The lesser spotted pregnant surgeon.

With more women entering surgical training, it will become more commonplace to encounter pregnant surgeons. This paper discusses the evidence for work-related risk factors as well as outlining the rights of a pregnant doctor. There are, in fact, very few real risks to pregnancy encountered as a surgeon, with the main risks involving standing or sitting for long periods and fatigue, which can be managed with support from the department. It is important for women in surgery to know that it is possible to continue their training while pregnant so they do not feel pressured into changing to a less demanding specialty or even leaving medicine entirely. It is also important for other professionals to understand the risks and choices faced by pregnant surgeons so that they can better support them in the workplace.

Genomic evidence of hybridization between two independent invasions of European green crab (Carcinus maenas) in the Northwest Atlantic.

Invasive species have been associated with significant negative impacts in their introduced range often outcompeting native species, yet the long-term evolutionary dynamics of biological invasions are not well understood. Hybridization, either among waves of invasion or between native and introduced populations, could alter the ecological and evolutionary impacts of invasions yet has rarely been studied in marine invasive species. The European green crab (Carcinus maenas) invaded eastern North America twice from northern and southern locations in its native range. Here we examine the frequency of hybridization among these two distinct invasions at locations from New Jersey, USA to Newfoundland, Canada using restriction-site-associated DNA sequencing (RAD-seq), microsatellite loci and cytochrome c oxidase subunit I mitochondrial DNA (mtDNA) sequences. We used Bayesian clustering and hybrid assignment analyses to investigate hybridization between the northern and southern populations. Of the samples analyzed, six locations contained at least one hybrid individual, while two locations were characterized by extensive hybridization, with 95% of individuals collected from Placentia Bay, Newfoundland being hybrids (mostly F2) and 90% of individuals from Kejimkujik, Nova Scotia being classified as hybrids, mostly backcrosses to the northern ecotype. The presence of both F2 hybrids and backcrossed individuals suggests that these hybrids are viable and introgression is occurring between invasions. Our results provide insight into the demographic and evolutionary consequences of hybridization between independent invasions, and will inform the management of green crabs in eastern North America.

Mid-term results of the modular ANCA-Fit femoral component in total hip replacement.

We report the minimum five-year follow-up of 352 primary total hip replacements using the uncemented hydroxyapatite-coated ANCA-Fit femoral component with a modular neck and head. The series comprised 319 patients (212 men, 107 women) with a mean age at operation of 64.4 years (28 to 97). The principal diagnosis was osteoarthritis. A total of 18 patients (21 hips) died before their follow-up at five years, nine patients (11 hips) were lost to follow-up, and four (four hips) declined further follow-up. Patient-reported outcomes have been recorded for 288 patients (316 hips). Their mean Oxford Hip Score improved significantly from 41 points (16 to 57) pre-operatively to 20 points (12 to 44) at five-year follow-up. Radiological assessment showed good bony stability in 98% of implants. There were two cases of aseptic loosening of the femoral component. There were no clinical or radiological complications related to modularity. In our series we did not see the high rate of intra-operative fracture previously reported for this implant. This medium-term follow-up study demonstrates that the clinical outcome of the ANCA-Fit femoral component is, to date, comparable with that of other metaphyseal loading femoral components.

Isolated pseudogout diagnosed on hip arthroscopy.

Idiopathic calcium pyrophosphate deposition disease (pseudogout) has a variable presentation. Many joints are usually affected; single joint disease is uncommon. We present a case report of primary monoarticular pseudogout affecting the hip. The diagnosis was made on the appearance and analysis of specimens obtained at arthroscopy. Monoarticular pseudogout is rare, but should be considered in the differential diagnosis of any presentation of joint pain.

Immediate-early gene response to methamphetamine, haloperidol, and quinolinic acid is not impaired in Huntington's disease transgenic mice.

