Sentinel lymph node biopsy is a reliable method for lymph node evaluation in neoadjuvant chemotherapy-treated patients with breast cancer.

Sentinel lymph node (SLN) mapping in patients with breast cancer treated with neoadjuvant chemotherapy has been debated by surgeons as a result of potential compromise of lymphatic drainage. Whether clinicopathologic variables traditionally associated with SLN positivity differ in patients who have been treated with neoadjuvant chemotherapy has not been well studied. Patients diagnosed with breast carcinoma who underwent neoadjuvant chemotherapy, definitive breast surgery, sentinel node biopsy (SNB), and axillary lymph node dissection (ALND) were retrospectively identified over a 75-month period. Clinicopathologic parameters including age, clinical tumor and node stage, neoadjuvant chemotherapy regimen, pathological tumor and node stage, lymphovascular invasion (LVI), SLN and non-SLN involvement, and extranodal extension were recorded. Ninety-seven patients met inclusion criteria. Ninety-eight per cent had successful SLN mapping. Eight patients with negative SLNs had positive ALND (false-negative rate, 8.3%). Clinicopathological variables associated with SLN status included clinical axillary status (P = 0.038), pathologic tumor size, and nodal status and LVI (P < 0.001). Extranodal extension was significantly associated with non-SLN status (P = 0.004). In patients achieving a pathologic complete response (PCR), SNB remained feasible and accurate (false-negative rate, 11.6%). Successful SLN mapping in patients who have undergone neoadjuvant chemotherapy is highly accurate with a low false-negative rate even in patients who have a PCR.

DNATwist: a Web-based tool for teaching middle and high school students about pharmacogenomics.

DNATwist is a Web-based learning tool (available at http://www.dnatwist.org) that explains pharmacogenomics concepts to middle- and high-school students. Its features include (i) a focus on drug responses of interest to teenagers (e.g., alcohol intolerance), (ii) reusable graphical interfaces that reduce extension costs, and (iii) explanations of molecular and cellular drug responses. In testing, students found the tool and topic understandable and engaging. The tool is being modified for use at the Tech Museum of Innovation in California.

Family tracing to identify patients with familial hypercholesterolaemia: the second audit of the Department of Health Familial Hypercholesterolaemia Cascade Testing Project.

BACKGROUND: Family tracing is a method recognized to find new patients with familial hypercholesterolaemia (FH). We have implemented family tracing led by FH Nurses and have determined acceptability to patients, feasibility and costs. METHODS: Nurses were located at five National Health Service (NHS) Trusts; they identified FH patients and offered them family tracing. Responses and test results were recorded on a database and summarized on a family pedigree. RESULTS: The majority ( approximately 70%) of index cases participated; the proportion was lower when patients had been discharged from the clinics and in metropolitan areas. On average, 34% (range 13-50%) of relatives lived outside the catchment area of the clinics and could not attend the nurse-led FH clinics. Of the previously untested relatives, 76% who lived in the catchment area of the clinic came forward to be tested. One-third of the relatives who came forward for testing were children

Are patients with familial hypercholesterolaemia well managed in lipid clinics? An audit of eleven clinics from the Department of Health Familial Hypercholesterolaemia Cascade Testing project.

BACKGROUND: Familial hypercholesterolaemia (FH) is an autosomal co-dominant disorder which is relatively common, leads to high levels of LDL-cholesterol and if untreated to early coronary heart disease. An audit of current practice at National Health Service Trusts in England was undertaken to determine whether FH patients meet the diagnostic criteria for FH; are being offered appropriate advice and treatment; and to what extent their families are contacted and offered testing for the disorder. METHODS: Medical records of known FH patients (over 18 years of age and diagnosed before 31 December 2003) were accessed to obtain information on diagnosis, treatment and family tracing. RESULTS: The records of 733 FH patients were examined, 79% met the UK 'Simon Broome' register criteria for the diagnosis of definite or possible FH. Analyses showed that patients were usually offered appropriate advice and treatment, with 89% being on a statin. However, the audit indicated a high variability in family tracing between the sites, with significant differences in the frequency of inclusion of a family pedigree in the notes (range 1-71%, mean 35%); the general practitioner (GP) being advised that first-degree relatives should be tested (range 4-52%, mean 27%); and the proportion of relatives contacted and tested (range 6-50%, mean 32%). CONCLUSION: FH patients are well cared for in lipid clinics in England, are being given appropriate lifestyle advice and medication, but an increase in recording of LDL-cholesterol levels may lead to improvements in their management. Practice in family tracing appears to vary widely between clinics.

