How effective is patient-controlled analgesia? A randomized comparison of two protocols for pain relief during oocyte recovery

Although the conventional method of pain relief during outpatient oocyte recovery involves physician-administered drugs, patient- controlled analgesia (PCA) offers an alternative technique with the potential to give women more control over peroperative analgesia. We conducted a prospective randomized study to compare the effect of fentanyl administered either through a PCA delivery system or by a physician. Thirty-nine women were randomized to PCA during egg collection while 42 were allocated to receive intermittent doses administered by a physician. Pain was evaluated by means of a 100 mm linear analogue scale. The mean (SD) pain score in the PCA group was 38.5 (19.8) while in the other group it was 46.1 (21.3) (P = 0.1). In the PCA group, 64% of women felt very satisfied with their analgesia as compared with 57% in the non-PCA group (P = 0.6). Among the PCA users, 39% of demands were successful. Significantly more fentanyl (97.5 microg) was used in the PCA group than in the other group (84.6 microg) (P = 0.03). Though intraoperative PCA with fentanyl is an effective alternative to physician-administered techniques, many women still feel the need for more analgesia during the procedure.      

Microglia are more susceptible than macrophages to apoptosis in the central nervous system in experimental autoimmune encephalomyelitis through a mechanism not involving Fas (CD95)

Morphological studies have shown that macrophages and microglia undergo apoptosis in the central nervous system (CNS) in acute experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. To assess the relative levels of macrophage and microglial apoptosis, and the molecular mechanisms involved in this process, we used three-colour flow cytometry to identify CD45lowCD11b/c+ microglial cells and CD45highCD11b/c+ macrophages in the inflammatory cells isolated from the spinal cords of Lewis rats 13 days after immunization with myelin basic protein (MBP) and complete Freund's adjuvant. Simultaneously, we analyzed the DNA content of these cell populations to assess the proportions of cells undergoing apoptosis and in different stages of the cell cycle or examined their expression of three apoptosis- regulating proteins, i.e. Fas (CD95), Fas ligand (FasL) and Bcl-2. Microglia were highly vulnerable to apoptosis and were over-represented in the apoptotic population. Macrophages were less susceptible to apoptosis than microglia and underwent mitosis more frequently than microglia. The different susceptibilities of microglia and macrophages to apoptosis did not appear to be due to variations in Fas, FasL or Bcl- 2 expression, as the proportions of microglia and macrophages expressing these proteins were similar, and were relatively high. Furthermore, in contrast to T cell apoptosis, apoptosis of microglia/macrophages did not occur more frequently in cells expressing Fas or FasL, or less frequently in cells expressing Bcl-2. These results indicate that the apoptosis of microglia and CNS macrophages in EAE is not mediated through the Fas pathway, and that Bcl-2 expression does not protect them from apoptosis. Expression of FasL by macrophages and microglia may contribute to the pathogenesis and immunoregulation of EAE through interactions with Fas+ oligodendrocytes and Fas+ T cells. The high level of microglial apoptosis in EAE indicates that microglial apoptosis may be an important homeostatic mechanism for controlling the number of microglia in the CNS following microglial activation and proliferation.      

Innovation and restrictive conformity among hospital employees: individual outcomes and organizational considerations

Two factors characterize innovative organizational climates as perceived by nonmanagerial hospital employees. The first, innovation, comprises perceptions about the consequences or contingencies (e.g., punished, ignored, rewarded) of such proactive activities as implementing new ideas, questioning established methods, and communicating with other departments and the supervisor. The second, restrictive conformity, comprises perceptions about the consequences of risk-aversive, conflict-avoidant activities that suggest dysfunctional conformity (e.g., "sticking to the rules no matter what"). Positive personal outcomes--greater role clarity, organizational involvement, and satisfaction, and lower role conflict and willingness to leave the organization--are associated with innovation; negative personal outcomes are associated with restrictive conformity. The dialectical tension between conformity and innovation is discussed in terms of loose coupling and a reward systems perspective.     

