The cost and distribution of firefighter injuries in a large Canadian Fire Department.

BACKGROUND: There is limited data available regarding the cost of firefighter injuries. This information is necessary to develop targeted injury prevention strategies. OBJECTIVE: To categorize the cost of injuries filed in 2012 by firefighters from a from a large department by job duty, injury type, body part affected, and the general motion pattern employed at the time of injury. METHODS: Data were taken from reports filed by CFD personnel and claims filed with the Workers' Compensation Board (WCB) of Alberta between January 1, 2012 and December 31, 2012. RESULTS: Of the 244 injuries reported, 65% were categorized as sprains and strains, the most frequent of which affected the back (32%). The total cost of all claims was $555,955; 77% were sprain/strain-related. Knee and back injuries were most costly ($157,383 and $100,459). Categorized by job duty, most sprains/strains (31%) were sustained while attending to fire station responsibilities, although physical training was associated with the highest costs (34%). Fireground operations were attributed to 18% of sprains/strains and 16% of costs. Lifting injuries were more frequent (23%) and costly (20%) than all injuries. CONCLUSIONS: The most common and costly injuries occurred while attending to fire station-related responsibilities and during physical training.

Firefighter injuries are not just a fireground problem.

BACKGROUND: Linking firefighter injury reporting to general motion patterns may provide insight into potential injury mechanisms and the development of prevention strategies. OBJECTIVE: To characterize the injuries sustained by members of a large Canadian metropolitan fire department over a 5-year span. METHODS: Data were taken from injury reports filed by career firefighters between 2007 and 2011. Injuries were described by job duty, type, body part affected, and the general motion pattern employed at the time of injury (e.g. lifting). RESULTS: Of the 1311 injuries reported, 64% were categorized as sprains and strains (musculoskeletal disorders -MSDs), the most frequent of which affected the back (32%). Categorized by job duty, 65% of MSDs were sustained while working at the fire station or during physical training-related activities. Only 15% were attributed to fireground operations. Furthermore, the associated job duty could not differentiate the types of injuries sustained; back injuries occurred primarily while lifting, knee injuries while stepping, and shoulder injuries during pushing/pulling-related activities. CONCLUSIONS: Firefighter injuries are not just a fireground problem. Injury causation may be better understood by linking the injury location and type with motion patterns rather than job duties. This information could assist in developing general prevention strategies for the fire service.

Schizophrenia: a systematic review of the disease state, current therapeutics and their molecular mechanisms of action.

The treatment of schizophrenia, one of the most debilitating mental illnesses, began by the serendipitous discovery of chlorpromazine. Since then, researchers have endeavored to find the cause of the illness but it remains unresolved. As a result, literature on the etiology of schizophrenia is littered with hypotheses and theories that are constantly reviewed, modified and rejected. Two hypotheses, however, have withstood the test of time and serve as the basis for the drug treatment, namely the dopamine and serotonin hypotheses. This review introduces the disease state, summarizes in detail the two leading hypotheses on schizophrenia, presents drugs that are currently available for treatment, and discusses some of the promising drug candidates based on their pre and early clinical trial results.

JL13 has clozapine-like actions on thermoregulatory cutaneous blood flow in rats: Involvement of serotonin 5-HT1A and 5-HT2A receptor mechanisms.

