Does salmon calcitonin cause cancer? A review and meta-analysis.

Recently an association between the use of calcitonin and cancer has been postulated. We reviewed the biological rationale and performed an additional analysis of historical data with respect to the possibility. An association cannot be excluded, but the relationship is weak and causality is unlikely. The purpose of the present study is to review the strength of association and likelihood of a causal relationship between use of calcitonin and cancer. We reviewed the evidence for this association, including the molecular signaling mechanisms of calcitonin, preclinical data, an "experiment of nature," and the results of a previous meta-analysis which showed a weak association. We performed an additional meta-analysis to incorporate the data from a novel investigational oral formulation of salmon calcitonin. Review of the literature did not identify a cellular signaling mechanism of action which might account for a causal relationship or toxicologic or postmarketing data to support the thesis. Additional clinical results incorporated into previous meta-analyses weakened but did not completely negate the possibility of association. A causal association between calcitonin use and malignancy is unlikely, as there is little biological plausibility. The preponderance of nonclinical and clinical evidence also does not favor a causal relationship.

Dose effect of gestational ethanol exposure on placentation and fetal growth.

INTRODUCTION: Prenatal ethanol exposure compromises fetal growth by impairing placentation. Invasive trophoblastic cells, which mediate placentation, express the insulin-IGF regulated gene, aspartyl-asparaginyl ß-hydroxylase (ASPH), which has a critical role in cell motility and invasion. The aims of this study were to characterize effects of ethanol on trophoblastic cell motility, and assess ethanol dose-dependent impairments in placentation and fetal development. METHODS: Pregnant Long Evans dams were fed with isocaloric liquid diets containing 0%, 8%, 18% or 37% ethanol (caloric content) from gestation day (GD) 6 to GD18. Fetal development, placental morphology, density of invasive trophoblasts at the mesometrial triangle, as well as placental and mesometrial ASPH and Notch-1 protein expression were evaluated. Directional motility of control and ethanol-exposed HTR-8/SVneo cells was assessed by ATP Luminescence-Based assay. RESULTS: Severity of fetal growth impairment correlated with increasing doses of ethanol. Ethanol exposure produced dose-dependent alterations in branching morphogenesis at the labyrinthine zone, and inhibited physiological transformation of maternal arteries. ASPH and Notch-1 protein expression levels were reduced, corresponding with impairments in placentation. DISCUSSION: Prenatal ethanol exposure compromises fetal growth and placentation in a dose-responsive manner. Ethanol's adverse effects on placental development are mediated by: (1) altered branching morphogenesis in labyrinthine zone; (2) suppression of invasive trophoblastic precursor cells; and (3) inhibition of trophoblastic cell adhesion and motility, corresponding with reduced ASPH and Notch-1 protein expression.

Efficacy and safety of oral recombinant calcitonin tablets in postmenopausal women with low bone mass and increased fracture risk: a randomized, placebo-controlled trial.

UNLABELLED: The effect of an investigational oral calcitonin tablet upon bone mineral density (BMD) of the spine was investigated in postmenopausal women with low bone mass and at increased risk of fracture. Compared to placebo, calcitonin tablets increased lumbar spine BMD. This agent may provide an additional choice for patients. INTRODUCTION: An investigational oral salmon calcitonin preparation was previously shown to increase lumbar spine BMD in postmenopausal women with osteoporosis. Our objective was to evaluate the use of this agent in postmenopausal women with low bone mass and at increased fracture risk but not meeting BMD criteria for osteoporosis. METHODS: Treatment-naïve women were randomized to receive oral recombinant salmon calcitonin tablets or placebo once daily for 1 year. Dual-energy X-ray absorptiometry was performed at baseline and at study weeks 28 and 54. CTx-1, a bone resorption marker, was obtained at the same time points. Subjects returned periodically for tolerability assessment and adverse event (AE) recording. RESULTS: One hundred twenty-nine women in the USA were randomized, 86 to calcitonin and 43 to placebo. Calcitonin recipients experienced a significant increase from baseline in lumbar spine BMD; the difference compared with placebo was significant. Dosing at bedtime or with dinner was equally effective. CTx-1 was suppressed in calcitonin recipients but not in placebo subjects. Gastrointestinal AEs were common, but the overall safety profile was comparable between groups. CONCLUSIONS: Oral calcitonin may provide a useful therapeutic alternative for some women with low bone mass.

Precision-cut slice culture method for rat placenta.

Primary trophoblasts, placental explants, and cell line cultures are commonly used to investigate placental development, physiology, and pathology, particularly in relation to pregnancy outcomes. Organotypic slice cultures are increasingly used in other systems because they maintain the normal three-dimensional tissue architecture and have all cell types represented. Herein, we demonstrate the utility of the precision-cut placental slice culture model for studying trophoblastic diseases.

