Aspirin and non-steroidal anti-inflammatory drug use and the risk of upper aerodigestive tract cancer.

BACKGROUND: Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesics and preventative agents for vascular events. It is unclear whether their long-term use affects cancer risk. Data on the chemopreventative role of these drugs on the risk of the upper aerodigestive tract cancer (UADT) are insufficient and mostly refer to oesophageal cancer. The aim of this study was to investigate the effect of aspirin and other NSAIDs on the risk of UADT cancers. METHODS: A nested case-control study using the Primary Care Clinical Informatics Unit (PCCIU) database. Conditional logistics regression was used for data analysis. RESULTS: There were 2392 cases of UADT cancer diagnosed between 1996 and 2010 and 7165 age-, gender- and medical practice-matched controls from 131 general medical practices. Mean age of cases was 66 years (s.d. 12) and most were male (63%). Aspirin was prescribed in a quarter of cases and controls, COX-2 inhibitors in 4% of cases and 5% of controls and other NSAIDs in 33% of cases and 36% of controls. Aspirin prescription was associated with a nonsignificant risk reduction of cancer of UADT (adjusted OR=0.9, 95% CI=0.8, 1.0), head and neck (HN; adjusted OR=0.9, 95% CI=0.7, 1.1) or the oesophagus (adjusted OR=0.8, 95% CI=0.7, 1.0). Similar results were found for COX-2 inhibitors prescription. Prescription of other NSAIDs was associated with significantly reduced risk of cancer of UADT (adjusted OR=0.8, 95% CI=0.7, 0.9), HN (adjusted OR=0.8, 95% CI=0.7, 0.9) and the oesophagus (adjusted OR=0.8, 95% CI=0.7, 0.9). An increased volume of aspirin prescriptions was associated with a significant risk reduction (test for trend P<0.001). CONCLUSIONS: The decreased risk of cancer of the UADT associated with the use of non-COX-2 inhibitors, NSAIDs and long-term aspirin therapy warrants further exploration of the benefits vs risks of the use of these agents.

Incidence and drug treatment of emotional distress after cancer diagnosis: a matched primary care case-control study.

BACKGROUND: Emotional distress is common in cancer patients. This study aimed to describe, in the year after a cancer diagnosis: the incidence of anxiety, depression and excessive alcohol use; the pattern of these diagnoses and treatment over time; and the nature and duration of the prescribed treatment. METHODS: A matched case-control study was conducted using routinely collected primary care data from 173 Scottish general practices. A presumptive diagnosis of emotional distress (anxiety, depression and/or excessive alcohol use) was based on prescription data or diagnostic code. Prescriptions for psychotropic drugs were described in terms of drug class, volume and treatment duration. RESULTS: In total, 7298 cancer cases and 14 596 matched-controls were identified. Overall, 1135 (15.6%) cases and 201 (1.4%) controls met criteria for emotional distress (odds ratio 13.7, 95% confidence interval 11.6-16.1). Psychotropic drugs were prescribed in the 6 months following initial cancer diagnosis for 1066 (14.6%) cases and 161 (1.1%) controls. The volume and duration of anxiolytic and antipsychotic prescribing was significantly different between cases and controls. CONCLUSION: This study quantified the higher incidence of new emotional distress in cancer patients in the first year post diagnosis. Clinicians should be aware of the possibility of emotional distress at any time in the year after cancer diagnosis.

Introduction of a new incentive and target-based contract for family physicians in the UK: good for older patients with diabetes but less good for women?