Clozapine is an effective atypical antipsychotic agent, with serious side effects. JL13 [5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine] is a potential new atypical antipsychotic, structurally modified from clozapine to resist oxidation so as to reduce haematological and cardiological side effects. To assess the potential clinical potency of JL13 we tested its action in a newly described animal model based on the ability of clozapine-like agents to affect brain mechanisms controlling sympathetic outflow to thermoregulatory cutaneous vascular beds. We determined whether JL13 has clozapine-like inhibitory actions on alerting-induced falls in tail artery blood flow (sympathetic cutaneous vasomotor alerting responses, SCVARs) in rats, and whether actions on dopamine D(2), and/or 5-HT(1A) receptors are involved in these effects of JL13. The tail artery Doppler flow signal was recorded in conscious freely moving Sprague-Dawley rats before and after alerting stimuli (e.g. cage tap). The percentage fall in flow in response to an alerting stimulus was quantified as a SCVAR index (fall to zero flow implies SCVAR index of 100%, no fall implies 0%). We used pre-treatment with spiperone and WAY100635, before JL13, to assess the role of D(2) and 5-HT(1A) receptors. In addition, the role of 5-HT(2A) receptors in the action of JL13 was assessed by determining whether JL13 prevented and reversed the CNS-mediated tail artery vasoconstricting actions of DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), an agonist at 5-HT(2A) receptors. JL13 (0.0625-5.0mg/kg s.c.) dose-dependently inhibited SCVARs, less potently than clozapine. WAY100635 but not spiperone reduced the inhibition. JL13 prevented and reversed DOI-induced vasoconstriction. Thus JL13 has clozapine-like actions on thermoregulatory cutaneous blood flow, but the drug is 5 times less potent than clozapine. Stimulation of 5-HT(1A) and blockade of 5-HT(2A) receptors may contribute to the effects, but dopamine D(2) receptors are apparently not involved in the action of JL13.

Platensimycin: a promising antimicrobial targeting fatty acid synthesis.

Platensimycin was recently discovered by Merck Research Laboratories and has created considerable interest given its potent antibacterial activity and mode of action. The use of RNA gene-silencing techniques and screening libraries of natural products allowed Merck to find this antibiotic which may have otherwise been missed using conventional methods. Interestingly, platensimycin has shown good activity against a panel of Gram positive organisms which included various resistant strains. Platensimycin works by inhibiting beta-ketoacyl synthases I/II (FabF/B) which are key enzymes in the production of fatty acids required for bacterial cell membranes. So far, a number of groups have explored synthetic strategies for platensimycin and this work has subsequently lead to the synthesis of active analogues. Given its mode of action, it is intriguing as to why Merck themselves patented only a single compound and have not apparently sought to generate further libraries. This review will discuss the origins of platensimycin, its mechanism of action, synthetic schemes and where the future may take us following this fascinating discovery.

Repair of an anomalous left coronary artery.

We describe a patient with an anomalous single coronary artery who presented with a syndrome of atypical chest pain. Coronary angiography revealed a single right coronary ostium, with a narrowed left coronary artery originating at the right coronary ostium. The proximal portion of the left coronary artery that was narrowed was noted to run in the aortic wall. We describe the operative management of this patient using ostial remodeling.

Schizophrenia: genesis, receptorology and current therapeutics.

Schizophrenia is a debilitating mental disease affecting approximately 1% of the population worldwide. Since the discovery of the first modern treatment for schizophrenia, chlorpromazine, in 1952 there have been many new structures investigated, only a small fraction of which have resulted in clinically useful drugs. Of these, haloperidol may be regarded as the drug for first line treatment. Since then, clozapine has emerged as the benchmark therapeutic ameliorating positive and negative symptoms and devoid of movement disorders, with its greatest feature being improvement of treatment-resistant patients. However, a major, potential lethal side-effect of clozapine is the induction of agranulocytosis, a blood disorder with unknown mechanism that results in lowered white-blood cell counts and consequent susceptibility to infections. In the 50 years of antipsychotic drug development, several novel theories have evolved that focus on receptor sub-types (serotonin 5-HTsub>2A, dopamine D(2) and D(4)) and the degree to which they need to be selectively attenuated by the drugs. Also of significance is the location of these receptors in the brain in relation to the disease state, the myriad of side-effects associated with antipsychotics and physicochemical properties of antipsychotic molecules relative to models of the drugs and the GPCR receptors involved. The techniques for investigation have shown increasing sophistication and refinement over this period, involving cloned receptors and PET scanning for determination of receptor location, density and binding, and rate constants at receptors. Knowledge of receptor structure, although in its infancy since no membrane bound CNS-receptor has yet been crystallized, is likely to benefit substantially with advances in computer-aided modelling. Overall, these new techniques have resulted in a number of novel antipsychotics such as risperidone, sertindole, olanzapine, seroquel, zotepine and ziprasidone, whose design, synthesis and testing has benefited enormously from the accumulated knowledge base of the past 50 years. In this review, we will provide a comprehensive update of the theories of action and clinical profiles of the latest drugs listed. The following appraisal of the literature will provide the practising medicinal chemist interested in this critical area of research with sufficient insight and understanding, to embark on productive investigations into the design and development of new therapeutic agents devoid of clinically limiting side-effects.