Organ procurement and mandated choice: an alternative to the existing system.

One of the greatest problems facing medicine today is the allocation of scarce resources. A manifestation of this problem that affects everyone is the procurement and allocation of donor organs. This paper examines the current system of donor organ procurement in the US, points to its weaknesses, and examines three proposed alternatives. It proposes the adoption of one these alternatives, the system of mandated choice, wherein all potential donors are required to make an informed and legally binding decision to donate or not.

Stimulation of basal and L-DOPA-induced motor activity by glutamate antagonists in animal models of Parkinson's disease.

In parkinsonism, glutamate pathways within the basal ganglia become overactive, leading to the suggestion that glutamate antagonists might possess antiparkinsonian qualities. This report examines the motor properties of antagonists of NMDA and AMPA-type glutamate receptors, as well as some inhibitors of glutamate release, in animal models of idiopathic Parkinson's disease. High affinity NMDA open-channel blockers (e.g. MK 801, phencyclidine), are highly potent antagonists with inconsistent antiakinetic and strong myorelaxant activity. Other compounds are better tolerated and are capable of relieving immobility and muscular rigidity by themselves (e.g. 1-aminoadamantanes, polyamine site antagonists, kappa agonists, riluzole). Yet others do not restore movements alone (e.g. dextromethorphan, ketamine), but may interact with and strengthen the antiparkinsonian action of L-DOPA (e.g. competitive NMDA and AMPA antagonists, lamotrigine). They may do this by potentiating dopaminergic behaviours mediated by D1 or D2 receptors, or by some other mechanism.

Implementation of a comprehensive skin care program across care settings using the AHCPR pressure ulcer prevention and treatment guidelines.

Healthcare professionals in the Central Midwest identified the need for a comprehensive skin care program for pressure ulcer prevention and treatment across care settings. A multidisciplinary team, representing acute, extended and home care, was formed to create a program for all three settings based upon the AHCPR pressure ulcer guidelines. The team performed literature reviews on which to base the development and use of tools, conducted prevalence studies, and developed educational approaches. Implementation of the program was tailored for each setting. Some of the approaches used were a skin care fair, quality studies, continuous quality improvement concepts, a "Product Book" and educational presentations. Outcomes include improvement of continuity of care across settings and the use of the Braden Scale and the NPUAP pressure ulcer staging system. The focus has turned toward patient outcomes. Professionals have a better understanding of the care that is provided by other disciplines. Referrals are made based upon decision trees. Appropriate resources are used. Other outcomes anticipated include a decrease in nosocomial pressure ulcers, shortened wound healing time, appropriate referral of unresponsive chronic wounds, decreased discrepancies in wound documentation, decreased length of stay, improved financial outcomes, and improved client knowledge and participation.

Motor actions of eliprodil in the normal and monoamine-depleted mouse: a role in the treatment of Parkinson's disease?

The non-competitive NMDA polyamine site antagonist, eliprodil, was examined for its effects on exploratory activity in non-habituated mice and for its antiakinetic potential in reserpine-treated mice. A low dose of eliprodil (5 mg/kg) weakly stimulated locomotion in naive animals, whilst higher doses depressed rearing (20-40 mg/kg) and grooming (40 mg/kg), consistent with a sedative action. At no dose did eliprodil cause ataxia. In 24 h reserpine-treated mice, eliprodil (10-40 mg/kg) reversed akinesia, but this effect was subject to considerable inter-animal variation and was not statistically significant. Eliprodil did not alter the motor recovery elicited by the dopamine D1 agonist SKF 38393, or the dopamine D2 agonist RU 24213, and suppressed the motor stimulation induced by L-DOPA. These results indicate that eliprodil displays a far lower propensity than many other NMDA receptor antagonists for disturbing posture and gait, but lacks the essential motor stimulant action required to make it a safe and effective antiparkinsonian agent, at least in the reserpine-treated mouse model of Parkinson's disease.