Striatal neurons in symptomatic Huntington's disease (HD) transgenic mice are resistant to a variety of toxic insults, including quinolinic acid (QA), kainic acid and 3-nitropropionic acid. The basis for this resistance is currently unknown. To investigate the possibility that the immediate-early gene (IEG) response is defective in symptomatic HD mice leading to a lack of response to these compounds, we examined the expression of c-Fos and Krox 24 after administration of the indirect dopamine agonist methamphetamine, the dopamine D(2) receptor antagonist haloperidol and the neurotoxin QA in 5- and 10-week-old R6/2 transgenic HD and wild-type mice. Unlike wild-type and pre-symptomatic R6/2 transgenic HD mice, 10-week-old symptomatic HD mice were resistant to methamphetamine-induced gliosis and QA lesion. There was, however, no difference in the number or distribution of c-Fos-immunoreactive nuclei 2 hr after single injections of methamphetamine or haloperidol among 5- and 10-week-old wild-type mice and 5- and 10-week-old R6/2 HD mice. Similarly, despite their resistance to QA-induced lesioning and lower basal levels of krox-24 mRNA, the symptomatic R6/2 mice had equivalent increases in the amount of c-fos and krox-24 mRNA compared to wild-type and pre-symptomatic R6/2 HD mice as determined by in situ hybridization and densitometry 2 hr after QA administration. These data demonstrate that the c-Fos and Krox 24 IEG response to dopamine agonists, dopamine antagonists and neurotoxic insult is functional in symptomatic R6/2 HD mice. Resistance to toxic insult in R6/2 mice may be conferred by interactions of mutant huntingtin with proteins or transcriptional processes further along the toxic cascade.

Protein kinase C beta II mRNA levels decrease in the striatum and cortex of transgenic Huntington's disease mice.

Huntington's disease (HD) is caused by the inheritance of the huntingtin gene with an expanded CAG repeat. The function of the normal or mutant form of the huntingtin protein remains to be determined. We used differential display to determine differences in steady-state mRNA levels between wild-type and the R6/2 transgenic mouse model of HD. Using this method, we determined that the steady-state mRNA levels of protein kinase C beta II (PKC beta II) subunit are decreased in symptomatic HD mice compared with age-matched wild-type controls. The decrease in PKC beta II mRNA levels occurred in both the striatum and cortex. Previously, it had been demonstrated that PKC beta II immunoreactivity is decreased in the caudate-putamen of patients with Huntington's disease. PKC has been implicated in the long-term potentiation model of brain plasticity and learning, and the loss of PKC may affect information storage in HD. The expression of htt-HD throughout the brain affects the transcription of specific genes in regions not associated with widespread neurodegeneration.

A771726, the active metabolite of leflunomide, directly inhibits the activity of cyclo-oxygenase-2 in vitro and in vivo in a substrate-sensitive manner.

1. The immunosuppressive and anti-inflammatory drug leflunomide has several sites of action, although its precise mode of action is unknown. 2. Here we show in vitro and in vivo that leflunomide and/or its active metabolite A771726, inhibit the activity of cyclo-oxygenase (COX) at doses below those that affect protein expression. 3. In J774.2 macrophages treated with endotoxin for 24 h to induce COX-2 and iNOS, leflunomide and A771726 inhibited more potently the accumulation of PGE2 (A771726, IC50 3.5 microg ml-1) than of NO2 (A771726, IC50 380 microg ml-1). At high concentrations (>300 microg ml-1) A771726 also exhibited the expression of COX-2 and iNOS proteins. 4. In A549 cells treated for 24 h with interleukin-1beta, to induce COX-2, A771726 potently inhibited PGE2 synthesis (IC50 0.13 microg ml-1). In the same cells, A771726 was notably less active (IC50, 52 microg ml-1) at inhibiting the formation of PGE2 stimulated by exposure to 30 microM arachidonic acid. 5. In a human whole blood assay, measuring the accumulation of TxB2 in response to calcium ionophore as a measure of COX-1 activity and in response to incubation with bacterial endotoxin as a measure of COX-2 activity, leflunomide inhibited COX-1 and COX-2 with IC50 values of 31 and 185 microg ml-1; for A771726 the corresponding values were 40 and 69 microg ml-1. 6. Pre-treatment of rats with leflunomide or A771726 (10 mg kg-1, i.p.) inhibited the plasma accumulation of 6-keto-PGF1alpha but not NO2/NO3 following infusion of endotoxin. Injection of a bolus of arachidonic acid following 6 h infusion of endotoxin caused a marked acute rise in plasma 6-keto-PGF1alpha which was inhibited only by higher doses of A771726 (50 mg kg-1, i.p.). 7. In conclusion, leflunomide via A771726 can directly inhibit the activity of COX, an effect that appears blunted both by increases in substrate supply and possibly by plasma binding. Only at much higher drug levels does leflunomide and/or A771726 inhibit the induction of COX-2 or iNOS proteins.

