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Biomedical subjects

A R White

Publications and source records attributed to A R White.

At least 37 records · Page 2Linked to original sources
PubMed2001

Clinical trials of acupuncture: consensus recommendations for optimal treatment, sham controls and blinding.

Evidence of effectiveness is increasingly used to determine which health technologies are incorporated into public health provision. Acupuncture is a popular therapy that has been shown to be superior to placebo in the treatment of nausea and dental pain, and promising for migraine and osteoarthritis of the knee. For many other conditions, such as chronic pain, in which acupuncture is often used, the evidence is either insufficient or negative. Misleading results may occur for a number of reasons. False negative results may arise from inadequate treatment schedules and inappropriate control interventions. This consensus document considers these issues with the aim of improving the design of efficacy trials of acupuncture in order that they are more likely to be conclusive and more meaningfully interpreted. Clinical trials of acupuncture must use an optimal form of treatment; this can be defined by examining standard texts, by surveying and consulting experts. There are a great many variables in treatment (such as point selection, form of stimulation) all of which need to be addressed in designing and reporting clinical trials. The control procedure is determined by the precise research question that is being addressed. For efficacy studies, in which the question is whether acupuncture has specific effects (i.e. is superior to placebo), sham forms of acupuncture appear the most appropriate method of controlling for needle penetration. A recent development of blunted, telescopic needles may represent a major advance. Such procedures may produce a therapeutic response so should preferably be recorded as 'sham' procedures rather than true 'placebo' controls. Blinding in clinical trials is an accepted means of reducing bias. Patient blinding in acupuncture studies can be achieved by sham procedures and its success should be measured. While practitioner blinding is difficult, though not impossible, blinding of the observer and the analyst should be considered as the ideal for all studies. A number of recommendations are made which aim to improve the quality of sham-controlled acupuncture studies.

Acupuncture Points↗
PubMed2000

Amyloidogenicity and neurotoxicity of peptides corresponding to the helical regions of PrP(C).

An alpha-helical to beta-sheet conformational change in the prion protein, PrP(C), is believed to be causative in transmissible spongiform encephalopathies. Recent nuclear magnetic resonance structures of PrP(C) have identified three helical regions in the normal full-length protein. We have synthesised peptides corresponding to these helical regions (PrP144-154, helical region one; PrP178-193, helical region two; and PrP198-218, helical region three). Circular dichroism results show that the peptide corresponding to helical region one is unstructured, while peptides corresponding to the second and third helical regions have a high propensity to form beta-sheet structure in a pH-dependent manner in aqueous solutions. Peptides corresponding to the second helical region, PrP180-193 and PrP178-193, are the only ones that form amyloid by electron microscopy and congo red birefringence. PrP178-193 and the amyloidogenic Alzheimer's disease Abeta25-25 peptide were found to promote Cu (II)-induced lipid peroxidation and cytotoxicity in primary neuronal cultures, while PrP144-154, PrP198-218 and the nonamyloidogenic Abeta1-28 had no effect on Cu (II) toxicity. There was no increase in toxicity induced by PrP178-193 in cultures treated with Fe (II) or hydrogen peroxide, indicating a preferential modulatory effect on Cu (II) toxicity by PrP178-193. The data suggest that the PrP178-193 peptide has both structural and bioactive properties in common with Abeta25-35 and that the second putative helical region of PrP could be involved in modulation of Cu (II)-mediated toxicity in neurons during prion disease.

Amyloid beta-Peptides↗
PubMed2000

Efficacy of acupuncture as a treatment for tinnitus: a systematic review.

BACKGROUND: Tinnitus is a prevalent condition for which patients may seek treatment with acupuncture since no conventional treatment has been shown to be effective. OBJECTIVE: To summarize and critically review all randomized controlled trials on the efficacy of acupuncture as a treatment for tinnitus. DATA SOURCES: Four independent computerized literature searches (MEDLINE, Cochrane Controlled Trials Register, Embase, and CISCOM) were conducted in December 1998 using the key words acupuncture and tinnitus. STUDY SELECTION: All randomized controlled trials that compared any form of acupuncture with any control intervention in the treatment of tinnitus were included. DATA EXTRACTION: Data were extracted by 2 authors independently. The methodological quality of the included randomized controlled trials was assessed using the Jadad score. DATA SYNTHESIS: Six randomized controlled trials were included in the review, 4 of which used crossover design. Four studies used manual acupuncture and 2 used electroacupuncture. Five of 6 studies used inconsistent acupoints. Three studies scored 3 points or more on the Jadad scale. MAIN OUTCOME MEASURES: Outcome measurements were visual analog scale scores for loudness, annoyance, and awareness of tinnitus; subjective severity scale scores for tinnitus; or Nottingham Health Profile scores. RESULTS: Two unblinded studies showed a positive result, whereas 4 blinded studies showed no significant effect of acupuncture. CONCLUSION: Acupuncture has not been demonstrated to be efficacious as a treatment for tinnitus on the evidence of rigorous randomized controlled trials.

