Inhibitors of apoptosis proteins in prostate cancer cell lines

BACKGROUND: The caspases are the central executioners of apoptosis. The inhibitors of apoptosis proteins (IAPs) are a family of recently described caspase inhibitors. We hypothesised that tumor resistance to apoptosis could be due in part to IAP expression. METHODS: The expression of NAIP, cIAP-1, cIAP-2, XIAP, and survivin was investigated in the prostate cancer cell lines LNCaP, PC3, and DU145. RNase protection assays and Western blotting were used to assess RNA and protein expression. Apoptotic susceptibility was determined using etoposide and assessed by propidium iodide (PI) DNA incorporation using flow cytometry. RESULTS: DU145 and PC3 cells were more resistant to apoptosis than LNCaP cells. All the IAPs were identified in the cell lines with variation in IAP expression between different cell types. Immunohistochemistry demonstrated cIAP-1 expression in PC3 cells was nuclear, while the expression of cIAP-2 and XIAP was perinuclear. Growing LNCaP cells in charcoal-stripped or androgen-supplemented medium resulted in no alteration in IAP expression. CONCLUSIONS: This study characterises the expression of IAP in three of the most commonly used prostate cancer cells. IAP may make an important contribution to apoptotic resistance in patients with prostate cancer.     

Propranolol and thyroidectomy in the treatment of thyrotoxicosis.

For decades, the preparation of a hyperthyroid patient for surgery took several weeks or months utilizing thyroid blocking agents and iodine. In 1973, a preliminary report of 20 patients with hyperthyroidism treated with propranolol and thyroidectomy was presented. It was found that a thyrotoxic patient could be prepared for surgery, in an emergency, by intravenous propranolol in less than an hour, or electively by oral propranolol within 24 hours. Since then, 140 additional patients have been similarly treated. It continues to be true at this institution that propranolol, a beta-adrenergic blocking agent, effectively neutralizes the symptoms of autonomic hyperactivity, including sweating, tremor, fever, dilation of blood vessels, and increased pulse rate without significantly affecting thyroid function. An average dose of 160 mg/day was used, with a range of 40 to 320 mg/day. In none of these patients was iodine used; in fact, its use with propranolol is considered unnecessary. A subtotal, near total, or total thyroidectomy was done in all patients, resulting in a 55% incidence of hypothyroidism. There was no postoperative thyroid storm, nerve injury, or permanent hypoparathyroidism. It is believed that the administration of propranolol alone provides a rapid, safe, and effective preparation of the thyrotoxic patient for thyroidal or extrathyroidal surgical procedures during the perioperative period.     

Specific antibodies to soluble alpha-synuclein conformations in intravenous immunoglobulin preparations

Alpha‐synuclein is the major protein in Lewy bodies, the hallmark pathological finding in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Although normally intracellular, it also can be secreted, so extracellular alpha‐synuclein may contribute to neuronal injury. Serum antibodies to alpha‐synuclein could exert protective effects by increasing alpha‐synuclein's movement out of the brain and, if they cross the blood–brain barrier, by inhibiting its neurotoxic effects. The objective of this study was to measure antibody concentrations to alpha‐synuclein monomer and soluble oligomers in three intravenous immunoglobulin (IVIG) preparations, Gamunex (Talecris Biotherapeutics), Gammagard (Baxter Healthcare) and Flebogamma (Grifols Biologicals). Antibodies were measured in native IVIG preparations and after antibody–antigen complex dissociation. IVIG's non‐specific binding was subtracted from its total binding to alpha‐synuclein to calculate specific anti‐alpha‐synuclein antibody concentrations. Specific antibodies to alpha‐synuclein monomer and/or soluble oligomers were detected in all IVIG products. In native IVIG preparations, the highest anti‐monomer concentrations were in Gammagard and the highest anti‐oligomer concentrations were in Gamunex; the extent to which lot‐to‐lot variation may have contributed to these differences was not determined. Antibody–antigen complex dissociation had variable effects on these antibody levels. The IVIG preparations did not inhibit alpha‐synuclein oligomer formation, although they changed the distribution and intensity of some oligomer bands on Western blots. The presence of antibodies to soluble alpha‐synuclein conformations in IVIG preparations suggests that their effects should be studied in animal models of synucleinopathies, as a first step to determine their feasibility as a possible treatment for PD and other synucleinopathies.     