Synergy between cyclo-oxygenase-2 induction and arachidonic acid supply in vivo: consequences for nonsteroidal antiinflammatory drug efficacy.

Prostanoids produced via the action of cyclo-oxygenase-2 (COX-2) appear central to many inflammatory conditions. Here we show in LPS-treated rats, however, that COX-2 induction alone does not greatly increase prostanoid production in vivo. For this, a second, arachidonic acid liberating stimulus is also required. Thus, only after intravenous injection of bradykinin or exogenous arachidonic acid was a marked increase in prostanoid formation seen. There is, therefore, synergy between proinflammatory mediators: both induction of COX-2 protein and an increase in the supply of arachidonic acid are required to greatly enhance prostanoid production. Second, we show that supplying arachidonic acid to increase prostanoid production reduces the effectiveness of both currently used nonsteroidal antiinflammatory drugs (NSAIDs) (diclofenac) and novel COX-2-selective inhibitors (NS-398, celecoxib) as inhibitors of COX-2 activity. Our data lead to two important conclusions. First, increased prostanoid production in inflammation is a two-component response: increased COX-2 expression and increased arachidonic acid supply. Second, the supply of arachidonic acid to COX-2 determines the effectiveness of NSAIDs. NSAIDs and selective COX-2 inhibitors, therefore, will generally be less effective at more inflamed sites, providing a rationale for the very high doses of NSAIDs required in human conditions such as rheumatoid arthritis.--Hamilton, L. C., Tomlinson, A. M., Mitchell, J. A., Warner, T. D. Synergy between cyclo-oxygenase-2 induction and arachidonic acid supply in vivo: consequences for nonsteroidal antiinflammatory drug efficacy.

Interactions between inducible isoforms of nitric oxide synthase and cyclo-oxygenase in vivo: investigations using the selective inhibitors, 1400W and celecoxib.

1. Exposure of tissues to endotoxin (LPS) and/or cytokines leads to the induction of both inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2). It has previously been reported that there is 'cross-talk' between these two systems. However, such previous studies have been limited by the availability of highly selective inhibitors. Here we have investigated the interactions between iNOS and COX-2 in vivo using 1400W, an iNOS-selective inhibitor, and celecoxib, a COX-2-selective inhibitor. 2. Infusion of LPS to rats for 6 h caused a time-dependent increase in the plasma concentrations of 6 keto-prostaglandin F1alpha (6 keto-PGF1alpha) and nitrite/nitrate (NO2/NO3), consistent with the induction of iNOS and COX-2. Bolus injection of arachidonic acid (AA) at t=6 h resulted in a further increase of circulating levels of 6 keto-PGF1alpha in LPS-treated animals. 3. Treatment of rats with 1400W or the non-selective NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) inhibited the increase in plasma NO2/NO3 but were both without effect on the plasma concentration of 6 keto-PGF1alpha before or after AA. 4. Treatment with the non-steroidal anti-inflammatory drugs (NSAIDs), A771726 or diclofenac, or with celecoxib significantly reduced the increase in circulating 6 keto-PGF1alpha caused by LPS, and the large increase in 6 keto-PGF1alpha following injection of AA. None of the COX inhibitors affected the increase in plasma NO2/NO3. Dexamethasone, however, significantly inhibited both the increase in 6 keto-PGF1alpha and the increase in NO2/NO3. 5. In conclusion, the use of selective inhibitors does not support the concept of cross talk in vivo between iNOS and COX-2.