Acupuncture Therapy↗
PubMed2000

Acupuncture for smoking cessation.

BACKGROUND: Acupuncture is promoted as a treatment for smoking cessation, and is believed to reduce withdrawal symptoms. OBJECTIVES: The objective of this review is to determine the effectiveness of acupuncture in smoking cessation in comparison with: a) sham acupuncture b) other interventions c) no intervention. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register, Medline, PsycLit, Dissertation Abstracts, Health Planning and Administration, Social SciSearch, Smoking & Health, Embase, Biological Abstracts and DRUG. SELECTION CRITERIA: Randomised trials comparing a form of acupuncture with either sham acupuncture, another intervention or no intervention for smoking cessation. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of subjects, the nature of the acupuncture and control procedures, the outcome measures, method of randomisation, and completeness of follow-up. We assessed abstinence from smoking at the earliest time-point (before 6 weeks), at six months and at one year follow-up in patients smoking at baseline. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Those lost to follow-up were counted as continuing to smoke. Where appropriate, we performed meta-analysis using a fixed effects model. MAIN RESULTS: We identified 18 publications involving 20 comparisons. Acupuncture was not superior to sham acupuncture in smoking cessation at any time point. The odds ratio (OR) for early outcomes was 1.22 (95% confidence interval 0.99 to 1.49); the OR after 6 months was 1.38 (95% confidence interval 0.90 to 2.11) and after 12 months 1.02 (95% confidence interval 0.72 to 1.43). Similarly, when acupuncture was compared with other anti-smoking interventions, there were no differences in outcome at any time point. Acupuncture appeared to be superior to no intervention in the early results, but this difference was not sustained. The results with different acupuncture techniques do not show any one particular method (i.e. auricular acupuncture or non-auricular acupuncture) to be superior to control intervention. REVIEWER'S CONCLUSIONS: There is no clear evidence that acupuncture is effective for smoking cessation.

Acupuncture Therapy↗
PubMed2000

Hypnotherapy for smoking cessation.

BACKGROUND: Hypnotherapy is widely promoted as a method for aiding smoking cessation. It is proposed to act on underlying impulses to weaken the desire to smoke or strengthen the will to stop. OBJECTIVES: The objective of this review was to evaluate the effects of hypnotherapy for smoking cessation. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register. SELECTION CRITERIA: We considered randomised trials of hypnotherapy which reported smoking cessation rates at least six months after the beginning of treatment. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data on the type of subjects, the type and duration of the hypnotherapy, the nature of the control group,the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. We used the most rigorous definition of abstinence in each trial, and biochemically validated rates where available. Subjects lost to follow-up were counted as smokers. Where possible, we performed meta-analysis using a fixed effects model. MAIN RESULTS: Nine studies compared hypnotherapy with 14 different control interventions. There was significant heterogeneity between the results of the individual studies, with conflicting results for the effectiveness of hypnotherapy compared to no treatment or to advice. We therefore did not attempt to calculate pooled odds ratios for the overall effect of hypnotherapy. There was no evidence of an effect of hypnotherapy compared to rapid smoking or psychological treatment. REVIEWER'S CONCLUSIONS: We have not shown that hypnotherapy has a greater effect on six month quit rates than other interventions or no treatment. The effects of hypnotherapy on smoking cessation claimed by uncontrolled studies were not confirmed by analysis of randomised controlled trials.

Humans↗
PubMed2000

Economic analysis of complementary medicine: a systematic review.

