Are fur farms a potential source of persistent organic pollutants or mercury to nearby freshwater ecosystems?

Farming of carnivorous animals for pelts potentially contaminates nearby ecosystems because animal feed and waste may contain persistent organic pollutants (POPs) and metals. Mink farms in Nova Scotia (NS), Canada, provide mink with feed partially composed of marine fish meal. To test whether mink farms potentially contribute contaminants to nearby lakes, we quantified organochlorine pesticides (OCP), polychlorinated biphenyls (PCB), and total mercury (THg) in mink/aquaculture feed, waste, and sediment collected from 14 lakes within rural southwest NS where mink farms are abundant and have operated for decades. Mercury, PCBs, dichlorodiphenyltrichloroethane (DDT), hexachlorocyclohexane (HCH), and dieldrin were present in mink/aquaculture feed and mink waste, indicating they are potential contaminant sources. Lakes with mink farms in their catchment exhibited significantly higher THgflux than lakes downstream of mink farming activity and reference lakes (p < 0.0001) after the intensification of mink farming in 1980, indicating mink farming activity is likely associated with increased lacustrine THgflux. Sedimentary Æ©PCBflux was elevated in lakes with mink farms in their catchments, suggesting possible PCB contributions from mink farming, local agriculture, and atmospheric deposition. Elevated Æ©DDT in lakes near mink farms relative to reference lakes suggests a possible enrichment related to mink farming, although mixed land use and historical DDT usage related to forestry in the region complicates DDT source attribution. Maximum dieldrinflux and HCHflux in lake sediment occurred coeval with peak worldwide usage in the 1970s and are unlikely to be associated with local mink farming. Lakes with mink farming activities in their catchments were associated with increased THgflux, Æ©PCBflux, and possibly Æ©DDTflux, suggesting a possible connection between marine fish meal, fur farms, and aquatic ecosystems in NS.

Acute isolated tuberculous appendicitis.

Non-pulmonary tuberculosis is found with different frequencies in different countries of the world. It is said to constitute about 4% of all tuberculosis cases in Poland, about 25% in England and Wales and about 17% in the USA. It seems that these differences are the result of differences in rates of diagnosis and registration of new tuberculosis cases. This in turn is influenced by public health funding in the individual countries. In this work, we present a case of acute, isolated, tuberculous inflammation of the appendix. We call attention to the fact that pre-operative diagnosis is practically impossible. Clinical symptoms do not point to inflammatory changes. Only surgical evaluation, and especially the result of histopathological examination make it to possible to establish the final diagnosis to initiation of anti-tuberculous treatment.

Cytotoxicity of paclitaxel or cisplatin on carcinoma cell lines is not inhibited by leukemia inhibitory factor (LIF).

We have established a reliable, reproducible and objective growth assay to measure whether leukemia inhibitory factor (LIF) was able to protect tumour-derived cell lines from toxic effects of the chemotherapy agents, cisplatin and paclitaxel. Using this assay, we demonstrated that LIF did not alter the cytotoxic action of these drugs, on a panel of seven cancer cell lines. This was not because of the inactivity of the LIF or because the cell lines did not express components of the LIF receptor. These findings suggest that the potential clinical use of LIF, as a neuroprotective agent, in conjunction with chemotherapy will not interfere with the anti-tumour treatment.

Leukemia inhibitory factor by systemic administration rescues spinal motor neurons in the SOD1 G93A murine model of familial amyotrophic lateral sclerosis.

Leukemia inhibitory factor (LIF) is a survival factor for motoneurons. In this study we investigated whether intense systemic LIF therapy prevents the loss of lumbar motoneurons in the transgenic SOD1 G93A mouse model of familial amyotrophic lateral sclerosis. Treatment involved daily 25 microg/kg intraperitoneal injection for a period of 6 weeks starting at 70 days of age. Using the unbiased optical dissector technique, significant rescue of motoneurons in the LIF-treated group (3809+/-455) was found compared to the vehicle group (1085+/-140).

Luminescence spectroscopy as a screening tool for the potential carcinogenicity of asphalt fumes.