Effects of inhibitors of the activity of cyclo-oxygenase-2 on the hypotension and multiple organ dysfunction caused by endotoxin: a comparison with dexamethasone.

1. Endotoxaemia is associated with the expression of the inducible isoform of cyclo-oxygenase, cyclo-oxygenase-2 (COX-2), and an overproduction of arachidonic acid (AA) metabolites. The role of the AA metabolites generated by COX-2 in the circulatory failure and multiple organ dysfunction caused by endotoxin is unclear. Dexamethasone prevents the expression of COX-2 and exerts beneficial effects in animal models of shock. 2. Here we compare the effects of two inhibitors of COX-2 activity, namely NS-398 (5 mg kg(-1), i.p., n=7) and SC-58635 (3 mg kg(-1), i.p., n=9) with those of dexamethasone (3 mg kg(-1), i.p., n=9) on the circulatory failure and organ dysfunction caused by lipopolysaccharide (LPS, E. coli, 6 mg kg(-1), i.v., n=11) in the rat. 3. Endotoxaemia for 6 h caused hypotension, acute renal dysfunction, hepatocellular injury, pancreatic injury and an increase in the plasma levels of 6-keto-PGF1alpha (indicator of the induction of COX-2) and nitrite/nitrate (indicator of the induction of iNOS). 4. Pretreatment of rats with dexamethasone attenuated the hypotension, the renal dysfunction, the hepatocellular and pancreatic injury and the induction of COX-2 and iNOS caused by LPS. In contrast, inhibition of COX-2 activity with SC-58635 or NS-398 neither attenuated the circulatory failure nor the multiple organ failure caused by endotoxin. 5. Thus, the prevention of the circulatory failure and the multiple organ injury/dysfunction caused by dexamethasone in the rat is not due to inhibition of the activity of COX-2. Our results suggest that an enhanced formation of eicosanoids by COX-2 does not contribute to the development of organ injury and/or dysfunction in rats with endotoxaemia.

Alcohol, drugs, and family violence: perceptions of high school students in southwest Alaska.

Many programs have attempted to address alcohol and drug use and family violence as issues of public health. This paper examines the degree to which high school students in Southwest Alaska identify these issues as problems in their communities. Qualitative and quantitative data come from a 1995 survey of children in grades 9 to 12 in four villages, one town, and one boarding school in Alaska. Alcohol policies differ in rural Alaska, with "dry" communities banning alcohol possession, "damp" communities allowing alcohol possession but not sale, and "wet" communities permitting purchase and importation of alcohol. Although the majority of all students believe alcohol and drugs are problems in their communities, only 45% of town students and 22% of village students report too much family violence in their communities. Qualitative data indicate that alcohol and drugs are of concern to young people. One female student, when asked if she would be a successful person, responded "Yes, because I look at my drunk relatives and tell myself, that will never happen to me."

Who will leave? Oil, migration, and Scottish island youth.

"Using survey data from high school students of Scotland's Shetland and Orkney Islands (affected by North Sea oil development), we explore relations between intentions to migrate and individual background, aspirations, and attitudes. Attitudes toward oil development do not predict migration intentions. Instead, migration intentions are predicted by essentially the same variables identified in other studies, in areas where energy development was not occurring. Thus, we found no evidence that oil development fundamentally changed young people's thoughts about leaving."