Incorporating economic analysis in evidence-based guidelines for mental health: the profile approach

BACKGROUND: Many western health systems are currently developing the role of clinical guidelines to promote effective and efficient health care. However, introducing economic data into guideline methodology designed to assess the effectiveness of interventions raises some methodological issues. These include providing valid and generalizable cost estimates, the weight placed upon cost "evidence" and presenting cost-effectiveness information in a way that is helpful to clinicians. AIM OF THE STUDY: To explore a framework for including economic concepts in the development of a series of primary care guidelines, two of which address mental health conditions. METHODS: A profile approach, setting out best available evidence about the attributes of treatment choices (effectiveness, tolerability, safety, health service delivery, quality of life, resource use and cost), was used to help clinicians to derive treatment recommendations in a manner consistent with both the clinical decision-making process and social objectives. RESULTS: Clinicians involved in guideline development responded well to the process. Although there was often considerable debate about the meaning and importance of different aspects of evidence about treatment, in none of the guideline groups was there failure to agree treatment recommendations. DISCUSSION: The profile approach may be particularly useful in the field of mental health where disease processes may often feature very disparate effects, over long periods of time and impacting upon a broad circle of relatives, carers and agencies in addition to the patients themselves. CONCLUSION: A method has been applied in a series of primary care guidelines, which appears to enable clinicians to consider the issue of resource use alongside the various clinical attributes associated with treatment decisions. The basis of this work is the belief that guidance presenting physical measures describing effectiveness, adverse events, safety, compliance and quality of life, alongside resource consequences, is most likely to appropriately inform doctor-patient interactions. IMPLICATIONS FOR HEALTH CARE PROVISON AND USE: This research may provide a useful platform for other groups considering how to introduce cost-effectiveness concepts into guideline development groups. Whether guidelines change clinical behaviour remains a research question, and the subject of forthcoming trials. IMPLICATIONS FOR HEALTH POLICY FORMULATION: It is important that government agencies realize that guideline development is a health policy tool with prescribed methods to produce valid guidelines. Attempts to tamper with the methodology for cost-containment purposes or other political reasons are likely to discredit a useful mechanism for improving the scientific basis of health care provision. IMPLICATIONS FOR FURTHER RESEARCH: There are a number of limitations to completed work: for example it has a primary care focus and addresses fairly narrowly defined conditions. Work is ongoing to extend the scope to broader disease areas and to secondary care.     

Differential modulation of proliferation, matrix metalloproteinase expression and invasion of human head and neck squamous carcinoma cells by c-erbB ligands

Evidence suggests that there is an association between the abnormal expression of members of the c-erbB receptor tyrosine kinase family and poor prognosis in head and neck squamous cell carcinomas (HNSCC). Until now, the relative contributions of different c-erbB ligands to HNSCC progression have not been clearly defined. In this paper we examined the effects of ligands with different c-erbB receptor specificities in terms of their stimulation of HNSCC proliferation, expression of matrix metalloproteinases (MMPs) and invasion. Heregulin-beta1 (HRG-β1; selective c-erbB3/B4 ligand) was found to stimulate proliferation in the majority of cell lines, whereas epidermal growth factor (EGF; EGFR ligand) and betacellulin (BTC; EGFR/B4 ligand) induced variable responses. All three ligands up-regulated multiple MMPs including collagenases, stromelysins, matrilysin and gelatinase B (MMP-9) but had minimal or no effects on gelatinase A (MMP-2), MT1-MMP and tissue inhibitors of MMPs (TIMPs). MMP-9 mRNA was induced to a higher level than other MMPs, although with slower kinetics. HRG-β1 was less active than EGF and BTC at the optimal concentration (relative potency of EGF:BTC:HRG = 3:4:1). In vitro invasion through Matrigel was also increased by all three ligands in proportion to their MMP up-regulation. A specific anti-EGFR monoclonal antibody (mAb ICR62) inhibited MMP up-regulation, migration and invasion induced by all three ligands, whereas an anti-c-erbB-2 mAb ICR12 inhibited mitogenic and motogenic responses following ligand stimulation but had no effect on MMP expression. These results suggest that c-erbB ligands may differentially potentiate the invasive phenotype of HNSCC via co-operative induction of cell proliferation, migration and proteolysis. The EGFR signalling pathway appears to be the dominant component controlling the proteolytic and invasive phenotype in HNSCC, whereas the c-erbB-2 signalling pathway is responsible, in part, for the mitogenic and motogenic effects of ligands. This revised version was published online in July 2006 with corrections to the Cover Date.     

A framework for incorporating cost-effectiveness in evidence-based clinical practice guidelines.