A subset of polycyclic aromatic compounds (PACs), which contain 4-6 annulated rings, has been documented as the source of carcinogenicity in animal skin painting studies of petroleum products and asphalt fumes (M. L. Machado, P. W. Beatty, J. C. Fetzer, A. H. Glickman and E. L. McGinnis, Fundam. Appl. Toxicol., 1993, 21, 492; T. A. Roy, S. W. Johnson, G. R. Blackburn and C. R. Mackerer, Fundam. Appl. Toxicol., 1988, 10, 466). Because of the chemical complexity of these materials, it has been difficult to identify the specific compounds within this broad range of PACs responsible for their carcinogenicity. An alternative approach using luminescence spectroscopy was taken in this study to quantify, without identification, a subset of these compounds that appears to cause cancer. The fluorescence response at a specific wavelength pair was obtained for 39 laboratory asphalt fume condensates from animal skin painting studies, yielding a linear correlation coefficient of R2 = 0.96 between the fluorescence response in these materials and the carcinogenicity found in animal studies. In the absence of other asphalt fume condensates from animal studies, 17 petroleum oils were also evaluated using this method and compared with the available animal skin painting data. The details of the method include a clean-up step that removes the highly polar compounds and spectral subtraction of two- and three-ring PAC interference, both of which add to the fluorescence response, yet were not found to contribute to a carcinogenic response from skin painting studies. Full scan fluorescence plots also produce a fingerprint which can be used to assess contamination, such as coal tar products or mixtures of materials, that are not defined as asphalt, yet may be present in the working environment.

Leukemia inhibitory factor enhances regeneration in skeletal muscles after myoblast transplantation.

Cell-based therapies, such as myoblast transfer therapy, are likely to become an integral part of any approach to treat myopathies such as Duchenne muscular dystrophy. Previous studies have shown that an increased level of regeneration in the host muscle enhances incorporation of donor myoblasts. Leukemia inhibitory factor (LIF) increases the number of dystrophic fibers expressing dystrophin after myoblast transplantation and enhances regeneration in injured and diseased muscle. Morphometric analysis was used to investigate whether an increased level of regeneration is induced by LIF after myoblast transplantation. We found that, in muscles treated with LIF, the number of fibers undergoing regeneration was increased. The increased incorporation of donor myoblasts and thus dystrophin expression induced by LIF may be due, at least in part, to an increased level of regeneration of dystrophic muscle.

The experimental neuroprotectant leukaemia inhibitory factor (LIF) does not compromise antitumour activity of paclitaxel, cisplatin and carboplatin.

PURPOSE: Peripheral neuropathy caused by the anticancer agents cisplatin and paclitaxel is a significant dose-limiting toxicity of these drugs. The growth factor leukaemia inhibitory factor (LIF) has neuroprotectant activity in preclinical models of nerve injury and degeneration and is now in a phase II trial in chemotherapy-induced peripheral neuropathy (CIPN). It is therefore important to ensure that LIF neither inhibits the antitumour activity of these drugs, nor stimulates tumour growth. METHODS: Mature female Dark Agouti rats were implanted subcutaneously with a mammary carcinoma, DAMA. It was confirmed that the tumour expressed LIF receptors by reverse transcriptase polymerase chain reaction. Paclitaxel was administered at a dose of 5 mg/kg daily for 6 days, cisplatin at a dose of 3 mg/kg twice weekly and carboplatin at a dose of 10 mg/kg twice weekly. The effect of LIF on tumour growth and response to chemotherapy was assessed at two doses (2 and 10 microg/kg per day). Peripheral neuropathy was assessed in terms of gait disturbance and tail-flick threshold. RESULTS: Neither dose of LIF stimulated growth of control tumours. Mean tumour volumes were lower on day 14 in all paclitaxel-, cisplatin- and carboplatin-treated groups, compared to controls (ANOVA P<0.001). LIF did not interfere with this antitumour effect. Cisplatin- and paclitaxel-treated groups had developed increasing tail-flick thresholds by day 14. These manifestations of sensory neuropathy were prevented by LIF administration. CONCLUSIONS: These results suggest that LIF may be safely used in human trials as a neuroprotectant for patients receiving cisplatin, paclitaxel and carboplatin without concern for impairment of antitumour effect.

AM424: history of a novel drug candidate.

