Functional and anatomical deficits in visceral nociception with age: a mechanism of silent appendicitis in the elderly?

The ability to sense visceral pain during appendicitis is diminished with age leading to delay in seeking health care and poorer clinical outcomes. To understand the mechanistic basis of this phenomenon, we examined visceral nociception in aged mouse and human tissue. Inflamed and noninflamed appendixes were collected from consenting patients undergoing surgery for the treatment of appendicitis or bowel cancer. Supernatants were generated by incubating samples in buffer and used to stimulate multiunit activity in intestinal preparations, or single-unit activity from teased fibres in colonic preparations, of young and old mice. Changes in afferent innervation with age were determined by measuring the density of calcitonin gene-related peptide-positive afferent fibres and by counting dorsal root ganglia back-labelled by injection of tracer dye into the wall of the colon. Finally, the effect of age on nociceptor function was studied in mouse and human colon. Afferent responses to appendicitis supernatants were greatly impaired in old mice. Further investigation revealed this was due to a marked reduction in the afferent innervation of the bowel and a substantial impairment in the ability of the remaining afferent fibres to transduce noxious stimuli. Translational studies in human tissue demonstrated a significant reduction in the multiunit but not the single-unit colonic mesenteric nerve response to capsaicin with age, indicative of a loss of nociceptor innervation. Our data demonstrate that anatomical and functional deficits in nociception occur with age, underpinning the atypical or silent presentation of appendicitis in the elderly.

Changes in neuromuscular structure and functions of human colon during ageing are region-dependent.

OBJECTIVE: To determine if human colonic neuromuscular functions decline with increasing age. DESIGN: Looking for non-specific changes in neuromuscular function, a standard burst of electrical field stimulation (EFS) was used to evoke neuronally mediated (cholinergic/nitrergic) contractions/relaxations in ex vivomuscle strips of human ascending and descending colon, aged 35-91 years (macroscopically normal tissue; 239 patients undergoing cancer resection). Then, to understand mechanisms of change, numbers and phenotype of myenteric neurons (30 306 neurons stained with different markers), densities of intramuscular nerve fibres (51 patients in total) and pathways involved in functional changes were systematically investigated (by immunohistochemistry and use of pharmacological tools) in elderly (≥70 years) and adult (35-60 years) groups. RESULTS: With increasing age, EFS was more likely to evoke muscle relaxation in ascending colon instead of contraction (linear regression: n=109, slope 0.49%±0.21%/year, 95% CI), generally uninfluenced by comorbidity or use of medications. Similar changes were absent in descending colon. In the elderly, overall numbers of myenteric and neuronal nitric oxide synthase-immunoreactive neurons and intramuscular nerve densities were unchanged in ascending and descending colon, compared with adults. In elderly ascending, not descending, colon numbers of cell bodies exhibiting choline acetyltransferase immunoreactivity increased compared with adults (5.0±0.6 vs 2.4±0.3 neurons/mm myenteric plexus, p=0.04). Cholinergically mediated contractions were smaller in elderly ascending colon compared with adults (2.1±0.4 and 4.1±1.1 g-tension/g-tissue during EFS; n=25/14; p=0.04); there were no changes in nitrergic function or in ability of the muscle to contract/relax. Similar changes were absent in descending colon. CONCLUSION: In ascending not descending colon, ageing impairs cholinergic function.

Human native kappa opioid receptor functions not predicted by recombinant receptors: Implications for drug design.

If activation of recombinant G protein-coupled receptors in host cells (by drugs or other ligands) has predictive value, similar data must be obtained with native receptors naturally expressed in tissues. Using mouse and human recombinant κ opioid receptors transfected into a host cell, two selectively-acting compounds (ICI204448, asimadoline) equi-effectively activated both receptors, assessed by measuring two different cell signalling pathways which were equally affected without evidence of bias. In mouse intestine, naturally expressing κ receptors within its nervous system, both compounds also equi-effectively activated the receptor, inhibiting nerve-mediated muscle contraction. However, whereas ICI204448 acted similarly in human intestine, where κ receptors are again expressed within its nervous system, asimadoline was inhibitory only at very high concentrations; instead, low concentrations of asimadoline reduced the activity of ICI204448. This demonstration of species-dependence in activation of native, not recombinant κ receptors may be explained by different mouse/human receptor structures affecting receptor expression and/or interactions with intracellular signalling pathways in native environments, to reveal differences in intrinsic efficacy between receptor agonists. These results have profound implications in drug design for κ and perhaps other receptors, in terms of recombinant-to-native receptor translation, species-dependency and possibly, a need to use human, therapeutically-relevant, not surrogate tissues.