TNFB gene polymorphism in insulin-dependent diabetes mellitus: association with HLA-DR alleles.

A polymorphism of the TNF-beta gene can be detected by restriction digestion of a PCR product with NcoI. In this study we look at the risk associated with this polymorphism in a study of 69 insulin-dependent diabetes patients and 119 healthy controls. The risk was further characterized by comparison to the HLA type of the individual, since the TNF polymorphism is in linkage disequilibrium with HLA genes.

Proliferative lymphocyte responses to virus antigens homologous to GAD65 in IDDM.

Virus infection has been proposed as an initiating factor in the aetiology of insulin-dependent diabetes mellitus (IDDM). We have examined lymphocyte proliferation to virus proteins which demonstrate sequence similarity to the beta-cell autoantigen glutamic acid decarboxylase (GAD)65. The magnitude and frequency of response to coxsackie B viruses and adenovirus in a T-cell proliferation assay was significantly higher in a group of recently diagnosed IDDM subjects than in non-diabetic control subjects. The frequency of positive response to the coxsackie B viruses was also significantly higher in IDDM subjects expressing the DRB 1*04 major histocompatibility complex (MHC) haplotype than the DRB 1*03 haplotype. There was no evidence that non-aspartate residue at position 57 of DQB 1 genes influenced virus responses in the IDDM group. The coxsackie homology was in amino acids 258-266 and the adenovirus homology was in amino acids 509-524 of GAD65. Both these regions are suspected to be T-cell epitopes in IDDM. These results indicate a disease and MHC class II association between coxsackie B virus infection and IDDM and an association between adenovirus infection and IDDM.

Human T cells expressing V beta 8 do not predominantly recognize DR2 alloantigen.

A panel of seven monoclonal antibodies recognizing human T-cell antigen receptor (TcR) V alpha or V beta subsets has been used to measure TcR gene expression in peripheral blood lymphocytes and mixed lymphocyte culture responses (MLR) between DR2- and DR2+ (DRw15+) donors. There were no significant differences between DR2- and DR2+ donors in per cent T cells in fresh peripheral blood labelled with any of these antibodies, which included an antibody recognizing V beta 8. This indicates strongly that increased negative selection of V beta 8+ T cells does not occur in DR2+ compared with DR2- individuals. In MLR between DR2- and DR2+ donors the only significant change compared with fresh peripheral lymphocytes was that T cells expressing V beta 5.1 were decreased in DR2- lymphocyte populations responding to DR2 alloantigen. No changes in levels of V beta 8+ T cells were detected in MLR between DR2- and DR2+ donors. This suggests that V beta 8+ T cells are not predominantly reactive against DR2 (DRw15). The data support the concept that alloreactivity against a single class II major histocompatibility complex (MHC) mismatch is mediated by T cells expressing a range of different TcR V beta molecules.

Traumatic rupture of the thoracic aorta.

Between 1968 and 1981, 25 patients with acute traumatic rupture of the aorta were treated at the University of Virginia. Twenty-two of these patients (88%) had serious concomitant injuries. The aortic tear was just distal to the left subclavian artery in 19 patients (76%), and at other sites in six patients (24%). Lacerations were at multiple sites in three patients (12%), in the ascending aorta in one (4%), in the distal aortic arch in two (8%), and in the descending aorta well beyond the subclavian artery in six (24%). Two of the patients (8%) died of free rupture of the aorta before reaching the operating room. The other 23 patients (92%) had operation and 17 (68%) survived. At least ten of the 17 survivors (59%), with an average follow-up of seven years, do not have a disability as a result of the injury. In this group, 24 of the 25 traumatic aortic injuries (96%) occurred in the distal aortic arch or the descending aorta and could be repaired through a left posterolateral thoracotomy.

