Stereoselectivity of actions of the calcium sensitizer [+]-EMD 60263 and its enantiomer [-]-EMD 60264

The thiadiazinone derivative [+]-EMD 60263 ((+)-5-(1-(α-ethylimino-3,4-dimethoxybenzyl)-1,2,3,4- tetrahydroquinoline-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4 -thiadiazine-2-on) is a Ca²⁺-sensitizing agent with only minor phosphodiesterase inhibitory activity. Our aim was to characterize the inotropic and electrophysiological effects of [+]-EMD 60263 and its enantiomer [-]-EMD 60264 in several cardiac muscle preparations. The Ca²⁺-sensitizing activity resided in the [+]-enantiomer only. [+]-EMD 60263 (3 μM) shifted the EC₅₀ of Ca²⁺ for contractile activation of skinned fibers of pig heart from 2.41 μM to 0.73 μM, whereas [-]-EMD 60264 (30 μM) was ineffective. In Langendorff-perfused guinea pig hearts, [+]-EMD 60263 and [-]-EMD 60264 induced concentration-dependent positive and negative inotropic effects, respectively; both enantiomers reduced spontaneous heart rate but did not influence perfusion pressure. The maximum increase in force of human atrial trabeculae was 35 % of pre-drug control with [+]-EMD 60263 in comparison to 113 % with forskolin. In guinea-pig papillary muscles, [+]-EMD 60263 and [-]-EMD 60264 had opposite inotropic responses, however, both agents similarly prolonged action potential duration. Both enantiomers concentration-dependently blocked the rapidly activating component I_Kr of the delayed rectifier in guinea-pig myocytes. The block saturated at potentials positive to +30 mV, closely resembling the effects of the antiarrhythmic agent E-4031 which had been originally used to define I_Kr. It is concluded, that the positive inotropic action of [+]-EMD 60263 can be explained by prevalence of the Ca²⁺-sensitizing effect. The accompanying prolongation in action potential duration is caused by block of the I_Kr component of the delayed rectifier. While the inotropic effects are stereoselective, most of the electrophysiological actions are clearly independent of sterical configuration. The combination of Ca²⁺-sensitizing with class-III antiarrhythmic action may provide an interesting pharmacological profile of potential therapeutic use. Received: 7 January 1997 / Accepted: 25 February 1997     

Nonoperatively treated burst fractures of the thoracic and lumbar spine in adults: a 23- to 41-year follow-up

BACKGROUND CONTEXT: Several studies report a favorable short-term outcome after nonoperatively treated two-column thoracic or lumbar burst fractures in patients without neurological deficits. Few reports have described the long-term clinical and radiological outcome after these fractures, and none have, to our knowledge, specifically evaluated the long-term outcome of the discs adjacent to the fractured vertebra, often damaged at injury and possibly at an increased risk of height reduction and degeneration with subsequent chronic back pain. PURPOSE: To evaluate the long-term clinical and radiological outcome after nonoperatively treated thoracic or lumbar burst fractures in adults, with special attention to posttraumatic radiological disc height reduction. STUDY DESIGN: Case series. PATIENT SAMPLE: Sixteen men with a mean age of 31 years (range, 19-44) and 11 women with a mean age of 40 years (range, 23-61) had sustained a thoracic or lumbar burst fracture during the years 1965 to 1973. Four had sustained a burst fracture Denis type A, 18 a Denis type B, 1 a Denis type C, and 4 a Denis type E. Seven of these patients had neurological deficits at injury, all retrospectively classified as Frankel D. OUTCOME MEASURES: The clinical outcome was evaluated subjectively with Oswestry score and questions regarding work capacity and objectively with the Frankel scale. The radiological outcome was evaluated with measurements of local kyphosis over the fractured segment, ratios of anterior and posterior vertebral body heights, adjacent disc heights, pedicle widths, sagittal width of the spinal canal, and lateral and anteroposterior displacement. METHODS: From the radiographical archives of an emergency hospital, all patients with a nonoperatively treated thoracic or lumbar burst fracture during the years 1965 to 1973 were registered. The fracture type, localization, primary treatment, and outcome were evaluated from the old radiographs, referrals, and reports. Twenty-seven individuals were clinically and radiologically evaluated a mean of 27 years (range, 23-41) after the injury. RESULTS: At follow-up, 21 former patients reported no or minimal back pain or disability (Oswestry Score mean 4; range, 0-16), whereas 6 former patients (of whom 3 were classified as Frankel D at baseline) reported moderate or severe disability (Oswestry Score mean 39; range, 26-54). Six former patients were classified as Frankel D, and the rest as Frankel E. Local kyphosis had increased by a mean of 3 degrees (p<.05), whereas the discs adjacent to the fractured vertebrae remained unchanged in height during the follow-up. CONCLUSIONS: Nonoperatively treated burst fractures of the thoracic or lumbar spine in adults with or without minor neurological deficits have a predominantly favorable long-term outcome, and there seems to be no increased risk for subsequent disc height reduction in the adjacent discs.     