What is the role of screening in the management of abdominal aortic aneurysms?

A best-evidence topic in vascular surgery was written according to a structured protocol. The question addressed was whether screening asymptomatic individuals for an abdominal aortic aneurysm (AAA) is feasible and improves disease-free survival. Seven studies presented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and limitations of the studies are tabulated. In total, four randomized population-based studies have evaluated ultrasound screening for AAA: two British studies, Multicentre Aneurysm Screening Study (MASS) and the Chichester trial, and one each in Viborg County, Denmark and Western Australia. Participants were randomized to receive an invitation to screen or not. The MASS trial randomized 67 770 men, followed participants over 10 years and concluded that screening would almost half AAA-related deaths in men aged 65-74 years. The smaller Chichester trial included only 6040 men but demonstrated a 42% reduction in AAA-related mortality at 5 years, with ongoing benefit at 15 years (11% reduction). The Viborg County trial recruited 12 639 men aged 64-73 years, showed a 66% reduction in AAA-related mortality over 14 years. Finally, the Western Australia trial evaluated 41 000 men but included an older population of 65-83 years old. No benefit was seen in this age group but subgroup analysis of men aged 65-74 showed a significant mortality benefit. Only a small or insignificant benefit in all-cause mortality was seen in any of these studies. A recent meta-analysis of these trials has shown a significant benefit in AAA-related mortality in the long term and concluded that AAA screening is superior to other established screening programmes. The cost-effectiveness of screening was assessed in the MASS and Viborg County trials and was found to be substantially below the cost threshold set by the National Institute of Clinical Excellence for acceptance of interventions. Quality of life was assessed in the MASS and in a case-control study and showed no adverse effects that outweigh the benefits. We concluded that ultrasound screening for AAAs has met all the criteria to become a screening programme and would substantially reduce disease-related death with no adverse effect on quality of life.

Is it safe to perform coronary angiography during acute endocarditis?

A best evidence topic was written according to a structured protocol. The question addressed was 'Is it safe to perform coronary angiography (CA) in acute endocarditis?' Three hundred and ninety-seven papers were found using the reported search, of which six represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes, key results and limitations of these papers are tabulated. One of the papers is a case report, which reported a fatal vegetation embolism from an infected aortic valve into the left main coronary artery 14 h after angiography. The remaining five papers are cohort studies. Four of these studies were performed between 1970 and 1980 before the era of echocardiography and were aimed at quantifying the severity of valvular regurgitation. No embolic complications or dislodgement of vegetations occurred in any of the five studies (186 patients). Guidelines published by the European Society of Cardiology (ESC) in 2009 recommended CA in the context of infective endocarditis (IE) for men >40 years old, postmenopausal women, and patients with at least one cardiovascular risk factor or a history of coronary artery disease. Exceptions include patients with large aortic vegetations which may be dislodged during catheterisation, and when emergency surgery is necessary - 1) native aortic or mitral IE with severe acute regurgitation or valve obstruction, or prosthetic valve IE with severe prosthetic dysfunction (dehiscence or obstruction) causing refractory pulmonary oedema or cardiogenic shock; 2) native aortic, mitral, or prosthetic valve IE with fistula into a cardiac chamber or pericardium causing refractory pulmonary oedema or shock. This is reiterated by the guidelines on the management of valvular heart disease published by the ESC in 2007. From the findings of the six papers, it can be concluded that coronary angiography can be performed safely in IE and should be performed if deemed necessary, unless the patients are haemodynamically unstable requiring emergency surgery, or have large vegetations of the aortic valve. This is consistent with the ESC guidelines.