Calcitonin for osteoporosis and bone pain.

Calcitonin has been approved for the treatment of osteoporosis and other diseases involving accelerated bone turnover for approximately 25 years. The most commonly studied and prescribed form is salmon calcitonin, which has a greater efficacy in clinical use. A wealth of well-controlled clinical studies have demonstrated that calcitonin preserves or increases bone mineral density (BMD) and reduces the risk of vertebral fractures in osteoporosis. Recent studies have indicated that while a low BMD is correlated with an increase in fracture risk, increases in BMD alone do not explain the antifracture efficacy of antiresorptive therapies such as calcitonin. Therapies that moderately increase BMD may reduce fracture risk by reducing the rate of bone turnover and maintaining the integrity of the trabecular architecture, resulting in the preservation of bone strength and quality in osteoporotic patients. An advantage of calcitonin that is not shared by other antiresorptive therapies is its direct analgesic effect on bone pain. Calcitonin has been demonstrated to be clinically useful in improving pain, not only from the acute vertebral fractures of osteoporosis, but also in Paget's disease, bone malignancies, and other sources of musculoskeletal pain. Drugs containing calcitonin may be approved for additional indications in the near future, and as more convenient routes of administration such as the oral route become available, the demand for the calcitonin peptide is expected to increase.

Risperidone in chronic schizophrenia: a detailed audit, open switch study and two-year follow-up of patients on depot medication.

Little information exists on the medium- to long-term outcome of switching patients with schizophrenia from traditional depot to atypical oral antipsychotic agents. By detailed clinical audit, we identified a representative group of 102 patients of an Irish psychiatric service with DSM-IV chronic schizophrenia and on depot neuroleptics for a mean of 15 years. Of 69 eligible to participate, 33 entered a 6-month switch study of risperidone, with limited follow-up of consenters and non-consenters at 1 and 2 years. At 6 months, 23 of 33 were still on risperidone and had small significant improvements in clinical and extrapyramidal side effects, QOL and adjunct medication measures over baseline. At 12 months, 19 of 33 were still on risperidone, reducing to 13 of 33 at 2 years. At 2 years, of 32 surviving consenters to switch, 19 had suffered clinically detrimental events and were no longer on risperidone, compared to none of the 33 surviving non-consenters, who were all still on depot. These findings suggest that switching from depot to risperidone may encounter high rates of refusal and attrition subsequent to switch. While a majority of switched patients may improve to least 6 months, audit plus switch may have clinically unfavourable effects on others over a 2-year follow-up period [corrected].

Camel racing: a new cause of extradural haemorrhage in Australia.

Camel racing is a relatively new sport in Australia. A 52 year old woman fell from her camel during a country race. Although she was wearing an approved equestrian helmet, she suffered a skull fracture and a life-threatening extradural haematoma. Her treatment highlights the key issues of management of head injuries in remote places. A paramount requirement is close collaboration between country medical practitioner, neurosurgeon and retrieval specialist.

Spectroscopic scanning near-field optical microscopy with a free electron laser: CH2 bond imaging in diamond films.

Hydrogen chemistry in thin films and biological systems is one of the most difficult experimental problems in today's science and technology. We successfully tested a novel solution, based on the spectroscopic version of scanning near-field optical microscopy (SNOM). The tunable infrared radiation of the Vanderbilt free electron laser enabled us to reveal clearly hydrogen-decorated grain boundaries on nominally hydrogen-free diamond films. The images were obtained by SNOM detection of reflected 3.5 microm photons, corresponding to the C-H stretch absorption, and reached a lateral resolution of 0.2 microm, well below the lambda/2 (lambda = wavelength) limit of classical microscopy.

The last mental hospital.

The public mental hospital system was created in part because many mentally ill people were being held in prisons and jails. Support for those hospitals waned over time, however, and by the time they had degenerated into "snake pits" a consensus was reached to close them down. Unfortunately, they were not replaced with adequate community mental health resources, so as the hospitals have emptied, the prisons and jails have filled, partly with the mentally ill. That is the destructive reason for the growth of prison psychiatry in this country: the prison has become the last mental hospital. The constructive one has been a new emphasis on bringing psychiatric treatment to a previously neglected population: people who have committed serious violence, whether because of Axis I mental illnesses or Axis II character disorders. Unfortunately, four inter-related, mutually reinforcing nationwide trends threaten to reinforce that destructive development and vitiate the constructive one.

Systemic injection of a nitric oxide synthase inhibitor suppresses sleep responses to sleep deprivation in rats.