AIMS: To determine whether the recording of diabetes-related health indicators has increased and differences diminished between age, gender and deprivation groups, following the introduction of the new General Medical Services contract (nGMS), an incentive- and target-based contract for UK family physicians. METHODS: A serial cross-sectional study set in 310 primary care practices in Scotland serving a population of 1.5 million registered patients, focussing on diabetic patients. Data were taken immediately before the introduction of the nGMS and after it had been in place for 1 year. RESULTS: One year after the introduction of the nGMS contract, there was a 54.2% relative increase in the number of patients electronically recorded as having diabetes. In addition, measurement of the quality indicators glycated haemoglobin (HbA(1c)), blood pressure, serum creatinine and cholesterol significantly increased (P < 0.05). Women were less likely than men to have HbA(1c)[odds ratio (OR) 0.85, 95% confidence intervals (CI) 0.80-0.91], serum creatinine (OR 0.90, 95% CI 0.84-0.96) and cholesterol recorded (OR 0.83, 95% CI 0.77-0.90) or achieve HbA(1c) (

Will Systematized Nomenclature of Medicine-Clinical Terms improve our understanding of the disease burden posed by allergic disorders?

Analysis of data collected through the use of high-quality computerized systems is vital if we are to understand the health burden from allergic disease. Coding systems currently used, such as the World Health Organization's International Classification of Diseases and the Read system, have however been criticized as being unduly restrictive and hence inadequate for the detailed coding of allergic problems. Greater granularity of coding can be achieved by using the Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT) system, which will be adopted by several countries including the United States and United Kingdom. Before the introduction of SNOMED-CT, it is important that several issues are resolved, including ensuring that adequate mapping occurs from existing systems, that the SNOMED-CT is trialled before general implementation, and that training is provided for users new to coding as part of their clinical practice. Of particular importance is that the allergy fraternity bring to light any gaps in allergy coding through the creation of a working group to advise the newly formed International Healthcare Terminology Standards Development Organisation. There is also a role for allergy experts, working in conjunction with government agencies and professional bodies, to determine a recommended set of codes, which will obviate some of the inevitable challenges raised by a very fluid coding structure for those wishing to undertake secondary analysis of health care datasets.

Dual role of the NF-kappaB transcription factor in the death of immature neurons.

We have previously shown that the extent of axotomy-induced death of retinal ganglion cells is reduced by cycloheximide, an inhibitor of protein synthesis, and that an earlier sublethal oxidative insult induced by buthionine sulfoximine, a glutathione synthesis inhibitor, enhances the protective effects of cycloheximide. Thus, axotomy-induced ganglion cell death seems to involve an interaction between the redox status and genetic expression. The redox-sensitive transcription factor nuclear factor-kappaB (NF-kappaB) is a logical candidate for providing this interaction. In the present study, we injected intraocularly selective inhibitors of NF-kappaB in chick embryos either unlesioned, or after a unilateral tectal lesion, which axotomizes ganglion cells. The number of dying cells in the retina contralateral to the lesion was reduced in embryos receiving NF-kappaB inhibitors as compared with vehicle-injected controls. In contrast, the same NF-kappaB inhibitors administered as pretreatment before intraocular injection of buthionine sulfoximine and cycloheximide drastically raised neuronal death and induced fulgurant degenerative changes in the retina. The most parsimonious interpretation of our results is that in axotomized retinal ganglion cells of chick embryos NF-kappaB may have either death-promoting or death-inhibiting effects. We propose a theoretical model to explain these dual effects assuming the existence of parallel death pathways differently affected by NF-kappaB. These results may have implications for future redox-based therapeutic strategies for neuroprotection.

Relationships between neuronal death and the cellular redox status. Focus on the developing nervous system.

During the development of the nervous system, a large number of neurons are eliminated through naturally occurring neuronal death. Many morphological and biochemical properties of such dying neurons are reminiscent of apoptosis, a type of death involving the action of genetically-programmed events but also epigenetic phenomena including oxidative stress. The following review contains three parts focusing respectively on basic knowledge of neuronal death and redox regulation, the mechanisms involved in neuronal death which are ordered in three sequential phases, and on the complex relations between neuronal fate and the redox status. Finally, we point out that oxidants are not always detrimental for neuronal survival. On the one hand, dying neurons often display signs of oxidative stress, including an elevation of their intracellular concentration of free radicals. Antioxidants may reduce the extent of neuronal death, suggesting a causal implication of free radicals in the death-process. On the other hand, at high concentrations antioxidants may lose their protective effects on developing neurons, and a non-lethal oxidative stress may potentiate the protective effects of other agents. These data suggest that free radicals, perhaps through their effects on cellular signalling pathways, may have positive effects on neuronal survival, provided that their intraneuronal concentrations are maintained at low levels. Much evidence suggests that the neuronal redox status must be maintained within a narrow range of values compatible with survival. Antioxidants may protect neurons subjected to an oxidative stress following axotomy or trophic factor-deprivation; but excessive reduction may become equally detrimental for neurons.

Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors.

Among the recently cloned serotonin (5-hydroxytryptamine, 5-HT) receptors, the 5-HT6 subtype is of special interest for at least two reasons: 1) it is abundant in limbic areas which participate in the control of mood and emotion; and 2) some antidepressants and antipsychotics are potent 5-HT6 receptor antagonists. Studies using polyclonal anti-5-HT6 receptor antibodies and an antisense oligonucleotide were performed in order to investigate further the function(s) of 5-HT6 receptors in the rat brain. Immunocytochemistry at the light and electron microscope levels showed that 5-HT6 receptors are mainly confined to the dendritic compartment, suggesting that they could mediate 5-HT actions on neuronal firing. In some limbic areas, 5-HT6 receptor-like immunoreactivity is also associated with neuronal cilia with yet unknown functions. Continuous i.c.v. infusion with an antisense oligonucleotide for 3-4 days resulted in decreased 5-HT6 receptor-like immunostaining of the nucleus accumbens and anxiogenic behaviours in the social interaction and elevated plus maze tests. Selective 5-HT6 receptor ligands are eagerly expected to investigate further the potential implication of these receptors in limbic-dependent behaviours.

An optimal redox status for the survival of axotomized ganglion cells in the developing retina.

The neuronal redox status influences the expression of genes involved in neuronal survival. We previously showed that antioxidants may reduce the number of dying ganglion cells following axotomy in chick embryos. In the present study, we show that various antioxidants, including the new spin trap azulenyl nitrone and 1,3-dimethyl-2-thiourea, protect axotomized ganglion cells, confirming that neuronal death involves an imbalance of the cellular redox status towards oxidation. However, high concentrations of antioxidants did not protect ganglion cells, suggesting that excessive reduction is detrimental for neurons. Simultaneous injections of two different antioxidants gave results only partly supporting this view. Combinations of azulenyl nitrone and N-acetyl cysteine in fact gave greater protection than either antioxidant alone, whereas N-acetyl cysteine lost its neuroprotective effects and diminished those of alpha-phenyl-N-tert-butyl nitrone when the two compounds were injected simultaneously. The results of the combined treatments suggest that azulenyl nitrone and alpha-phenyl-N-tert-butyl nitrone do not have the same chemical effects within the ganglion cells. Moreover, N-acetyl cysteine's own antioxidant properties enhance the spin trapping effects of azulenyl nitrone but potentiate the toxicity of alpha-phenyl-N-tert-butyl nitrone. Our main conclusion is that neuronal survival requires the maintenance of the redox status near an optimal set-point. "Reductive stress" may be as dangerous as oxidative stress.

Parent-offspring recognition in thick-billed murres (Aves: Alcidae).

Using field experiments, we investigated the development of parent-offspring recognition in the thick-billed murre, Uria lomvia. Cross-fostering experiments (N=73) showed that the likelihood of parents accepting a foreign chick decreased with chick age. Simultaneous-choice playback experiments demonstrated that chicks discriminate between the calls of their parents and both strange and familiar adult conspecifics from as early as 3 days old. In presentation experiments with chicks of fledging age (>/=14 days), adults responded more strongly to the calls of their own chicks than to other familiar chicks from the same breeding ledge. Results are consistent with those of earlier studies of parent-offspring recognition in the congeneric and ecologically similar common murre, U. aalge, which were among the first to suggest that parent birds and their chicks can identify each other's calls. Copyright 1998 The Association for the Study of Animal Behaviour. Copyright 1998 The Association for the Study of Animal Behaviour.