Control of protein synthesis during early cleavage of sheep embryos.

Sheep embryos, radiolabelled with [35S]methionine, were studied during the first four cell cycles after fertilization to determine the stage at which the regulation of protein synthesis switches from the direction by maternal mRNA to mRNA transcribed by the embryonic genome. Total protein synthesis was consistently high during the first 2 cleavage divisions, dropped by 95% in the 3rd cell cycle, remained low in the 4th and increased again in the 5th cycle. A consistent pattern of proteins was synthesized during the first 3 cell cycles after fertilization followed by major changes in subsequent cycles. The inhibition of transcription by alpha-amanitin, an inhibitor of polymerase II, did not affect cleavage or protein synthesis during the first 3 cell cycles but blocked cleavage and protein synthesis thereafter. The results indicate that the full activation of transcription in sheep embryos occurs in the 4th cell cycle.

Anterolateral thoracotomy as an alternative to repeat median sternotomy for replacement of the mitral valve.

Median sternotomy is the most common approach for repeat cardiac surgery despite the potential complications of cardiac injury. Right anterolateral thoracotomy has been recommended as an alternative for patients undergoing mitral valve replacement, but data supporting one approach over the other do not exist. To compare these procedures, the records of 43 patients who had had a previous median sternotomy and who underwent mitral valve replacement were reviewed. No statistically significant differences between patients undergoing repeat median sternotomy (33 patients) and those undergoing right anterolateral thoracotomy (10 patients) were demonstrable when compared for age, gender, New York Heart Association Functional Class, other diseased valves, urgency of operation, indication for operation, type of valve removed, type of valve implanted, length of postoperative hospitalization, length of operation, days of ventilatory support, length of intensive care unit stay, and survival (90% for thoracotomy group; 76% for median sternotomy group; p, NS). Significant differences between the two groups, favoring right anterolateral thoracotomy, were apparent when comparisons were made for length of perfusion (means, 94.8 min, thoracotomy group; 121.4 min, sternotomy group; p = .03), incidence of reexploration (0%, thoracotomy group; 13%, sternotomy group; p = .001), and blood transfusion (means, 5.3 units, thoracotomy group; 11.4 units, sternotomy group; p = .003). Right anterolateral thoracotomy is an effective alternative to repeat median sternotomy for replacement of the mitral valve in patients who have had a previous median sternotomy.

Cellular origin, hormonal regulation and biochemical characteristics of polypeptides secreted by graafian follicles of sheep.

The pattern, chemical nature and biological role of polypeptides secreted by ovine follicles exposed to gonadotrophins in vivo were studied. Follicles were removed at intervals before ovulation (in-vivo groups), separated into granulosa and cumulus compartments, and incubated for 3 h with radiolabelled amino acids. No differences were detected in the polypeptides (Mr 46,000-60,000) secreted by granulosa and cumulus cells before exposure to the preovulatory LH surge. Each class of polypeptides was characterized by different degrees of phosphorylation, sulphation and glycosylation. Within 15 h of the LH surge the secretion of the Mr 46,000-60,000 polypeptides had ceased and was replaced by a non-sulphated Mr 30,000 secretory product. Significant differences in the secretory pattern of granulosa and cumulus cells were detected after exposure to LH. Intact follicles and granulosa cells were cultured for 24 h (in-vitro groups) and then incubated with radiolabelled amino acids. The profile of polypeptides secreted by intact follicles cultured in the presence or absence of LH corresponded closely with the profile observed in vivo. By contrast, granulosa cells grown as monolayers switched spontaneously to the secretion of Mr 30,000 polypeptides in medium devoid of gonadotrophin. This aberrant secretory switch did not occur in granulosa cells maintained in suspension culture. Inhibition of transcription in follicles exposed to LH prevented both the appearance of the Mr 30,000 polypeptide and the disappearance of the Mr 46,000-60,000 polypeptides. Although the inhibition of steroidogenesis by a variety of steroid enzyme inhibitors was without effect on secretion, evidence was obtained to suggest that one of the secreted polypeptides binds oestradiol-17 beta.