"Endoview" project of intrapartum endoscopy.

INTRODUCTION: The change in obstetrical practices over the last decade in favor of trials of labor in patients with uterine scars has resulted in increased incidences of uterine ruptures. Although neither repeat cesarean delivery nor a trial of labor is risk free, evidence from a large multicenter study shows vaginal birth after the cesarean (VBAC) is associated with shorter hospital stays, fewer postpartum blood transfusions, and a decreased incidence of postpartum maternal fever. The uterine rupture remains the most serious complication associated with VBAC. Factors associated with uterine rupture include excessive exposure to oxytocin, dysfunctional labor, and a history of more than 1 cesarean delivery.2 Because uterine rupture may be a life-threatening event, intrapartum surveillance and the ability to perform an emergency surgery are both necessary when trial of labor is allowed. Until now, no early symptoms pathognomonic to uterine rupture had been described. We share our experiences with the novel approach to the problem - an intrapartum endoscopy. MATERIALS AND METHODS: Endoscopic examination was accomplished by using the intraoperational fiberscope (Olympus and Endoview system (Costa Mesa, CA, USA). A gas-sterilized 25-cm long fiberscope is introduced into the amniotic cavity through the cervical canal after rupture of the membranes. The distance between the fiberscope and the object varies from 3 to 50 mm. The fiberscope has a separate channel for the fluid infusion (normal saline) throughout the procedure; the surgeon looks through the eyepiece directly and exhibits control over the flexible scope. The duration of endoscopy is less than 15 minutes. The inserting of the endoscopic device is very similar to that of insertion of an intrauterine pressure catheter. The IRB Committees of both participating institutions approved the study protocol. Twenty-eight patients with an unknown or poorly documented site of the uterine scar were included in the study. An ultrasound examination had been performed on all patients prior to endoscopy to assess fetal wellbeing and placental location. The ages of the patients ranged from 21 to 38 years. Eighteen women had 1 previous cesarean delivery, and 10 had 2. The performance of intrapartum endoscopy did not interfere with fetal monitoring; 21 fetuses were monitored externally, 7 internally. Indications for previous cesarean deliveries were as follows: fetal distress in 11 cases, failure to progress in labor in 8, placenta previa in 2, and unknown in 7. Twenty-one patients delivered vaginally; 7 had had repeat cesarean deliveries. All neonates were born in satisfactory condition. The Apgar scores at 1 minute varied from 7 to 9 and at 5 minutes from 8 to 10. The integrity of the uterine wall was assessed by manual postpartum uterine exploration in each case of vaginal delivery and by visualization and palpation of the scar site in each abdominal delivery. RESULTS: The lower uterine segment and contractile portion of the anterior uterine wall were visualized successfully in all patients. In 25 patients, the presumed scar site looked totally indistinguishable from the rest of the lower uterine segment and anterior uterine wall. Two scars were identified as vertical in 2 patients who were delivered by a repeat abdominal operation. A vertical scar appears as a groove running in a cephalad-caudad direction from the lower uterine segment into the contractile portion of the anterior uterine wall. The usefulness of the intrapartum endoscopy is best demonstrated by the following case reports (2 of 28 study cases).     

