The FGF receptor-1 tyrosine kinase domain regulates myogenesis but is not sufficient to stimulate proliferation

STUDY OBJECTIVES: The aims of this study were: to evaluate the performance of a novel arterial biopsy catheter in obtaining pulmonary endovascular samples in hypertensive dogs; to compare the results of pulmonary endoarterial biopsy in hypertensive vs normotensive dogs; and to assess the histologic changes in the hypertensive model. DESIGN AND INTERVENTIONS: Thirty-four dogs (27 with normal pulmonary arterial pressures and seven with pulmonary hypertension) were catheterized through an external jugular vein to obtain endovascular biopsy samples from distal pulmonary arteries 2 to 3 mm in luminal diameter. To induce pulmonary hypertension, seven dogs were given repeated infusions of 0.6- to 0.9-mm ceramic microspheres into the superior vena cava. Endoarterial samples were obtained at pulmonary systolic arterial pressures ranging from 10 to 110 mm Hg. MEASUREMENTS AND RESULTS: Sixty-two biopsy catheterization procedures were performed in the 34 dogs. After 12 initial procedures of technique refinement, endoarterial samples were obtained in each of the last 50 procedures (21 in normotensive dogs and 29 in hypertensive dogs). The average number of endovascular biopsy samples retrieved was 7.1 (range, 2 to 12) from a mean of 8.6 (range, 2 to 15) biopsy attempts per catheterization (success rate=83%). The average biopsy piece measured 1.13 mm in length, 0.33 mm in depth, and up to 1.0 mm in width. The biopsy success rates and endoarterial sample sizes were similar in normotensive and hypertensive dogs. Smooth muscle cells and endothelial cells were grown from the biopsy samples. There were no significant procedural complications, except for one self-limited hemorrhage. Histologically, samples obtained from dogs with pulmonary hypertension showed characteristic changes when compared with biopsies from normotensive dogs. CONCLUSION: This new endoarterial biopsy catheter was safe and effective when used to obtain pulmonary endoarterial samples in dogs with normal and experimentally elevated pulmonary arterial pressures. The quality and quantity of the biopsy samples allowed identification of pathologic changes.     

The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency

Combined pituitary hormone deficiency (CPHD) has an incidence of approximately 1 in 8000 births. Although the proportion of familial CPHD cases is unknown, about 10% have an affected first degree relative. We have recently reported three mutations in the PROP1 gene that cause CPHD in human subjects. We report here the frequency of one of these mutations, a 301-302delAG deletion in exon 2 of PROP1, in 10 independently ascertained CPHD kindreds and 21 sporadic cases of CPHD from 8 different countries. Our results show that 55% (11 of 20) of PROP1 alleles have the 301-302delAG deletion in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles of our 21 sporadic cases were 301-302delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given TRH stimulation tests) was 50% (3 of 6) and 0% (0 of 34) in the CPHD cases with pituitary and hypothalamic defects, respectively. Using whole genome radiation hybrid analysis, we localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. Analysis of this marker in affected subjects with the 301-302delAG deletion suggests that rather than being inherited from a common founder, the 301-302delAG may be a recurring mutation.     

Late-onset rheumatoid arthritis: is pitting oedema of the hands at onset a good prognostic indicator?

Selectin and alpha 4 beta 7-integrins have been shown to mediate transient leucocyte interactions with endothelial cells which is a crucial step in the initial immune response to pathogens. We have previously shown that stimulation of T lymphocytes via L-selectin results in activation of a signalling cascade from the L-selectin molecule via the tyrosine kinase p56lck and tyrosine phosphorylation of L-selectin to the stimulation of p21Ras and Rac proteins. In the present study we demonstrate that stimulation of Jurkat T lymphocytes via L-selectin results in an activation of Jun N-terminal kinase (JNK) but not of p38-K. L-selectin-initiated activation of JNK is mediated by src-like tyrosine kinases and the small G-protein Rac 1/2, since genetic or pharmacological inhibition of p56lck or Rac proteins prevent the stimulation of JNK by L-selectin. Thus, the data point to a novel signalling cascade from L-selectin via src-like tyrosine kinases and Rac proteins to JNK.     

Effect of mimosine on DNA synthesis in mammalian cells

We have designed a general protocol to assess the rate of replicon initiation in mammalian cells in the presence of inhibitors of DNA synthesis. It is based on cross-linking DNA in vivo with trioxsalen, which effectively blocks the movement of the replication forks along DNA, while having little effect on initiation of replication. We applied this protocol to study the effect of the plant amino acid mimosine on the rate of replicon initiation in exponentially growing murine erythroleukemia F4N cells. We found out that during the first 2 h after application of 25-400 microM mimosine, the initiation step was inhibited more efficiently than the overall DNA synthesis. In this respect, the effect of mimosine was similar to that of gamma-ray irradiation and differed from that of hydroxyurea and aphidicolin. The results suggest that in addition to inhibiting the elongation step of DNA synthesis, mimosine inhibits the initiation of DNA replication as well.     