Potential neurotoxicity of a novel aminoacridine analogue.

1. A class of compounds, 9-aminoacridines, have long been known to be reversible inhibitors of acetylcholinesterase (AChE-EC 3.1.1.7), the most familiar of which is 9-amino-1,2,3,4-tetrahydroacridine (Tacrine). 2. A novel aminoacridine was synthesised: -2-tertiary-butyl-9-amino-1,2,3,4- tetrahydroacridine (2tBuTHA). 3. In vitro comparisons of the acetylcholinesterase inhibitory potential and neurotoxicity compared to Tacrine were performed using a chemically differentiated neuroblastoma cell line (Neuro 2A). 2tBuTHA, but not Tacrine, was cytotoxic to the neural cell following 20 h exposure, despite being the least potent AChE inhibitor (IC80 AChE 12.53 microM +/- 1.14 s.e.m., Neutral Red Uptake IC50 9.53 microM +/- 0.98 s.e.m., MTT Reduction IC80 14.6 microM +/- 1.43 s.e.m.). 4. In vivo studies used a novel application of a five arm radial maze to assess neuropharmacological effects on working memory in control and Scopolamine (1 mg kg-1 i.p.) treated mice. There was an impairment of short term cognitive function with 2tBuTHA (15 mg kg-1 i.p.), but not Tacrine (10 mg kg-1 i.p.) which improved the Scopolamine deficit as expected. 5. This combined in vitro and in vivo data infers a neurotoxic property for the novel compound 2tBuTHA, a close structural analogue of Tacrine.

Motor actions of 7-OH-DPAT in normal and reserpine-treated mice suggest involvement of both dopamine D2 and D3 receptors.

In non-habituated mice, 7-hydroxy-N,N-di-n-propylaminotetralin (7-OH-DPAT, 0.04-10 mg/kg s.c.) potently and rapidly suppressed species-typical behaviours and induced frozen postures, with only occasional evidence of weak behavioural stimulation occurring at 5-10 mg/kg. This inhibitory effect was reversed by the dopamine D1 receptor agonist 2,3,4,5-tetrahydro-7,8-di-hydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF 38393, 10 mg/kg i.p.). 7-OH-DPAT (3-10 mg/kg) did not reinstate locomotion in 4 h habituated mice, either when administered alone or in conjunction with a threshold dose of SKF 38393 (3 mg/kg). By contrast, 7-OH-DPAT (0.2-10 mg/kg) dose-dependently reversed the akinesia of 24 h reserpine-treated mice. This response was blocked by the dopamine D2 receptor antagonist raclopride (10 mg/kg i.p.), but not by the dopamine D1 receptor antagonist (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3- benzazepine-7-ol hemimaleate (SCH 23390, 0.05 mg/kg i.p.), and was potentiated synergistically by coinjection of SKF 38393 (3 mg/kg). These and earlier data suggest the motor inhibitory effects of 7-OH-DPAT (low doses) in normal animals are mediated by dopamine autoreceptors (D2 and/or D3), whilst its motor stimulant actions in normal (high doses) and in dopamine-depleted, supersensitive animals, are mediated by dopamine D2 receptors.

Inhibition of tumor growth by elimination of granulocytes.

As observed for many types of cancers, heritable variants of ultraviolet light-induced tumors often grow more aggressively than the parental tumors. The aggressive growth of some variants is due to the loss of a T cell-recognized tumor-specific antigen; however, other variants retain such antigens. We have analyzed an antigen retention variant and found that the variant tumor cells grow at the same rate as the parental tumor cells in vitro, but grew more rapidly than the parental cells in the T cell-deficient host. The growth of the variant cells was stimulated in vitro by factors released from tumor-induced leukocytes and by several defined growth factors. In addition, the variant cancer cells actually attracted more leukocytes in vitro than the parental cells. Furthermore, elimination of granulocytes in vivo in nude mice by a specific antigranulocyte antibody inhibited the growth of the variant cancer, indicating that this tumor requires granulocytes for rapid growth.