We hypothesized that nitric oxide (NO) may play a role in homeostatic sleep regulation. To test this hypothesis, we studied the sleep deprivation (SD)-induced homeostatic sleep responses after intraperitoneal administration of an NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME, a cumulative dose of 100 mg/kg). Amounts and intensity of sleep were increased in response to 8 h of SD in control rats (n = 8). Sleep amounts remained above baseline for 16 h after SD followed by a negative rebound. Rapid eye movement sleep (REMS) and non-REMS (NREMS) intensities were elevated for 16 and 4 h, respectively. L-NAME treatment (n = 8) suppressed the rebound increases in NREMS amount and intensity. REMS rebound was attenuated by L-NAME in the first dark period after SD; however, a second rebound appeared in the subsequent dark period. REMS intensity did not increase after SD in L-NAME-injected rats. The finding that the NO synthase inhibitor suppressed rebound increases in NREMS suggests that NO may play a role as a signaling molecule in homeostatic regulation of NREMS.

Targeted expression of calcitonin gene-related peptide to osteoblasts increases bone density in mice.

The neuropeptide calcitonin gene-related peptide (CGRP) is concentrated in fine sensory nerve endings innervating all tissues, including bone. CGRP inhibits osteoclasts, stimulates insulin-like growth factor I and inhibits tumor necrosis factor alpha production by osteoblasts in vitro. To investigate the role of CGRP in bone in vivo, mice were engineered to express CGRP in osteoblasts by placing the human CGRP gene under the control of the rat osteocalcin promoter (Ost-CGRP tg+ mice). Calvaria cultures from transgene positive (tg+), but not tg- mice, produced bioactive CGRP. Trabecular bone density and bone volume, determined by peripheral quantitative computed tomography and bone histomorphometry, respectively, were higher in tg+ than tg- littermates. This increase in bone volume was associated with an increased bone formation rate. Trabecular bone density decreased in tg+ mice as a result of ovariectomy, but remained higher than in sham tg- mice. Targeting CGRP to osteoblasts appears to favor the establishment of a higher trabecular bone mass in mice.

Square pegs in round holes: has psychometric testing a place in choosing a surgical career? A preliminary report of work in progress.

Methods of selection of candidates for training in surgery has long been regarded as lacking explicit criteria and objectivity. Our purpose was to discover the aptitudes and personality types of applicants for surgical posts at the outset, in order to discover which were most likely to result in a satisfactory progression through training and which were associated with career difficulties. This longitudinal predictive validation study has been undertaken in a London Teaching Hospital since 1994. After short-listing, but immediately before interview, all candidates for senior house officer posts in basic surgical training and in geriatric medicine were asked to undertake psychometric tests of numerical (GMA) and spatial (SIT7) reasoning, personality type (MBTI), and self-rating of competency. There were no differences in ability scores between surgeons or geriatricians. Personality differences were revealed between the surgeons and the geriatricians, and between male and female surgeons. This study suggests that while there are no differences in ability between surgeons and geriatricians at the start of training, there are differences in personality. Long-term follow-up of the career development of this cohort of surgical SHOs is required to determine whether the psychometric measures described correlate with achievements of milestones in their surgical careers.

Biopharmaceutical approaches for developing and assessing oral peptide delivery strategies and systems: in vitro permeability and in vivo oral absorption of salmon calcitonin (sCT).

PURPOSE: To evaluate a biopharmaceutical approach for selecting formulation additives and establishing the performance specifications of an oral peptide delivery system using sCT as a model peptide. METHODS: The effect of formulation additives on sCT effective permeability and transepithelial electrical resistance (TEER) was evaluated in side-by-side diffusion chambers using rat intestinal segments. Baseline regional oral absorption of sCT was evaluated in an Intestinal and Vascular Access Port (IVAP) dog model by administration directly into the duodenum, ileum, and colon by means of surgically implanted, chronic catheters. The effect of varying the input rate and volume of the administered solution on the extent of sCT absorption was also evaluated. Citric acid (CA) was utilized in all studies to cause a transient reduction in local pH. In vitro samples and plasma samples were analyzed by radioimmunoassay (RIA). Two oral delivery systems were prepared based on the results of the in vitro and IVAP studies, and evaluated in normal dogs. RESULTS: Maximal permeability enhancement of sCT was observed using taurodeoxycholate (TDC) or lauroyl carnitine (LC) in vitro. Ileal absorption of sCT was higher than in other regions of the intestine. Low volume and bolus input of solution formulations was selected as the optimal condition for the IVAP studies since larger volumes or slower input rates resulted in significantly lower sCT bioavailability (BA). Much lower BA of sCT was observed when CA was not used in the formulation. The absolute oral bioavailability (mean+/-SD) in dogs for the control (sCT + CA) and two proprietary sCT delivery systems was 0.30%+/-0.05%, 1.10+/-0.18%, and 1.31+/-0.56%, respectively. CONCLUSIONS: These studies demonstrate the utility of in vitro evaluation and controlled in vivo studies for developing oral peptide delivery strategies. Formulation additives were selected, the optimal intestinal region for delivery identified, and the optimal release kinetics of additives and actives from the delivery system were characterized. These methods were successfully used for devising delivery strategies and fabricating and evaluating oral sCT delivery systems in animals. Based on these studies, sCT delivery systems have been fabricated and tested in humans with favorable results.

