Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome.

The aetiology of chronic fatigue syndrome (CFS) remains controversial and a number of hypotheses have been put forward to explain it. Research into the condition is hindered by the considerable heterogeneity seen across patients but several reports have highlighted disturbances to cholinergic mechanisms in terms of central nervous system activity, neuromuscular function and autoantibodies to muscarinic cholinergic receptors. This paper examines an altogether separate function for acetylcholine and that is its role as an important and generalized vasodilator. Most diseases are accompanied by a blunted response to acetylcholine but the opposite is true for CFS. Such sensitivity is normally associated with physical training so the finding in CFS is anomalous and may well be relevant to vascular symptoms that characterise many patients. There are several mechanisms that might lead to ACh endothelial sensitivity in CFS patients and various experiments have been designed to unravel the enigma. These are reported here.

Immunotherapy with Mycobacterium vaccae and peripheral blood flow in long-treated leprosy patients, a randomised, placebo-controlled trial.

OBJECTIVE: to evaluate immunotherapy as a means of improving peripheral blood flow in chronic leprosy patients. DESIGN: this was a double-blind, randomised, placebo-controlled, clinical trial. MATERIALS: heat-killed Mycobacterium vaccae 1mg plus 0.02 microg Tuberculin protein per 0.1 ml dose in borate buffer, with saline as placebo. Those studied were 92 long-treated residents of a leprosy centre in Iran, 10 of their healthy children and 10 staff members. Evaluation employed the Perimed PF2, Laser-Doppler Flowmeter, a platinum skin thermistor, and a thermal sensibility tester. METHODS: single intradermal injections of test or placebo were given to 103 patients 18 months before the blinded evaluation. Fingerpulp blood flux was measured in controlled conditions and vasomotor reflexes and skin sensation to touch, pain and heat were evaluated in 45 and 47 patients in the placebo and M. vaccae groups, respectively, and in 20 healthy control persons. RESULTS: Laser-Doppler flux, skin temperature, vasomotor reflexes and sensation were impaired in leprosy patients. Immunotherapy improved (p < 0.05) Laser-Doppler flux, skin temperature and temperature sensation. CONCLUSIONS: immunotherapy, given 18 months earlier, significantly improved blood flow and temperature sensation, in fully-treated, chronic, leprosy patients. The same principles might be employed in other conditions of reduced peripheral blood flow.

Spiritual healing as a therapy for chronic pain: a randomized, clinical trial.

Spiritual healing is a popular complementary and alternative therapy; in the UK almost 13000 members are registered in nine separate healing organisations. The present randomized clinical trial was designed to investigate the efficacy of healing in the treatment of chronic pain. One hundred and twenty patients suffering from chronic pain, predominantly of neuropathic and nociceptive origin resistant to conventional treatments, were recruited from a Pain Management Clinic. The trial had two parts: face-to-face healing or simulated face-to-face healing for 30 min per week for 8 weeks (part I); and distant healing or no healing for 30 min per week for 8 weeks (part II). The McGill Pain Questionnaire was pre-defined as the primary outcome measure, and sample size was calculated to detect a difference of 8 units on the total pain rating index of this instrument after 8 weeks of healing. VASs for pain, SF36, HAD scale, MYMOP and patient subjective experiences at week 8 were employed as secondary outcome measures. Data from all patients who reached the pre-defined mid-point of 4 weeks (50 subjects in part I and 55 subjects in part II) were included in the analysis. Two baseline measurements of outcome measures were made, 3 weeks apart, and no significant differences were observed between them. After eight sessions there were significant decreases from baseline in McGill Pain Questionnaire total pain rating index score for both groups in part I and for the control group in part II. However, there were no statistically significant differences between healing and control groups in either part. In part I the primary outcome measure decreased from 32.8 (95% CI 28.5-37.0) to 23.3 (16.8-29.7) in the healing group and from 33.1 (27.2-38.9) to 26.1 (19.3-32.9) in the simulated healing group. In part II it changed from 29.6 (24.8-34.4) to 24.0 (18.7-29.4) in the distant healing group and from 31.0 (25.8-36.2) to 21.0 (15.7-26.2) in the no healing group. Subjects in healing groups in both parts I and II reported significantly more 'unusual experiences' during the sessions, but the clinical relevance of this is unclear. It was concluded that a specific effect of face-to-face or distant healing on chronic pain could not be demonstrated over eight treatment sessions in these patients.

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.

Location bias in controlled clinical trials of complementary/alternative therapies.