Do NMDA receptor-mediated changes in motor behaviour involve nitric oxide?

Nitric oxide (NO) synthase inhibitors were investigated for their effects on motor behaviour. In normal mice, NG-nitro-L-arginine (5-125 mg/kg i.p.) and 7-nitroindazole (10-50 mg/kg i.p.), but not aminoguanidine (60-150 mg/kg i.p.) suppressed species-typical behaviours. In 24 h reserpine-treated mice, akinesia was reversed with the dopamine D1 receptor agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF 38393, 3-30 mg/kg i.p.) and by the dopamine D2 receptor agonist N-n-propyl-N-phenylethyl-p-(3-hydroxyethyl) ethylamine hydrochloride (RU 24213, 0.5-5 mg/kg s.c.), but not by any of the NO synthase inhibitors. NG-Nitro-L-arginine and 7-nitroindazole (not aminoguanidine) suppressed D1 and D2 receptor agonist-induced locomotion, but L-arginine (500 mg/kg i.p.) was not always able to prevent this effect. These results suggest that continued activity of constitutive NO synthase is necessary for normal body movements to occur. The difference in the interaction profiles of constitutive NO synthase inhibitors and NMDA antagonists with dopaminergic drugs, indicates that inhibition of NO generation is not a factor in the well-known D1-facilitatory effect of glutamate receptor blockade.

Locomotor effects of amantadine in the mouse are not those of a typical glutamate antagonist.

Amantadine has been shown to displace [3H]MK 801 from its binding site on the NMDA receptor. We have therefore studied the motor effects of amantadine in normal and 24 h reserpine-treated mice to determine whether the behavioural profile of this drug resembles that of other NMDA receptor antagonists (e.g. MK 801). In common with the latter, amantadine (5-40 mg/kg IP) produced a modest dose-dependent sedation in dopamine-intact mice, with a reduction in locomotion and other species-typical behaviours (e.g. rearing and grooming), but with no signs of the hyperactivity, stereotypy, ataxia or loss of muscle tone commonly seen with MK 801. Amantadine (5-80 mg/kg IP) effected a small increase in motility in akinetic reserpine-treated mice by itself, but this response was highly variable and not statistically significant. As with MK 801, amantadine significantly inhibited the locomotion induced by the selective D2 agonist RU 24213 (5 mg/kg SC) and the mixed D1/D2 agonist apomorphine (0.5 mg/kg SC) in monomine-depleted mice, without altering the animals' responsiveness to threshold doses of these drugs. However, amantadine did not facilitate the locomotion induced by threshold (3 mg/kg IP) or fully active doses (30 mg/kg IP) of the selective D1 agonist SKF 38393, which distinguishes amantadine from other NMDA receptor blockers. Since the potentiation of dopamine D1-dependent locomotion may be a major factor in the antiparkinson activity of MK 801 and other glutamate receptor antagonists, the inability of amantadine to potentiate SKF 38393 in this study suggests the mechanism of its anti-akinetic activity differs from that of conventional glutamate blocking drugs.

Mental health: solving the quality problem.

After several years of focusing on the costs of mental health care, employers have shifted their attention to improving access and quality.

Comparison of the effects of NMDA and AMPA antagonists on the locomotor activity induced by selective D1 and D2 dopamine agonists in reserpine-treated mice.