1. Leukaemia inhibitory factor (LIF) is a 180 amino acid single-chain protein, named after its effect on haematopoietic cells. Leukaemia inhibitory factor belongs to a group of cytokines that includes ciliary neurotrophic factor, interleukin (IL)-6, IL-11, cardiotrophin-1 and oncostatin M. All group members use the gp130 signal transducing subunit for intracellular signalling, but show differences in biological effect. 2. Research over the past 6-8 years has shown LIF to have potent neuromuscular activity. In vitro and in vivo studies on axotomy and nerve crush models demonstrate a powerful effect of LIF in enhancing the survival of both motor and sensory neurons, while reducing denervation-induced muscle atrophy. In models of both axotomy induced neuronal death and in the wobbler mouse, LIF is active at doses as low as 1 microgram/kg delivered systemically. 3. In muscle, LIF will increase the rate of muscle regeneration in vivo when applied exogenously after injury and will stimulate intrinsic muscle repair following its targeted release to dystrophic muscle in the mdx mouse. Leukaemia inhibitory factor may also have a role as an adjunct to myoblast transfer therapy, with studies showing that the transplantation of genetically competent myoblasts into mdx mouse muscle is enhanced when cells are injected with LIF. 4. Distribution and pharmacokinetic studies have been conducted in primates with doses of 20 micrograms/kg recombinant human LIF given subcutaneously over 2 weeks tolerated without major side effects. 5. A pharmaceutical form of recombinant human LIF (AM424; AMRAD Operations, Richmond, Victoria, Australia) entered human clinical trials during 1997 and a phase I clinical trial in healthy volunteers has been completed. A phase I repeat dose study has also been completed in cancer patients undergoing chemotherapy. The primary indication for a phase II study is the treatment of chemotherapy induced peripheral neuropathy. Other potential indications include muscle wasting diseases, acute nerve trauma and motor neuron disease. 6. The role of LIF in modulating nerve loss should make it an ideal candidate for the treatment of a number of neurological conditions. The phase I study represents the first trial in a programme for the clinical development of AM424.

[The application of biodegradable anastomosis ring Valtrac for intestinal anastomosis]. / Zastosowanie biorozpadalnego pierscienia zespoleniowego Valtrac do zespolen jelitowych.

UNLABELLED: In 1985 a biofragmentable anastomosis ring (BAR) Valtrac was introduced for intestinal anastomoses. From August 1994 trough March 1998, 49 intestinal anastomoses were performed in 44 patients: there were 28 jejunoileostomies, 8 colocolostomies and 3 gastrojejunostomies. In 5 patients after total gastrectomy, two anastomoses with the use of Valtrac ring were made during the same operation. The patient group consisted of 26 women and 18 men, aged 14 to 81 years (mean age: 54 years); there were 13 emergency and 31 elective procedures. The reasons for the operations were: cancer--35 cases, pancreatic cyst drainage--4 cases and reconstructive procedures in the digestive tract--5 cases. First intestinal gas passage and defecation were monitored in all patients; control X-ray was performed on the 10th postoperative day. No mortality nor serious complications were observed in the postoperative period. In an 81-year old patient, an inconsiderable leakage was found at the anastomotic site. This was successfully managed in the second operation. CONCLUSIONS: 1. Valtrac is an alternative method for intestinal anastomoses. 2. The anastomotic technique is atraumatic and easy even for an unexperienced surgeon.

LIF (AM424), a promising growth factor for the treatment of ALS.

Growth factors are theoretically promising agents for ALS therapy, but have been disappointing in subcutaneous delivery due to either toxicity or lack of major efficacy. Leukaemia inhibitory factor (LIF), was named after its effect on haemopoietic cells, and belongs to a group of cytokines which includes CNTF, IL-6, CT-1, OM and IL-11. All group members use the gp130 signal transducing subunit for intracellular signalling, but show differences in biological effect. In vitro and in vivo studies on axotomy and nerve crush models demonstrate a powerful effect of LIF in the survival of both motor and sensory neurones, while reducing denervation induced muscle atrophy. Its effects in muscle also include stimulating myoblast proliferation in vitro, and up-regulation after muscle injury. LIF will also stimulate muscle regeneration in vivo when applied exogenously after injury. In published studies of both axotomy induced neuronal death and in the Wobbler mouse models LIF is active at doses of 10 microg/kg delivered systemically, well below the expected maximum tolerated dose suggested by primate safety studies. LIF is expressed in low levels by spinal cord neurones with significant up-regulation when the neurones are damaged by BOAA toxin, an excitatory amino acid associated with a form of ALS. This augments other evidence suggesting LIF is a trauma factor playing a role in the injury response of adult neuronal tissue, and may be more effective than related growth factors. Taken together, the data suggests LIF is a physiologically relevant trophic factor with implications in clinical medicine as a therapy for ALS, and a human recombinant form (AM424), entered human clinical trials during 1998.