Are adolescents who moderate their cannabis use at lower risk of later regular and dependent cannabis use?

Aims   To examine whether moderation of cannabis use among adolescent cannabis users is associated with reductions in cannabis use frequency and risk of dependence in young adulthood.
Design   Ten-year representative cohort study with six surveys in adolescence (mean age 14.9–17.4 years) and two in young adulthood (mean age 20.7 and 24.1 years).
Participants   Inception cohort of 1943 Victorian secondary school students (96% response rate), with 1520 (78% of adolescent participants) interviewed in the final wave.
Measurements   Participants were classified into six groups according to the maximum level of adolescent use and the extent of subsequent moderation in such use: non-users, occasional to abstinence, occasional persisting, weekly to abstinence, weekly to occasional and weekly persisting. Outcome measures were weekly+ cannabis use and DSM-IV cannabis dependence at 20 and 24 years.
Findings   Thirty-one per cent reported cannabis use during adolescence. Most adolescent users had moderated their use: from occasional to abstinence (71% of occasional users), weekly to abstinence or weekly to occasional (28% and 48% of weekly+ users, respectively). By age 24, both occasional use groups were at similar, elevated risk of regular and dependent cannabis use compared to non-users. Weekly+ adolescent users were at greatest risk of these outcomes, although the weekly to abstinence group exhibited lower risk than those in the weekly persisting and weekly to occasional groups, who were at similar risk.
Conclusions   While many young people have dynamic cannabis use patterns, a pattern of moderating adolescent cannabis use was associated with less risk of later problematic use than among those persisting, but risks were still elevated substantially compared with never-users.     

Construction of modern Australian first trimester ultrasound dating and growth charts

Accurate pregnancy dating is vital to obstetric management. However, first trimester fetal charts commonly used in Australia rely on data reported more than three decades ago. This study reports first trimester dating and growth charts for crown‐rump length between 5 and 14 weeks of gestation and biparietal diameter between 9 and 14 weeks of gestation on an Australia population using modern real‐time ultrasound equipment. All consenting eligible women attending a large Sydney clinic for first trimester ultrasound between March 2005 and December 2006 were recruited. Measurements were carried out to Australasian Society for Ultrasound in Medicine standard protocols. Statistical analyses were undertaken using polynomial regression models and thorough diagnostic checks made. Overall 396 eligible women consented to the study, with 268 between 9 and 14 weeks of gestation. The average participant age was 34 years (range 22–45 years), 371 and all yielded valid biometry measurements. Equations, means and 90% reference intervals for crown‐rump length measurements and biparietal diameter measurements were derived using polynomial regression models. Thorough residual and diagnostic checks were made. Once validated by others, we believe they will warrant consideration for use by Australasian Society for Ultrasound in Medicine.     

Cerebrospinal fluid exchange after intrathecal methotrexate overdose. A report of two cases

Two patients aged 11 and four years, were accidentally given a 10-fold overdose of intrathecal methotrexate while being treated for malignant disease. Neither patient developed any signs of neurotoxicity and exchange of lumbar cerebro-spinal fluid was started 3 and 5 h later, respectively. In one of the patients, who received 120 mg of methotrexate intrathecally, 31% of the given dose was recovered during 2 h of cerebrospinal fluid exchange that was started 3 h after the accidental overdosage. No sequelae were observed in any of the patients. Cerebrospinal fluid exchange is safe and can be recommended in all cases of intrathecal methotrexate overdosage. Ventriculo-cisternal perfusion is not necessary in cases of a 10-fold overdose if the patient has no signs of acute neurotoxicity.