RESULTS: All ischemic groups of rats initially developed raised serum creatinine levels; however, no significant difference was observed between the groups (Kruskal-Wallis). Creatinines returned to preischemic values in all groups by the time of sacrifice. No significant difference in kidney weights or body weights was found between groups. Histologically, infiltration of Mo/Mphi was significantly reduced in groups treated with ETR antagonists (P < 0.001). The presence of myofibroblasts was also significantly reduced in the antagonist-treated groups (P < 0. 001). This was also paralleled by reduced quantities of collagen IV in the treated rat groups (P < 0.001). The interstitial area was also significantly greater in the saline group (P < 0.001). The amount of collagen III did not significantly differ between rat groups. Apoptosis was reduced (P < 0.001) by treatment with ETR antagonists, whereas proliferation was enhanced (P < 0.005). All non-ischemic groups showed no variation in any parameter studied at this time point. CONCLUSIONS: Treatment of ischemic ARF in the rat with ETR antagonists PD 156707 and SB 209670 attenuated cellular infiltration and matrix accumulation. An advantage of one antagonist over the other could not be determined in this study. The marked discrepancy between function and pathology (former unchanged, latter markedly improved) may be due to the time frame of this experiment, and longer outcome measures need to be assessed.     

Biological activity of carboxy-terminal gastrin analogs

Amidated forms of gastrin are derived by post-translational processing of a large precursor peptide and stimulate gastric acid secretion via the gastrin/CCK(B) receptor. Non-amidated biosynthetic intermediates may exert biological effects through other mechanisms, but their effect on gastric acid secretion is unclear. Amidated gastrins stimulate acid secretion mainly by releasing histamine from mucosal enterochromaffin-like cells. This study examines the effects on histamine release from the vascularly perfused rat stomach of amidated gastrin-17, COOH-terminal glycine-extended gastrin-17, gastrin-17 extended at the COOH-terminal including the remaining progastrin sequence, and carboxy-terminal progastrin fragments (SAEDEN and GRRSAEDEN). Carboxy-terminal extended gastrins induced histamine release which was inhibited by the gastrin/CCK(B) antagonist L-740,093, but had to be given in concentrations 100-fold higher than amidated gastrin-17 to produce comparable effects. These progastrin-derived peptides are found in high concentrations in some patients with the Zollinger-Ellison syndrome and may contribute to acid hypersecretion and other gastrin/CCK(B) receptor mediated responses.