Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis

Telomere shortening and telomerase activation both occur in human tumors. Telomere shortening has been proposed to have two conflicting roles in tumorigenesis: tumor suppression and initiation of chromosomal instability. Similarly, while telomerase activation is suggested to be necessary for tumor growth, telomerase may help to stabilize genomic instability. Here we review what is known about these conflicting roles and propose a framework to understand the role of telomerase in cancer progression.     

Mammalian germ-line transgenesis by transposition

Transposons have been used in invertebrates for transgenesis and insertional mutagens in genetic screens. We tested a functional transposon called Sleeping Beauty in the one-cell mouse embryo. In this report, we describe experiments in which transposon vectors were injected into one-cell mouse embryos with mRNA expressing the SB10 transposase enzyme. Molecular evidence of transposition was obtained by cloning of insertion sites from multiple transgenic mice produced by SB10 mRNA/transposon coinjection. We also demonstrate germ-line transmission and expression from transposed elements. This technique has promise as a germ-line transgenesis method in other vertebrate species and for insertional mutagenesis in the mouse.     

Effects of meniscal and articular surface status on knee stability,function, and symptoms after anterior cruciate ligament reconstruction: a long-term prospective study

BACKGROUND: Concomitant injuries to secondary structures have been proposed as a major cause of failure of anterior cruciate ligament reconstruction. PURPOSE: Our purpose was to determine the relationship between meniscal status at the time of anterior cruciate ligament reconstruction and ultimate long-term function and stability. STUDY DESIGN: Prospective cohort study. METHODS: We prospectively studied 63 patients for an average of 10.4 years after arthroscopically assisted bone-patellar tendon-bone anterior cruciate reconstruction. All surgeries were performed between 1988 and 1991; concomitant meniscal surgery was performed if necessary. Subjects were divided into subgroups relative to the integrity of their menisci at the end of the reconstruction procedure (intact meniscus, partial meniscectomy, complete meniscectomy). RESULTS: Patients who had undergone any degree of meniscal resection reported significantly more subjective complaints and activity limitations than those with intact menisci. Subjective International Knee Documentation Committee and Lysholm scores were lower in the meniscectomy subgroups than in the meniscus-intact group. Objective testing revealed a significantly lower ability to perform the single-legged hop in the meniscectomy subgroups. Ligament stability based on instrumented laxity measurements was not significantly different between the subgroups. Radiographic abnormalities were also more common in the subgroups that had undergone meniscectomy. CONCLUSIONS: The menisci should be repaired if at all possible, especially in the setting of anterior cruciate ligament reconstruction, for optimal functional outcome and patient satisfaction.     

Citalopram and demethylcitalopram in human milk; distribution, excretion and effects in breast fed infants

AIMS: To characterize milk/plasma (M/P) ratio and infant dose, for citalopram and demethylcitalopram, in breast-feeding women taking citalopram for the treatment of depression, and to determine the plasma concentration and effects of these drugs in their infants. METHODS: Seven women (mean age 30.6 years) taking citalopram (median dose 0.36 mg kg(-1) day(-1)) and their infants (mean age 4.1 months) were studied. Citalopram and demethylcitalopram in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval. Infant exposure was estimated (two separate methods) as the product of milk production rate and drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean M/PAUC values of 1.8 (range 1.2-3) and 1.8 (range 1.0-2.5) were calculated for citalopram and demethylcitalopram, respectively. The mean maximum concentrations of citalopram and demethylcitalopram in milk were 154 (95% CI, 102-207) microg l(-1) and 50 (23-77) microg l(-1). Depending on the method of calculation, mean infant exposure was 3.2 or 3.7% for citalopram and 1.2 or 1.4% for demethylcitalopram. Citalopram (2.0, 2.3 and 2.3 microg l(-1)) was detected in three of the seven infants. Demethylcitalopram (2.2 and 2.2 microg l(-1) was detected in plasma from two of the same infants. No adverse effects were seen in the infants, all were within appropriate percentile limits for weight and all had normal Denver developmental quotients. CONCLUSIONS: The mean combined dose of citalopram and demethylcitalopram (4.4-5.1% as citalopram equivalents) transmitted to infants via breast milk is below the 10% notional level of concern. Plasma concentrations of these drugs in the infants were very low or absent and there were no adverse effects. These data support the safety of the use of citalopram in breast feeding women. Nevertheless, each decision to breast feed should always be made as an individual risk:benefit analysis.     

Ultrastructural events in early calcium oxalate crystal formation in rats.

A model system is described for the induction of renal calcium oxalate crystals with intraperitineal injections of sodium oxalate in rats. Early crystals are formed predominantly in cortical areas. Massive amounts of calcium are associated with this process, as demonstrated by potassium pyroantimonate staining. Actual crystal formation appears to be an involved process associated with calcium, oxalate, and cellular membranes. Although overt stone formation was not observed, we feel that the intimate involvement of membranes during crystal formation may be similar to that found in renal stones.