A new tonometer--the pressure phosphene tonometer: clinical comparison with Goldman tonometry

OBJECTIVE: This study aimed to compare the results of pressure phosphene tonometry, a new tonometric technique, with Goldmann applanation tonometry. DESIGN: Comparative case series. PARTICIPANTS: A total of 100 consecutive patients (192 eyes) without diagnostic specificity, plus a separate subset of 14 eyes with intraocular pressure (IOP) above 19 mmHg, participated. INTERVENTION: Intraocular pressure was measured with Goldmann tonometry by one examiner and pressure phosphene tonometry by a different examiner. There was no communication between the examiners regarding test results. MAIN OUTCOME MEASURES: Intraocular pressure. RESULTS: In the group without diagnostic specificity, the mean difference between the two techniques was 0.3 mmHg. Fifty-one percent of the measurements were within +/-1 mmHg, 74.9% of the measurements were within +/-2 mmHg of each other, and the average deviation for 100% of the data was 1.8 mmHg. For pressure phosphene tonometry, the mean IOP was 15.2 mmHg with a standard deviation of 2.9 and a range of 18 mmHg (minimum, 10; maximum, 28). With Goldmann, the mean was 15.5 mmHg, the standard deviation was 3.1, and the range was 20 mmHg (minimum, 8; maximum, 28). The t test for paired data showed a Gaussian approximation with a P value of 0.05. A comparison between the results of the two techniques gave a correlation coefficient of 0.71. Results for the separate 14 patients with higher IOPs yielded a statistically significant mean difference of 0.1 mmHg between the two techniques (P < 0.05, t test for paired data). For pressure phosphene, the mean was 21 mmHg with a standard deviation of 5.5 and a range of 24 mmHg (minimum, 14; maximum, 38). For Goldmann, the mean was 21.1 mmHg with a standard deviation of 4.7 and a range of 19 mmHg (minimum, 15; maximum, 34). The correlation coefficient was 0.73. CONCLUSIONS: The close agreement between the two techniques suggests that pressure phosphene tonometry offers an alternative method for measuring IOP. It has the advantages that it is simple, noninvasive, and inexpensive. Potential uses of the pressure phosphene tonometer may include self-administered home testing, in outreach clinics by nonophthalmic technicians, and in patients with corneal conditions that preclude the use of Goldmann tonometry.     

Determining priorities for family physician education in substance abuse by the use of a survey

As the initial stage in developing a curriculum to assist family physicians to diagnose and manage alcohol abuse in their practices, questionnaires were mailed to a selected group of family physicians. A total of 117 physicians (34%) completed the questionnaire. The majority of physicians (70.1%) reported that fewer than 10% of their caseload experienced alcohol-related problems. Most physicians (59.3%) did not use any of the standard diagnostic instruments but reported that screening and detection was the most challenging alcohol-related problem along with patient management. The questionnaire identified a number of areas that could be used in the development of educational strategies to increase the expertise of primary care physicians in the diagnosis and management of alcohol-related problems.     

Comparison of 0.25% ropivacaine and bupivacaine for epidural analgesia for labor and vaginal delivery

STUDY OBJECTIVE: Part 1: To measure ropivacaine levels in the mother and infant at delivery after continuous lumbar epidural infusion. Part 2: To compare epidural ropivacaine to epidural bupivacaine for labor analgesia in regard to effectiveness, motor blockade, and maternal and neonatal effects. DESIGN: Part 1: Open-labelled, non-blind study. Part 2: Randomized, double-blind study. SETTING: Labor and delivery units of two academic hospitals. PATIENTS: Part 1: 20 ASA physical status I and II parturients in active labor. Part 2: 81 ASA physical status I and II parturients in active labor. INTERVENTIONS: For Part 1, 8 to 12 ml of 0.25% ropivacaine was administered through a lumbar epidural catheter to achieve a T10 dermatomal sensory level. An infusion of 0.25% ropivacaine, 8 to 10 ml/hr, maintained this sensory level. Maternal and umbilical cord blood samples obtained at delivery were analyzed for ropivacaine concentration. For Part 2, anesthetic management was similar to that previously described except patients were randomized to receive either 0.25% ropivacaine or 0.25% bupivacaine. Onset, regression, maximal spread of sensory block, and onset and degree of motor blockade were measured. Contraction pain as assessed using a visual analog scale (VAS), maternal blood pressure, and heart rate were determined every 5 minutes until a stable VAS-contraction score was achieved, and every 30 minutes thereafter. Neonatal assessment included Apgar scores and neurologic and adaptive capacity scores (NACS) at 15 minutes, 2 hours, and 24 hours. MEASUREMENTS AND MAIN RESULTS: For Part 1, the total and free maternal arterial concentrations of ropivacaine at delivery were 0.64 +/- 0.14 microgram/ml and 0.10 +/- .02 microgram/ml, respectively; the umbilical venous total and free concentrations were 0.19 +/- 0.03 microgram/ml and 0.12 +/- 0.07 microgram/ml, respectively (n = 12). The umbilical arterial and venous concentrations did not differ for both the free and total concentrations. For Part 2, there was no difference between ropivacaine and bupivacaine in the variables measured. Umbilical cord gases and Apgar scores were not different between the two groups; NACS were higher at 15 minutes and 2 hours in the ropivacaine group (p < 0.05) than the bupivacaine group. CONCLUSION: Both ropivacaine and bupivacaine produced excellent analgesia for labor with no major adverse effect on the mother or neonate.