In England, recent health care reforms emphasise the role of clinical guidelines in promoting effective and efficient health care. Introducing economic data into guidelines raises some methodological issues: specifically, the provision of valid and generalisable cost estimates, the weight placed upon cost 'evidence', and the presentation of cost-effectiveness information in a manner accessible to clinicians. A series of primary care guidelines, explicitly including consideration of health economic information, have recently been published, intended to help clinicians to aggregate the attributes of treatment choices to derive treatment recommendations consistent with both the clinical decision-making process and social objectives. Clinicians involved in developing guidelines responded well to the process and consistently managed to agree treatment recommendations, often after considerable debate about the evidence for treatment. In none of the guideline areas, all of which addressed common diseases, was there adequate information to estimate a cost per quality-adjusted-life-year, and it is unclear how helpful this approach would have been had it been possible. The implications of this method are discussed, guidance offered for economists new to guideline development and future areas of work identified.     

Charged amino acids as spectroscopic determinants for chlorophyll in vivo

In this paper we propose that the large spectroscopic red shifts observed for chlorophyll (Chl) and bacteriochlorophyll (BChl) in vivo may be due to charged amino acids in the binding site. Molecular orbital calculations of the transition energies of Chl in the field of external charges are carried out. The calculated wavelength shifts induced by these charges are comparable in magnitude to those observed in vivo. Moreover the size of the shifts increases in the order BChl b > BChl a > Chl a, which is the observed trend. The ability of the calculations to account for both the absolute and relative magnitudes of the wavelength shifts argues for the validity of the model. Further indirect support comes from the recent demonstration that charged amino acids are responsible for the colors of visual pigments and bacteriorhodopsin. In addition to their effects on spectra the presence of external charges induces large changes in the ionization potential of Chl molecules and thus might explain the in vivo alteration of the oxidation potentials in reaction centers.     

The initiation of voluntary movements by the supplementary motor area

Summary The hypothesis is formulated that in all voluntary movements the initial neuronal event is in the supplementary motor areas (SMA) of both cerebral hemispheres.Experimental support is provided by three lines of evidence. 1. In voluntary movements many neurones of the SMA are activated probably up to 200 ms before the pyramidal tract discharge. 2. Investigations of regional cerebral blood flow by the radioactive Xenon technique reveal that there is neuronal activity in the SMA of both sides during a continual series of voluntary movements, and that this even occurs when the movement is thought of, but not excuted. 3. With voluntary movement there is initiation of a slow negative potential (the readiness potential, RP) at up to 0.8 s before the movement. The RP is maximum over the vertex, i.e. above the SMA, and is large there even in bilateral Parkinsonism when it is negligible over the motor cortex.An account is given of the SMA, particularly its connectivities to the basal ganglia and the cerebellum that are active in the preprogramming of a movement. The concept of motor programs is described and related to the action of the SMA. It is proposed that each mental intention acts on the SMA in a specific manner and that the SMA has an inventory and the addresses of stored subroutines of all learnt motor programs. Thus by its neuronal connectivities the SMA is able to bring about the desired movement.There is a discussion of the manner in which the mental act of intention calls forth neural actions in the SMA that eventually lead to the intended movement. Explanation is given on the basis of the dualist-interactionist hypothesis of mind-brain liaison. The challenge is to the physicalists to account for the observed phenomena in voluntary movement.Dedicated to Prof. Richard Jung on the occasion of his 70th birthday     

An unusually severe phenotype for familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is a dominantly inherited predisposition to the development of many hundreds to thousands of adenomatous polyps of the colon. The mean age of onset is around 15 years, symptoms may arise in the third decade, and the median age for the development of colonic cancer is 35-40 years. Prophylactic colectomy reduces the risk of death from colorectal cancer to such an extent that late sequelae such as upper gastrointestinal tumours have become the main cause of mortality in appropriately managed patients. The age at which colonic surveillance begins reflects the natural history of the disease. Onset of polyp formation and cancer in childhood is very unusual, but has recently been associated with a specific mutation at codon 1309 in exon 15 where a more severe phenotype is sometimes observed. The case histories of two families are reported in which there is childhood onset of polyps in the youngest generation and in one case a carcinoma, in whom mutations have been identified in exon 11 of the APC gene. Several other affected relatives were diagnosed at ages ranging from 5-48 years, some already with a cancer at the time of first screening. Since the aim of screening for colonic polyps is prevention of colonic cancer, family members at risk should be offered genetic assessment and direct mutation testing where this is possible, usually in the early teens. In the absence of a genetic test (the situation in about one third of families) or in a known gene carrier, annual colonoscopy examination is advised from the same age. Clinicians should take note of the family history and be prepared to consider much earlier intervention if symptoms occur in a child with a family history of FAP. Where childhood onset of polyps has occurred, other children at risk in the family must be offered earlier genetic testing and endoscopic surveillance.