This study examined the interaction between various glutamate antagonists and selective D1 (SKF 38393) and D2 (RU 24213) dopamine agonists in the production of locomotion in the reserpine-treated mouse. Firstly, in normal mice, the NMDA channel blocker MK 801 (0.1-1.6 mg/kg) caused a biphasic stimulation/depression of locomotor activity, whereas the competitive NMDA antagonists CGP 40116 (0.25-8 mg/kg) and CPP (0.2-20 mg/kg), and the NMDA glycine site antagonist HA 966 (0.4-10 mg/kg) inhibited locomotion monophasically. These compounds caused varying degrees of muscle weakness and impairment of posture and gait, whilst the AMPA receptor blocker NBQX (0.2-25 mg/kg) had no significant effect on unconditioned mouse motor behaviour. None of the antagonists reversed reserpine-induced akinesia by themselves, but they all potentiated the locomotor movements induced by 30 mg/kg SKF 38393. Movements remained fluent with low doses of CPP, HA 966 and NBQX, but became ataxic with MK 801 and CGP 40116, with sedation prevailing at high doses of all the antagonists, as in normal mice. CPP and NBQX also combined synergistically with SKF 38393 to promote tonic convulsions. By contrast, RU 24213-induced locomotion was dose-dependently depressed by MK 801, CGP 40116 and HA 966, but was unaffected by CPP or NBQX. These differential effects of NMDA and AMPA antagonists on D1 and D2 motor responding in the monoamine-depleted mouse are discussed in terms of possible mechanisms and sites of action within the brain, and the implications for their putative use as adjuvants to L-dopa in antiparkinson therapy.

Potentiation of dopamine-dependent locomotion by clonidine in reserpine-treated mice is restricted to D2 agonists.

Mice treated with reserpine (5 mg/kg IP), 24 h beforehand, were completely akinetic. Fluent locomotion was reinstated with the D1-selective agonist SKF 38393 (3-30 mg/kg IP), the D2-selective agonist RU 24213 (0.5-5 mg/kg SC) and the mixed D1/D2 agonist apomorphine (0.025-0.5 mg/kg SC). Clonidine (0.03125-1 mg/kg IP) caused a dose-dependent sedation in dopamine-intact mice, but had no effect by itself on the locomotor activity of monoamine-depleted mice. In drug interaction experiments, clonidine did not modify the motor stimulant action of SKF 38393, but greatly enhanced the motor responses to RU 24213 and apomorphine. These results support the hypothesis that alpha-adrenoceptor agonists facilitate dopamine D2 but not dopamine D1 motor responding in the reserpine-treated mouse model of Parkinson's disease.

Role of D1 receptor mechanisms in the potentiation of motor responses to L-dopa and apomorphine by MK 801 in the reserpine-treated mouse.

In 24 h reserpine-treated akinetic mice, locomotion was induced by the D1-selective agonist SKF 38393 (30 mg/kg IP), or by the mixed D1/D2 agonists L-dopa (150 mg/kg IP, plus benserazide 100 mg/kg IP) and apomorphine (0.5 mg/kg SC). The non-competitive NMDA receptor antagonist MK 801 (0.01-1.6 mg/kg IP) did not induce motor activity by itself, but potentiated the motor responses to L-dopa and apomorphine at roughly 10-fold lower doses than those which facilitated D1 responding. These data cast doubt on the notion that glutamate antagonists enhance the antiparkinsonian efficacy of mixed D1/D2 agonists solely through a D1 receptor mechanism.

The new competitive NMDA receptor antagonist CGP 40116 inhibits pilocarpine-induced limbic motor seizures and unconditioned motor behaviour in the mouse.

The biologically active enantiomer (CGP 40116) of the new competitive N-methyl-D-aspartate (NMDA) receptor antagonist CGP 37849 was investigated for its effects on pilocarpine-induced limbic motor seizures and unconditioned motor behaviour in the mouse. CGP 40116 (1-8 mg/kg IP) reduced the incidence and severity of pilocarpine-induced motor seizures, although the overall effect was weak. In contrast to the noncompetitive NMDA antagonist MK 801, there were no signs of CGP 40116 producing a proconvulsant response in this model. In the nonhabituated mouse, MK 801 promoted hyperlocomotion at low doses and hypolocomotion and ataxia at high doses, while CGP 40116 dose-dependently suppressed motor behaviour. Because CGP 40116 and MK 801 exert opposite effects on the seizure threshold to pilocarpine and differentially alter species-typical behaviours in the mouse, it is suggested that different populations of NMDA receptors may mediate their effects. The indivisibility of seizure suppression and motor impairment noted previously with noncompetitive NMDA antagonists such as MK 801 appears also to apply to the new generation competitive NMDA antagonist CGP 40116.