OBJECTIVE: To review systematically all reports of economic analysis of complementary and alternative medicine. METHOD: Searches were performed in Medline, Embase and AMED for reports of cost description, cost comparison, cost effectiveness, or cost benefit studies. Prospective studies that investigated comparative groups were considered to be of higher quality. RESULTS: A total of 34 reports was included. Retrospective studies in which a range of therapies are provided in primary care suggest that these may reduce referral and treatment costs, but prospective studies suggest that complementary medicine is an additional expense and does not substitute for orthodox care. For individual therapies, one thorough but retrospective study suggests that carefully targeted acupuncture may reduce referral costs for musculoskeletal problems. One large pragmatic study of spinal manipulative therapy suggests that this treatment may reduce the societal costs of back pain, but four controlled trials found that manipulative therapy does not reduce the costs incurred by the back pain patients themselves or by their health insurance provider. CONCLUSION: Spinal manipulative therapy for back pain may offer cost savings to society, but it does not save money for the purchaser. There is a paucity of rigorous studies that could provide conclusive evidence of differences in costs and outcomes between other complementary therapies and orthodox medicine. The evidence from methodologically flawed studies is contradicted by more rigorous studies, and there is a need for high quality investigations of the costs and benefits of complementary medicine.

Complementary Therapies↗
PubMed2000

A blinded investigation into the accuracy of reflexology charts.

OBJECTIVES: Reflexology is an increasingly popular complementary therapy in which parts of the body are deemed to be represented on the soles of the feet. The aim of this study was to investigate whether this representation can be used as a valid method of diagnosis. METHODS: Three experienced reflexologists took part in this study. Eighteen adults with one or more of six specified conditions were identified from primary care records. Two reflexologists, who were blinded to the patients' conditions and monitored, then examined each patient's feet and rated the probability that each of the six conditions was present. RESULTS: There is little evidence that the distribution of ratings vary with the status of the condition. Receiver operating curves suggest that this diagnostic method is very poor at distinguishing between the presence and absence of conditions. Inter-rater reliability (kappa) scores were very low, providing no evidence of agreement between the examiners. CONCLUSION: Despite certain limitations to the data provided by this study, the results do not suggest that reflexology techniques are a valid method of diagnosis.

Adult↗
PubMed2000

Are acupuncture points tender? A blinded study of Spleen 6.

OBJECTIVES: To explore the methodology for investigating the tenderness of acupuncture points, with particular reference to the hypothesis that the point Spleen 6 (SP6) is more tender in women than in men. DESIGN: Single-blind, observational study with volunteers. SETTING: University of Exeter, U.K. SUBJECTS: Student volunteers, 13 male and 13 female. OUTCOME MEASURES: Pressure thresholds at SP6, a control acupuncture point Stomach 36, and two nonacupuncture control sites in each leg were measured weekly for 4 weeks. RESULTS: No statistically significant differences were found between the pressure thresholds of SP6 in women and those in men. CONCLUSION: The present study provides no strong evidence to support the hypothesis that the acupuncture point SP6 is more tender in women and in men. Recommendations for further investigations are discussed.

Acupuncture Points↗
PubMed2000

Acupuncture for episodic tension-type headache: a multicentre randomized controlled trial.

A multicentre, randomized clinical trial was undertaken to test the hypothesis that acupuncture is more efficacious than sham control procedure in the prevention of episodic tension-type headache. Fifty subjects were randomized to receive a course of treatment with either brief acupuncture or a sham procedure. Subjects were followed up for 3 months. Changes in headache were assessed by daily diary, the primary outcome measure being the number of days with headache. No significant differences were found between the changes in the two groups for any measure at any time point. Results also show that patient blinding was successful. In conclusion, this study does not provide evidence that this form of acupuncture is effective in the prevention of episodic tension-type headache.

Acupuncture Therapy↗
PubMed1999

The Alzheimer's disease amyloid precursor protein modulates copper-induced toxicity and oxidative stress in primary neuronal cultures.