Radiographic prediction of failure after fixation of cervical hip fracture

During 1984-1985, 410 patients with cervical hip fracture were randomized between 2 methods of internal fixation-a single nail (Rydell) or 2 LIH hook pins (LIH). The patients were followed-up prospectively for at least 2 years. Radiographs were taken after 1 week, 1, 3, 6, 12, and 24 months. The radiographs of the 295 paients alive 2 years postoperatively were examined by one of the authors. The sliding and the diversion of the pins and the nail in the anteroposterior projection and the diversion in the lateral projection were measured. In the failure group (non-union, late segmental collapse), the greatest sliding was noted within 1 month postoperatively and the diversion increased up to 3 months. Significant differences between the failure and the non-failure groups could be seen even after 1 week. We also found that the degree of sliding of the LIH pins and the Rydell nail 1 month postoperatively is comparable to the scintigraphic pattern 2 weeks postoperatively in predicting failure after nternal fixation of cervical hip fractures.     

The detection of internal mammary lymph nodal chain metastases in breast cancer using radiolabelled colloids

The authors report their studies of 39 lymphoscintigraphies performed on patients with breast cancer. They point out that interpretation of scintigraphic imaging must take into account the morphologic variations of the lymph nodes of the internal mammary chains (i.e. single central chain, single central lymph node) and the morphological difference in the symmetry of lymph nodes considered non-pathologic to avoid false positives. The authors retain that lack of visualization of a chain, conspicuous increase in size of a lymph node, asymmetry of pathologic development, or reduced uptake by one or more lymph nodes of the internal mammary chains must be interpreted as a sign of metastatic spread. The authors recommend lymphoscintigraphy as an effective technique in the screening of breast cancer patients for staging, follow-up, restaging, and planning of radiotherapy.     

Functional substitution of the TibC protein of enterotoxigenic Escherichia coli strains for the autotransporter adhesin heptosyltransferase of the AIDA system

The plasmid-encoded AIDA (adhesin involved in diffuse adherence) autotransporter protein derived from diffuse-adhering clinical Escherichia coli isolate 2787 and the TibA (enterotoxigenic invasion locus B) protein encoded by the chromosomal tib locus of enterotoxigenic E. coli (ETEC) strain H10407 are posttranslationally modified by carbohydrate substituents. Analysis of the AIDA-I adhesin showed that the modification involved heptose residues. AIDA-I is modified by the heptosyltransferase activity of the product of the aah gene, which is located directly upstream of adhesin-encoding gene aidA. The carbohydrate modification of the TibA adhesin/invasin is mediated by the TibC protein but has not been elucidated. Based on the sequence similarities between TibC and AAH (autotransporter adhesin heptosyltransferase) and between the TibA and the AIDA proteins we hypothesized that the AIDA system and the Tib system encoded by the tib locus are structurally and functionally related. Here we show that (i) TibC proteins derived from different ETEC strains appear to be highly conserved, (ii) recombinant TibC proteins can substitute for the AAH heptosyltransferase in introducing the heptosyl modification to AIDA-I, (iii) this modification is functional in restoring the adhesive function of AIDA-I, (iv) a single amino acid substitution at position 358 completely abolishes this activity, and (v) antibodies directed at the functionally active AIDA-I recognize a protein resembling modified TibA in ETEC strains. In summary, we conclude that, like AAH, TibC represents an example of a novel class of heptosyltransferases specifically transferring heptose residues onto multiple sites of a protein backbone. A potential consensus sequence for the modification site is suggested.     

Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study

In an exploratory study, 11 common polymorphisms were examined for contributing to longevity including: apolipoprotein E (apoE), methylenetetrahydrofolate reductase (MTHFR), cathepsin D (CAD), superoxide dismutase 2 (SOD2), angiotensinogen (AGT) and insulin-like growth factor 2 (IGF2), Leiden factor 7, p53 oncogene, dopamine D4 receptor (DRD4) and the serotonin transporter (SERT). Genotype and allele frequencies of these genes were compared in 224 older (75 years) Jewish Jerusalem residents of Ashkenazi ethnicity to a group of 441 younger subjects (22 years). Nominally significant results provide suggestive evidence in the Ashkenazi group that apoE, MHTFR, SOD2, IGF2 ApaI, and factor VII are risk factors for a single outcome, survival to 75. Overall, the more genetically homogenous Ashkenazi ethnic group showed evidence for association in five genes examined suggesting that future studies in this population would gainfully focus on this ethnic group.