4. BREAST CANCER SCREENING

Mammographic screening reduces breast cancer mortality by 24% in women aged ≥50 years. Women aged 50–53 are invited for their first screen in the National Health Service Breast Screening Programme (NHSBSP), thereafter at three-year intervals until the age of 64. Two-view mammography is offered at the first (prevalent) screening examination and one-view for subsequent (incident) screens. The screening films are sorted into either ‘normal’ or ‘abnormal requiring further assessment’. Assessment is carried out by a specialist multidisciplinary team using the triple approach: clinical examination, imaging and, where appropriate, needle biopsy. Imaging is planned according to the mammographic abnormality – paddle compression view to assess parenchymal distortion, magnification view to assess microcalcification. After confirmation of a suspicious abnormality, needle biopsy is performed. Results of triple assessment are considered together by the multidisciplinary team and further management is planned. There are four likely outcomes: benign/normal, confirmed breast cancer, suspicious but needing diagnostic surgical excision, and diagnostic uncertainty needing early recall for screening.     

Sensitivity of transcranial magnetic stimulation of cortico-bulbar vs. cortico-spinal tract involvement in Amyotrophic Lateral Sclerosis (ALS)

Background An upper motor neuron (UMN) lesion in amyotrophic lateral sclerosis (ALS) is often difficult to identify because clinical signs may be discrete or masked by severe simultaneous LMN lesions. We compared the diagnostic sensitivity of transcranial magnetic stimulation (TMS) to cranial muscles and limb muscles in the detection of UMN lesions. Design We investigated corticobulbar and corticospinal tract function to the tongue/orofacial muscles and abductor digiti minimi/tibial anterior muscles with TMS in 51 patients with ALS to compare the diagnostic yield in the detection of UMN dysfunction. An UMN lesion was assumed when the following were found: the peripheral conduction time and amplitude of the M-wave were within the normal range, the response to cortical stimulation was absent, the TMS evoked/M-wave amplitude ratio was reduced, and the central motor conduction time or the interside difference was delayed (> mean+2.5 SD). Results On the basis of these criteria a UMN lesion to the orofacial muscles was identified in 24 patients (47 %), to the tongue in 27 (53 %), and to the upper and lower limbs in 13 (25 %) and 22 patients (43 %), respectively. Combined abnormalities from all sites increased the diagnostic yield to 39 patients (76 %). TMS of the limb muscles confirmed a UMN lesion in only 15 (54 %) of the 28 patients with clinically confirmed UMN involvement. This number increased to 23 patients (82 %) if tongue and orofacial muscles were taken into acount. Conclusion Our results indicate the early and in most cases subclinical corticobulbar tract involvement of the central motor pathways to the orofacial muscles and tongue in ALS. TMS of the tongue and orofacial muscles had a higher sensitivity in identifying UMN lesions than that of the upper and lower limbs. Received: 13 December 2000, Received in revised form: 15 March 2001, Accepted: 1 April 2001     

Abdominal aortic aneurysm repair results in aortic stiffening

Long-term follow-up studies show that all-cause mortality remains unchanged after repair of abdominal aortic aneurysm (AAA), possibly because of an increased cardiovascular risk in this high risk group. Repair of the AAA introduces a semirigid conduit into the circulation with unknown effects on the central aortic haemodynamics, such as pulse-wave velocity (PWV). One recent study revealed that a 1 m/s increase in PWV confers a 15% increased risk of cardiovascular events. We investigated whether central aortic haemodynamic changes resulting from AAA repair could be contributing to this excess cardiovascular risk.In nine patients undergoing endovascular aneurysm repair of infrarenal AAA who were assessed for changes in carotid-femoral PWV (cfPWV), mean cfPWV (n=9) was 10·3 m/s (SD 1·0) preoperatively. 1 week and 6 weeks postoperatively, mean cfPWV was 10·2 m/s and 11·2m/s, respectively (mean difference at 6 weeks 0·9m/s [95% CI 0·1–1·8], p=0·03).AAA repair appears to result in a functional stiffening of the aorta. A larger powered study is in progress to confirm this finding and also investigate whether this phenomenon is sustained in the long term. Intensive cardiovascular risk monitoring and pharmacomodulation may be indicated in this high-risk population.FundingBritish Heart Foundation.     

Activation of PAC1 and VPAC receptor subtypes elicits differential physiological responses from sympathetic preganglionic neurons in the anaesthetized rat

BACKGROUND AND PURPOSE

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide with central and peripheral cardiovascular actions. Intrathecal PACAP increases splanchnic sympathetic nerve activity and heart rate, but not mean arterial pressure (MAP). We hypothesize that the three PACAP receptors (PAC₁, VPAC₁ and VPAC₂) have different actions in central cardiovascular control, and that their summed effect results in the lack of MAP response observed following intrathecal PACAP injection.

EXPERIMENTAL APPROACH

The effects of the PACAP receptors on baseline cardiovascular parameters were investigated using selective agonists and antagonists administered into the intrathecal space of urethane-anaesthetized, vagotomized and artificially ventilated male Sprague-Dawley rats.