Mobile intensive care services in rural South Australia.

In the 12 years from 1984 to 1995, Adelaide-based mobile intensive care teams transported 4443 critically ill patients from rural areas in South Australia and adjacent States to tertiary-level hospitals in Adelaide. The SA Ambulance Service undertook communications, support staffing and deployment of transport. Average radial distances in 819 road missions were 71 km, in 808 helicopter missions 122 km, and in 2777 fixed-wing aircraft missions 398 km. The largest groups of patients were neonates (23%) and those with trauma (25%). Rural hospitals made 96% of the requests for intensive care transport; 4% came from ambulance or other emergency service crews at accident locations. Emergency surgical or operative obstetrical procedures were performed on 2.7% of patients before transport. One hundred and thirteen patients (2.5%) died during resuscitation or transport, with one death deemed to be preventable.

Effects of calcitonin gene-related peptide on bone turnover in ovariectomized rats.

Calcitonin gene-related peptide (CGRP) is a neuropeptide abundantly concentrated in sensory nerve endings innervating bone metaphysis and periosteum, which indicates that it plays a local role in bone metabolism. CGRP-alpha and -beta share structural and functional homology with calcitonin (CT) and have been shown to inhibit bone resorption in vitro and to induce hypocalcemia in vivo. We recently reported that CGRP stimulates the production of the growth factor insulin-like growth factor-I and inhibits that of the cytokine tumor necrosis factor-alpha by osteoblasts, suggesting that CGRP may control bone cell activity. To investigate this possibility, we used ovariectomized (ovx) rats as a high bone turnover model and compared the effects of CGRP to those of CT. ovx young female rats were injected daily starting the day after surgery with either phosphate-buffered saline, CGRP-alpha (1.15 mg/kg per day), or CT (3 micrograms/kg per day) for 28 days. Ovariectomy induced an increase in bone turnover associated with a 60% loss in trabecular bone volume of the proximal tibia. CGRP inhibited bone resorption but not bone formation, and was nevertheless less efficient than CT in preventing bone loss, since CGRP-treated rats had a loss of 46% of cancellous bone, whereas CT-treated rats had a loss of 21%. This suggests that CGRP is either less potent than CT at inhibiting bone resorption or else very rapidly degraded. These data indicate that CGRP can control bone cells through a mechanism that is in part different from that of CT, and further suggest that CGRP may play a local role in bone metabolism.

An airborne intensive care facility (fixed wing).

A fixed-wing aircraft (Beechcraft KingAir B200 C) fitted as an airborne intensive care facility is described. It completed 2000 missions from 1987-1992 for distances up to 1300 km. Features include: 1. Space for carriage of two stretchers, medical cabin crew of up to five persons and equipment and two-pilot operation if necessary. A third stretcher may be carried in emergencies. 2. Two CARDIOCAP (TM) fixed monitors for ECG, invasive and noninvasive pressures pulse oximetry and end-tidal C02 plus SIEMENS 630(TM)/PROPAQ(TM) compact monitors for the ground transport phase of missions, or the total duration. 3. A medical oxygen reservoir of 4650 litres sufficient for two patients on IPPV with FiO2 = 1.0 for a four-hour trip. The medical suction system is powered from the engine or a vacuum pump. 4. Other medical equipment and drugs in portable packs, for ground transport and resuscitation needs and for replenishment by nursing staff at the parent hospitals. 5. Stretchers compatible with helicopter and road ambulance vehicles used. 6. A stretcher loading device energized from the aircraft, operating through a wide (cargo) door. 7. Provision of 24Ov AC (alternating current) and 28v DC (direct current) electrical energy. 8. Pressurization and climate control. 9. Satisfactory aviation performance for conditions encountered, with single-pilot operation.

Incorporating psychometric measures in selecting and developing surgeons.

Provides a review of the recent literature on the selection and development of surgical trainees and surgeons, and discusses findings on the validity of psychometric measures of ability and personality in such processes. Drawing on this body of research, outlines the pilot project recently completed by the authors at St George's Hospital in London, which sought to test the appropriateness of incorporating psychometrics in supporting the career development of junior doctors applying for surgical training. The results of this pilot study tend to confirm those provided by similar research on surgeons, as well as other clinical groups--that psychometric measures have a significant role to play in aiding the assessment and career development of doctors.