The amyloid precursor protein (APP) of Alzheimer's disease can reduce copper (II) to copper (I) in a cell-free system potentially leading to increased oxidative stress in neurons. We used neuronal cultures derived from APP knock-out (APP(-/-)) and wild-type (WT) mice to examine the role of APP in copper neurotoxicity. WT cortical, cerebellar, and hippocampal neurons were significantly more susceptible than their respective APP(-/-) neurons to toxicity induced by physiological concentrations of copper but not by zinc or iron. There was no difference in copper toxicity between APLP2(-/-) and WT neurons, demonstrating specificity for APP-associated copper toxicity. Copper uptake was the same in WT and APP(-/-) neurons, suggesting APP may interact with copper to induce a localized increase in oxidative stress through copper (I) production. This was supported by significantly higher levels of copper-induced lipid peroxidation in WT neurons. Treatment of neuronal cultures with a peptide corresponding to the human APP copper-binding domain (APP142-166) potentiated copper but not iron or zinc toxicity. Incubation of APP142-166 with low-density lipoprotein (LDL) and copper resulted in significantly increased lipid peroxidation compared to copper and LDL alone. Substitution of the copper coordinating histidine residues with asparagines (APP142-166(H147N, H149N, H151N)) abrogated the toxic effects. A peptide corresponding to the zinc-binding domain (APP181-208) failed to induce copper or zinc toxicity in neuronal cultures. These data support a role for the APP copper-binding domain in APP-mediated copper (I) generation and toxicity in primary neurons, a process that has important implications for Alzheimer's disease and other neurodegenerative disorders.

Amino Acid Sequence↗
PubMed1999

Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice.

The pathological process in Alzheimer's disease (AD) involves amyloid beta (Abeta) deposition and neuronal cell degeneration. The neurotoxic Abeta peptide is derived from the amyloid precursor protein (APP), a member of a larger gene family including the amyloid precursor-like proteins, APLP1 and APLP2. The APP and APLP2 molecules contain metal binding sites for copper and zinc. The zinc binding domain (ZnBD) is believed to have a structural rather than a catalytic role. The activity of the copper binding domain (CuBD) is unknown, however, APP reduces copper (II) to copper (I) and this activity could promote copper-mediated neurotoxicity. The expression of APP and APLP2 in the brain suggests they could have an important direct or indirect role in neuronal metal homeostasis. To examine this, we measured copper, zinc and iron levels in the cerebral cortex, cerebellum and selected non-neuronal tissues from APP (APP(-/-)) and APLP2 (APLP2(-/-)) knockout mice using atomic absorption spectrophotometry. Compared with matched wild-type (WT) mice, copper levels were significantly elevated in both APP(-/-) and APLP2(-/-) cerebral cortex (40% and 16%, respectively) and liver (80% and 36%, respectively). Copper levels were not significantly different between knockout and WT cerebellum, spleen or serum samples. There were no significant differences observed between APP(-/-), APLP2(-/-) and WT mice zinc or iron levels in any tissue examined. These findings indicate APP and APLP2 expression specifically modulates copper homeostasis in the liver and cerebral cortex, the latter being a region of the brain particularly involved in AD. Perturbations to APP metabolism and in particular, its secretion or release from neurons may alter copper homeostasis resulting in increased Abeta accumulation and free radical generation. These data support a novel mechanism in the APP/Abeta pathway which leads to AD.

Alzheimer Disease↗
PubMed1999

Familial prion disease mutation alters the secondary structure of recombinant mouse prion protein: implications for the mechanism of prion formation.

A considerable body of data supports the model that the infectious agent (called a prion) which causes the transmissible spongiform encephalopathies is a replicating polypeptide devoid of nucleic acid. Prions are believed to propagate by changing the conformation of the normal cellular prion protein (PrPc) into an infectious isoform without altering the primary sequence. Proteins equivalent to the mature form of the wild-type mouse prion protein (residues 23-231) or with a mutation equivalent to that associated with Gerstmann-Straüssler-Scheinker disease (proline to leucine at codon 102 in human; 101 in mouse) were expressed in E. coli. The mutation did not alter the relative proteinase K susceptibility properties of the mouse prion proteins. The wild-type and mutant proteins were analyzed by circular dichroism under different pH and temperature conditions. The mutation was associated with a decrease in alpha-helical content, while the beta-sheet content of the two proteins was unchanged. This suggests the mutation, while altering the secondary structure of PrP, is not sufficient to induce proteinase K resistance and could therefore represent an intermediate isoform along the pathway toward prion formation.

Amino Acid Substitution↗
PubMed1999

Acupuncture as a treatment for temporomandibular joint dysfunction: a systematic review of randomized trials.

OBJECTIVE: To summarize the data from randomized controlled trials of acupuncture for temporomandibular joint dysfunction. METHODS: Four independent computerized literature searches were performed. Only randomized trials were admitted in which acupuncture was tested vs sham acupuncture, standard therapy, or no treatment at all. Data were extracted in a predefined, standardized fashion. RESULTS: Six reports met the inclusion and exclusion criteria, representing 3 distinct trials. Overall, their results suggest that acupuncture might be an effective therapy for temporomandibular joint dysfunction. However, none of the studies was designed to control for a placebo effect. CONCLUSION: Even though all studies are in accordance with the notion that acupuncture is effective for temporomandibular joint dysfunction, this hypothesis requires confirmation through more rigorous investigations.