KEY RESULTS

Selective activation of the PACAP receptors had different effects on MAP. When activated by maxadilan, PAC₁ receptors increased MAP. The VPAC receptors decreased MAP when both were activated with vasoactive intestinal polypeptide or when only VPAC₁ receptors were activated. The PAC₁ and VPAC₂ receptor antagonist PACAP(6–38) had no cardiovascular effects, suggesting that PACAP is not tonically released.

CONCLUSIONS AND IMPLICATIONS

PACAP neurotransmission was not responsible for the moment-to-moment tonic regulation of central cardiovascular control mechanisms. Nevertheless, PACAP release within the spinal cord may have pleiotropic effects on sympathetic outflow depending on the postsynaptic receptor type. PAC₁ and VPAC receptor subtypes produced opposing changes in blood pressure when activated by intrathecal PACAP-38 in the anaesthetized Sprague-Dawley rat, resulting in no net change in MAP.     

Mephedrone (4-methylmethcathinone) and d-methamphetamine improve visuospatial associative memory,but not spatial working memory,in rhesus macaques

BACKGROUND AND PURPOSE

The novel cathinone derivative 4-methylmethcathinone (4-MMC; mephedrone) is increasingly popular with recreational users. Little scientific information is available but users report both entactogen-like and classic stimulant-like subjective properties. A recent study in humans reported psychomotor speed improvement after intranasal 4-MMC suggesting classic stimulant properties. Limitations of the user group (which was impaired on some tasks) prompt controlled laboratory investigation.

EXPERIMENTAL APPROACH

Adult male rhesus monkeys were trained to perform tasks from the non-human primate Cambridge Neuropsychological Test Automated Battery, which assess spatial working memory, visuospatial associative memory, learning and motivation for food reward. Test of bimanual motor coordination and manual tracking were also included. The subjects were challenged with 0.178–0.56 mg·kg⁻¹ 4-MMC and 0.056–0.56 mg·kg⁻¹ d-methamphetamine (MA), i.m., in randomized order for behavioural evaluation.

KEY RESULTS

A pronounced improvement in visuospatial memory and learning was observed after the 0.32 mg·kg⁻¹ dose of each compound, this effect was confirmed with subsequent repetition of these conditions. Spatial working memory was not improved by either drug, and the progressive ratio, bimanual motor and rotating turntable tasks were all disrupted in a dose-dependent manner.

CONCLUSIONS AND IMPLICATIONS

These studies show that 4-MMC produces behavioural effects, including improvements in complex spatial memory and learning that are in large part similar to those of MA in non-human primates. Thus, the data suggest that the effects of 4-MMC in monkeys can be classified with classical psychomotor stimulants.     

Gray value differences to dentin of root posts radiographed with digital intraoral systems and conventional X-ray films

This study compared the gray value differences to dentin of titanium and FRC root posts in anterior and posterior teeth radiographed with digital intraoral systems and conventional x-ray film. Radiographic images (n=5) of titanium or fiber-reinforced composite (FRC) root posts placed in extracted teeth were taken with six digital intraoral radiographic devices and conventional x-ray film (control group). Gray value differences were evaluated between the root posts and root dentin. Statistical analyses of the results were performed with three-way and one-way ANOVA with Bonferroni-Dunn's multiple comparisons post-hoc analyses (α=0.05). Significantly higher gray value differences of titanium and FRC posts were found in anterior teeth but not in molars for XIOS, Sidexis and Visualix digital intraoral systems, but not for RVG, DenOptix and VistaScan (FRC posts). Except for DenOptix with incisors and molars and VistaScan with molars, conventional x-ray films showed significantly lower gray value differences of titanium posts in incisors and molars compared to the corresponding digital radiographs.     

Dual modulation of urinary bladder activity and urine flow by prostanoid EP3 receptors in the conscious rat

Background and purpose:

Cyclooxygenase inhibitors function to reduce levels of prostaglandin E₂ (PGE₂) and are broadly efficacious in models of bladder overactivity. We therefore investigated a regulation of urinary bladder function in conscious rats by modulation of the EP₃ receptor for PGE₂.

Experimental approach:

The activity of the EP₃ receptor agonist GR63799X, and EP₃ receptor antagonists, CM9 and DG041, at recombinant EP₃ receptors was evaluated in vitro. In vivo, intraduodenal dosing during conscious, continuous-filling cystometry of spontaneously hypertensive rats was utilized to determine the urodynamic effect of EP₃ receptor modulation.

Key results:

GR63799X dose-dependently (0.001–1 mg·kg⁻¹) reduced bladder capacity, as indicated by a reduction in both the micturition interval and volume of urine per void. In contrast, CM9 (10 and 30 mg·kg⁻¹) and DG041 (30 mg·kg⁻¹) enhanced bladder capacity, as indicated by significantly longer micturition intervals and larger void volumes. CM9 and DG041 inhibited the responses to GR63799X supporting the in vivo activity of these pharmacological agents at the EP₃ receptor. In addition to its effect on bladder capacity, GR63799X increased endogenous urine production. Intra-arterial infusion of saline mimicked the enhancement of urine flow observed with GR63799X, and the response was inhibited by CM9.

Conclusions and implications:

These data support the EP₃ receptor as a modulator of urinary bladder activity in the conscious rat, and in addition, indicate a role for EP₃ receptor activity in regulating urine flow.