Light and electron microscopic immunocytochemical visualization of 5-HT1B receptors in the rat brain.

Specific antipeptide antibodies were used for the immunohistochemical visualization of 5-HT1B receptors in the rat brain. A dense, specific 5-HT1B receptor-like immunoreactivity was found in the globus pallidus, the dorsal subiculum and the substantia nigra. At the light microscope level, immunostaining was diffuse within the neuropil but absent from cell bodies. Observations at the electron microscope level in the substantia nigra showed immunoperoxidase staining in fine unmyelinated axons and nerve terminals.

Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system.

In order to map the recently cloned serotonin 5-HT6 receptor in the rat brain and spinal cord, polyclonal antibodies were raised against a synthetic octadecapeptide corresponding to a specific portion (Leu398-Val415) of the C-terminal domain of this receptor. Antibodies were detected by enzyme-linked immunosorbent assay as soon as one month after the first injection to rabbits of the peptide coupled to keyhole limpet hemocyanin. Immunoautoradiographic experiments with antibodies affinity-purified on Affi-Gel coupled to the peptide antigen showed that 5-HT6-like immunoreactive material was abundant in the olfactory tubercle (plexiform layer), cerebral cortex (frontal and entorhinal areas), nucleus accumbens, striatum, hippocampus (strata oriens and radiatum of the CA1 area, molecular layer of the dentate gyrus) and the molecular layer of the cerebellum. A specific immunolabeling, but at moderate intensity, was also observed in the thalamus, substantia nigra, superficial layer of the superior colliculus, motor trigeminal nucleus and facial nucleus. In contrast, no 5-HT6-like immunoreactive material was found in white matter areas. As the regional distribution of 5-HT6 receptor-like immunoreactivity matched generally that previously found for the 5-HT6 receptor mRNA, one could infer that this receptor protein is addressed in the vicinity of its synthesis site, i.e. on somas and/or dendrites. Indeed, immunohistochemistry at the light and electron microscope level showed that 5-HT6-like immunoreactivity was associated with dendritic processes in both the striatum and the dentate gyrus of the hippocampus. The relative abundance of 5-HT6 receptor-like immunoreactivity in extrapyramidal and limbic areas suggests that 5-HT6 receptors may participate in the serotoninergic control of motor function and mood-dependent behavior, respectively.

The Camden schizophrenia surveys. II. High prevalence of schizophrenia in an inner London borough and its relationship to socio-demographic factors.

BACKGROUND: Investigation of the geographical distribution of schizophrenia and its relationship to socio-demographic factors is useful for planning services. METHOD: Individuals with schizophrenia (n = 980) were identified by key informants within an inner London borough and point prevalence calculated for broad, Feighner and DSM-III-R schizophrenia. The distribution of cases was tested for significant variation using the Poisson process model. Regression models using the Jarman-8 score and its component variables were tested for their ability to predict the prevalence of schizophrenia. RESULTS: A high point prevalence of schizophrenia (5.3 per 1000 resident population) was demonstrated. Case distribution showed a marked and significant variation associated with socio-demographic factors. The prediction of prevalence was more accurate for broad than for narrower definitions of schizophrenia; unemployment rate performed best. CONCLUSIONS: Unemployment rates and Jarman-8 scores may provide crude estimates for resource allocation in planning mental health services, highlighting the need for additional services in deprived inner city areas.

Polymyositis with plasma cell infiltrate in essential mixed cryoglobulinaemia.

A patient with essential cryoglobulinaemia who presented with polymyositis is described. Muscle biopsy showed intense plasma cell infiltration of muscle. Plasmapheresis produced a rapid resolution of the cutaneous manifestations of the disease, but little improvement in muscle strength. Oral steroids resulted in moderate improvement in muscle strength. There have been no previously reported cases of polymyositis in association with essential cryoglobulinaemia.