Leukaemia inhibitory factor (LIF) production in a mouse model of spinal trauma.

A model of spinal trauma was developed where spinal neurones of adult mice were exposed to the excitotoxic glutamate analogue beta-N-oxylamino-L-alanine (L-BOAA). After 24 h, the injured neurones received a single dose of [125I]-LIF at the same site of the spinal cord, and 2 h later, tissues were removed to assess the distribution of leukaemia inhibitory factor (LIF). There was a significant increase in LIF binding to the injured region of the spinal cord over saline controls, and this corresponded with a significant increase in LIF mRNA expression in the same region of the cord. There was a change in the expression of ciliary neurotrophic factor, but the expression of cardiotrophin-1 (CT-1) and the common receptor subunit LIF receptor beta (LIFRbeta) did not change after neurotoxin treatment. The results add to the evidence that LIF plays a significant role in the response of adult neuronal tissue to injury.

The role of leukemia inhibitory factor in skeletal muscle regeneration.

Although a number of cytokines have been implicated in tissue regeneration, it is unknown which ones actually function in vivo. Here, we use mice with a targeted mutation in the leukemia inhibitory factor (LIF) gene to examine the role of LIF in muscle regeneration. Using a muscle crush model, we show that muscle regeneration in LIF knockout mice is significantly, reduced compared to control littermates. Further, targeted infusion of LIF in both normal and LIF knockout animals stimulated muscle regeneration, but the stimulation observed was much greater in the mutant animals than in controls. In contrast, interleukin-6 and transforming growth factor-alpha, which also stimulate myoblast proliferation in vitro, had no effect on regeneration. These findings demonstrate directly that LIF is involved in regeneration of injured muscle and points to the use of LIF as a therapeutic agent in the treatment of neuromuscular disease.

Controlled release of leukaemia inhibitory factor (LIF) to tissues.

Leukaemia inhibitory factor (LIF) has been shown to effectively enhance skeletal muscle regeneration after mechanical injury and it may have potential therapeutic use in the muscular dystrophies as well as peripheral nerve repair after injury. When LIF is applied systemically to an animal, it is rapidly removed with a biological half life of only a few minutes, and at high doses it exhibits toxic effects. Calcium alginate rods have been developed for the purpose of insertion adjacent to skeletal muscles. These rods, when charged with LIF will release the growth factor to the muscle at a rate of less than 1% per day and for a period extending to several months. In addition, tubes of alginate are described which will be suitable for the continuous supply of LIF to repaired peripheral nerve.

Leukemia inhibitory factor and interleukin-6 are produced by diseased and regenerating skeletal muscle.

The process of skeletal muscle regeneration following injury or disease involves locally produced growth factors which control cellular proliferation and differentiation. Leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) have previously been shown to promote the proliferation of myoblasts in vitro, and thus may be involved in muscle regeneration. In the present investigation, the in vivo expression of these two myogenic growth factors was examined in regenerating muscle after a crush injury of wild type mice, and in diseased skeletal muscle and diaphragm of the mdxmouse. Using Reverse transcription polymerase chain reaction we have demonstrated that while normal muscle rarely expresses mRNA for these two molecules, there is significant up-regulation following injury, coinciding with the active period of muscle regeneration. This suggests these molecules act as locally produced trauma factors. This observation is reinforced in mdxmouse muscle, which is undergoing a cycle of degeneration and regeneration, and expresses both LIF and IL-6. Using in situ hybridization we have localized mRNA for LIF expression in the mdx diaphragm, suggesting that local production of these molecules by regenerating muscle itself, as well as by other cells in muscle, plays an important role in muscle regeneration.