Effect of alterations in follicular steroidogenesis on the nuclear and cytoplasmic maturation of ovine oocytes.

The effects of inhibitors of follicular steroidogenesis on biochemical changes occurring in oocytes maturing in vitro were studied using radiolabelling and polyacrylamide gel electrophoresis. These effects were correlated with previously investigated developmental abnormalities induced by the same inhibitors. The most severe effects were generated by inhibition of 17 alpha-hydroxylase with the drug SU10603 which resulted in a greatly increased ratio of progesterone to testosterone and oestrogen. Such treatment halved the rate of meiotic maturation. Treated oocytes were analysed individually on SDS-PAGE gels and quantitative analysis showed that the drug had induced synthetic abnormalities even in those oocytes that resumed meiosis. This conclusion was confirmed by separation of oocyte proteins on two-dimensional gels. The effects of SU were reduced by delaying addition of the drug until 6h after the beginning of maturation but were not alleviated by the addition of exogenous oestrogen to the culture medium. When oocytes from SU-treated follicles were transferred to inseminated, recipient ewes and recovered 24h later, two-dimensional electrophoresis again revealed abnormalities in their protein synthetic patterns. Almost total abolition of steroid secretion by aminoglutethimide (AG) had much less effect on oocyte protein synthesis, although the proportion of oocytes maturing was reduced from 65% to 46%. The aromatase inhibitor, androstatriendione (AST) although eliminating follicular oestrogen secretion, had no effect on the rate of maturation and very little effect on protein synthesis. These results correlate well with the effects of steroid inhibitors on fertilization and early cleavage.

Protein requirements for germinal vesicle breakdown in ovine oocytes.

The regulation of the cell cycle during the transition from prophase to metaphase I was studied by analysing protein changes and introducing protein blocks during the transition phase. The results show that the progression to metaphase in ovine oocytes is totally dependent on new protein synthesis. By delaying the addition of the inhibitor, cycloheximide, for progressively longer periods after the resumption of meiosis it was established that the required synthesis occurs in the 1-2 h immediately preceding germinal vesicle breakdown (GVBD). The action of cycloheximide was fully reversible: removal of the drug resulted in GVBD between 3 and 4 h later. The synthesis and modification of proteins during these first few hours of maturation were studied by short-term radiolabelling of oocytes with [35S]methionine and [32P]phosphate followed by rapid assessment of their precise nuclear configuration. Changes in phosphorylation of two polypeptides were detected 4-5 h after the beginning of culture, but these changes were not dependent upon protein synthesis. The earliest change in synthesis was the appearance of a new polypeptide 6-8 h after explantation, immediately before GVBD. This polypeptide (Mr 47 X 10(3), pI 5.8) was not significantly phosphorylated and was relatively stable. Oocytes released from cycloheximide treatment began to synthesize this molecule 3-4 h later, again coinciding with GVBD. Synthesis of the polypeptide was suppressed by inhibition of transcription with alpha-amanitin.

Temperature-induced abnormalities in sheep oocytes during maturation.

The susceptibility of sheep oocytes to temperature changes during maturation in vitro was tested by reducing the incubation temperature to 20 degrees C at various stages of meiosis. Cooling induced chromosomal abnormalities including disorganized metaphase plates and multipolar spindles in 28-54% of oocytes cooled at all stages of meiosis from germinal vesicle breakdown (GVBD) to metaphase II. The time of GVBD (8-11 h after the start of culture) was the most sensitive to cooling, whereas fewest abnormalities were found in oocytes cooled in late metaphase I (16-19 h). In addition to the chromosomal abnormalities, unusual vesicles appeared in the cytoplasm of oocytes cooled at 8-11 h and 12-15 h. No abnormalities in protein synthesis were detected by one-dimensional SDS gel electrophoresis. The consequences of the abnormalities for the developmental potential of the cooled oocytes were tested by transfer to recipient ewes and fertilization in vivo. After 12 days of development only 6% and 11% oocytes cooled at 12-15 h and 20-23 h respectively had developed to expanded blastocysts, compared with 44% of control oocytes. The results demonstrated that maturing sheep oocytes are very sensitive to a drop in temperature.