Acupuncture Therapy↗
PubMed1999

Prion protein-deficient neurons reveal lower glutathione reductase activity and increased susceptibility to hydrogen peroxide toxicity.

The prion protein (PrP) has a central role in the pathogenesis of transmissible spongiform encephalopathies (TSE). Accumulating evidence suggests that normal cellular PrP (PrP(c)) may be involved in copper homeostasis and modulation of copper/zinc superoxide dismutase (Cu/ZnSOD) activity in neurons. Hydrogen peroxide (H(2)O(2)) is a toxic reactive oxygen species generated through normal cellular respiration, and neurons contain two important peroxide detoxifying systems (glutathione pathway and catalase). To determine whether PrP expression affects neuronal resistance to H(2)O(2), we exposed primary cerebellar granule neuron cultures derived from PrP knockout (PrP(-/-)) and wild-type (WT) mice to H(2)O(2) for 3, 6, and 24 hours. The PrP(-/-) neurons were significantly more susceptible to H(2)O(2) toxicity than WT neurons after 6 and 24 hours' exposure. The increased H(2)O(2) toxicity may be related to a significant decrease in glutathione reductase activity measured in PrP(-/-) neurons both in vitro and in vivo. This was supported by the finding that inhibition of GR activity with 1,3-bis(2-chloroethyl)-1-nitrosurea (BCNU) increased H(2)O(2) toxicity in WT neurons over the same exposure period. The PrP toxic peptide PrP106-126 significantly reduced neuronal glutathione reductase activity and increased susceptibility to H(2)O(2) toxicity in neuronal cultures suggesting that PrP toxicity in vivo may involve altered glutathione reductase activity. Our results suggest the pathophysiology of prion diseases may involve perturbed PrP(c) function with increased vulnerability to peroxidative stress.

Animals↗
PubMed1999

Amyloid beta.

Amyloid beta (A beta) is a 39-43 residue amyloidogenic peptide that is deposited into the extracellular amyloid plaques which characterize an Alzheimer's disease (AD) brain. A beta is derived from the amyloid precursor protein (APP) and undergoes a toxic conformational change (gain of toxic function). The length of the A beta peptide dramatically influences its properties with the longer 42 and 43 residue species being more amyloidogenic. The genetics of familial AD (FAD) supports a central role for A beta in AD since mutations in the FAD causing genes APP and the presenilins (PS1 and PS2) increase the formation of A beta 42,43. Considerable activity is directed towards A beta as a therapeutic target. These strategies aim to inhibit A beta synthesis, A beta fibril formation, its toxic actions on cells or promote its clearance from the brain.

Alzheimer Disease↗
PubMed1999

Exacerbation of copper toxicity in primary neuronal cultures depleted of cellular glutathione.

Perturbations to glutathione (GSH) metabolism may play an important role in neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases. A primary function of GSH is to prevent the toxic interaction between free radicals and reactive transition metals such as copper (Cu). Due to the potential role of Cu in neurodegeneration, we examined the effect of GSH depletion on Cu toxicity in murine primary neuronal cultures. Depletion of cellular GSH with L-buthionine-[S,R]-sulfoximine resulted in a dramatic potentiation of Cu toxicity in neurons without effect on iron (Fe) toxicity. Similarly, inhibition of glutathione reductase (GR) activity with 1,3-bis(2-chloroethyl)-1-nitrosurea also increased Cu toxicity in neurons. To determine if the Alzheimer's amyloid-beta (Abeta) peptide can affect neuronal resistance to transition metal toxicity, we exposed cultures to nontoxic concentrations of Abeta25-35 in the presence or absence of Cu or Fe. Abeta25-35 pretreatment was found to deplete neuronal GSH and increase GR activity, confirming the ability of Abeta to perturb neuronal GSH homeostasis. Abeta25-35 pretreatment potently increased Cu toxicity but had no effect on Fe toxicity. These studies demonstrate an important role for neuronal GSH homeostasis in selective protection against Cu toxicity, a finding with widespread implications for neurodegenerative disorders.

Amyloid beta-Peptides↗