Leukaemia inhibitory factor treatment stimulates muscle regeneration in the mdx mouse.

A number of growth factors are involved in coordinating muscle cell proliferation and differentiation, particularly after injury and in disease. Leukaemia inhibitory factor (LIF) strongly stimulates the proliferation of myoblasts in vitro and in vivo and its expression in muscle after injury suggests that LIF may have a role as a trauma factor. The mdx mouse was used to study the effects of LIF on in vivo muscle regeneration during disease. The rationale for using trophic factors such as LIF to treat neuromuscular disease includes the understanding that these molecules show some degree of selectivity for the population of cells in which they are effective. LIF was administered to muscle of the mdx mouse using osmotic pumps implanted subcutaneously in unrestrained mice. The growth factor was continuously delivered into the vastus lateralis muscle at 7 U/mu 1 for 7 days via a catheter. The results show that LIF increased the rate of muscle regeneration in mdx mice by stimulating the formation of larger myotubes. LIF treatment also increased the number of regenerating myotubes in the perfused area. This myotrophic action indicates that LIF contributes to muscle regeneration. Together with its known neurotrophic action, LIF is a potential therapeutic agent for the treatment of neuromuscular disease.

Up-regulation of leukaemia inhibitory factor and interleukin-6 in transected sciatic nerve and muscle following denervation.

Leukaemia inhibitory factor (LIF) and Interleukin-6 (IL-6) are multifunctional cytokines that are related on the basis of their predicted structural similarities and shared signal transducing receptor components. Both these factors stimulate myoblast proliferation, and whereas LIF is neurotrophic for sensory neurons, and for the motor neurons which innervate muscle, IL-6 has only been reported to act on a population of septal neurons in the brain. We have looked at the effect of peripheral nerve trauma on the expression of these factors. We show here that whereas LIF and IL-6 mRNAs are expressed in low levels in normal sciatic nerve and skeletal muscle, there is significant up-regulation in the nerve segments after injury, with proximally and distally. There is also an increase in LIF and IL-6 expression in the denervated muscle located largely in the muscle cells. In addition, while there is retrograde axonal transport of LIF by the sciatic nerve, IL-6 is not retrogradely transported, and as a result, IL-6 does not stimulate the survival of sensory neurons in vitro. Both growth factors are produced by Schwann cells. These results show a rapid response in the expression of these genes after injury and suggest that LIF and IL-6 act as trauma factors but with different roles in injured peripheral nerve.

Acute exertional compartment syndrome of the medial foot.

A review of compartment syndrome, both acute and chronic, is presented. The pathophysiology, anatomy, diagnosis, and treatment are presented in relation to a unique case report. The case is one of acute exertional compartment syndrome of the medial foot treated by fasciotomy. This condition is uncommon in both its nature and location.

Effects of leukaemia inhibitory factor and other cytokines on murine and human myoblast proliferation.

It has been shown previously that leukaemia inhibitory factor (LIF) and transforming growth factor-alpha (TGF-alpha) stimulate proliferation of primary cultures of murine myoblasts. We now show that human myoblasts respond in a similar manner to LIF and TGF-alpha. These responses occur over a range of growth conditions. There are total additive effects in both human and murine myoblasts between LIF and TGF-alpha and LIF and fibroblast growth factor-beta (FGF-beta), but not between LIF and interleukin-6 (IL-6) or insulin-like growth factor 1 (IGF-1). The LIF response is initiated by a short exposure to the cytokine and is maintained for prolonged periods in its absence.

Preparation of monoclonal antibodies to C3b by immunization with C3b(i)-sepharose.

We have prepared and characterized four monoclonal antibodies (MAbs) to human C3b of high specificity and affinity. Our procedure did not require a purified source of C3b for immunization. Instead, C3b and C3bi were deposited on Sepharose 4B via the alternative pathway of complement activation in normal human serum, and this C3b(i)-Sepharose served as the immunogen. C3b(i)-Sepharose was also prepared from a number of primate and non-primate sources, and this allowed us to demonstrate that the anti-human C3b MAbs cross-reacted with primate-derived C3b, but not with C3b from non-primates. The procedures we have developed may be useful in the further investigation of species-specific C3 fragment-binding proteins from both primate and non-primate sources.