UNLABELLED: To systematically investigate location bias of controlled clinical trials in complementary/alternative medicine (CAM). METHODS: Literature searches were performed to identify systematic reviews and meta-analyses, which were used to retrieve controlled clinical trials. Trials were categorised by whether they appeared in CAM-journals or mainstream medical (MM)-journals, and by their direction of outcome, methodological quality, and sample size. RESULTS: 351 trials were analysed. A predominance of positive trials was seen in non-impact factor CAM- and MM-journals, (58) / (78) (74%) and (76) / (102) (75%) respectively, and also in low impact factor CAM- and MM-journals. In high impact factor MM-journals there were equal numbers of positive and negative trials, a distribution significantly (P < 0.05) different from all other journal categories. Quality scores were significantly lower for positive than negative trials in non-impact factor CAM-journals (P < 0.02). A similar trend was seen in low-impact factor CAM journals, but not to a level of significance (P = 0.06). There were no significant differences between quality scores of positive and negative trials published in MM-journals, except for high impact factor journals, in which positive trials had significantly lower scores than negative trials (P = 0.048). There was no difference between positive and negative trials in any category in terms of sample size. CONCLUSION: More positive than negative trials of complementary therapies are published, except in high-impact factor MM-journals. In non-impact factor CAM-journals positive studies were of poorer methodological quality than the corresponding negative studies. This was not the case in MM-journals which published on a wider range of therapies, except in those with high impact factors. Thus location of trials in terms of journal type and impact factor should be taken into account when the literature on complementary therapies is being examined.

Healing as a therapy for human disease: a systematic review.

OBJECTIVE: To assess, from published clinical trials, the evidence for the use of healing as a complementary medical intervention in human disease. DESIGN: Limited to studies involving random assignment to a treatment group consisting of "healing," broadly defined, or to a concurrent control group. All randomized trials published up to the year 2000, were identified from MEDLINE, CINAHL, BIDS-EMBASE, the CISCOM complementary medicine databases and from bibliographic references of published articles. Copies of all published studies were obtained, data were extracted, and methodological quality (Jadad) scores were derived where possible. RESULTS: Fifty-nine randomized clinical trials (RCTs) were found comparing healing with a control intervention on human participants. In 37 of these, healing was used for existing diseases or symptoms (22 existed as fully accessible published reports, 10 as dissertation abstracts only, and 5 as "preliminary" investigations with limited evidential value). The 22 full trials (10 reporting a "significant" effect of healing compared with control) constitute an extremely heterogeneous group, varying greatly in the method and duration of healing; the medical condition treated; the outcome measure employed; and the control intervention used. Many trials had a number of methodological shortcomings, including small sample sizes, and were inadequately reported. Only 8 studies (5 with a significant outcome for healing) had a maximum methodological quality score of 5, and in 10 studies this score was 3 or less. Two trials-both large scale and methodologically sound-were replicates, and each found a significant beneficial effect of intercessory prayer on the clinical progress of cardiac patients. Eleven of the 15 dissertation abstracts and pilot studies reported nonsignificant results for healing compared with control, a finding that probably reflects the relatively small sample sizes and the likelihood of type II errors. The significant heterogeneity found in this group of trials makes categorization problematic and inhibits the pooling of results by meta-analysis or similar techniques to obtain a global estimate of the "treatment effect" of healing. CONCLUSIONS: No firm conclusions about the efficacy or inefficacy of healing can be drawn from this diverse group of RCTs. Given the current emphasis on evidence-based medicine, future investigations should be adequately powered, appropriately controlled, and properly described. These future investigations would most usefully consist of: (1) pragmatic trials of healing for undifferentiated conditions on patients based in general practice and (2) larger RCTs of distant healing on large numbers of patients with well-defined measurable illness.

A randomized trial of distant healing for skin warts.

PURPOSE: Distant healing, a treatment that is transmitted by a healer to a patient at another location, is widely used, although good scientific evidence of its efficacy is sparse. This trial was aimed at assessing the efficacy of one form of distant healing on common skin warts. SUBJECTS AND METHODS: A total of 84 patients with warts were randomly assigned either to a group that received 6 weeks of distant healing by one of 10 experienced healers or to a control group that received a similar preliminary assessment but no distant healing. The primary outcomes were the number of warts and their mean size at the end of the treatment period. Secondary outcomes were the change in Hospital Anxiety and Depression Scale and patients' subjective experiences. Both the patients and the evaluator were blinded to group assignment. RESULTS: The baseline characteristics of the patients were similar in the distant healing (n = 41) and control groups (n = 43). The mean number and size of warts per person did not change significantly during the study. The number of warts increased by 0.2 in the healing group and decreased by 1.1 in the control group (difference [healing to control] = -1.3; 95% confidence interval = -1.0 to 3.6, P = 0.25). Six patients in the distant healing group and 8 in the control group reported a subjective improvement (P = 0.63). There were no significant between-group differences in the depression and anxiety scores. CONCLUSION: Distant healing from experienced healers had no effect on the number or size of patients' warts.

Articles on complementary medicine in the mainstream medical literature: an investigation of MEDLINE, 1966 through 1996.

OBJECTIVE: To investigate the growth of interest, if any, in complementary or alternative medicine by the professional scientific community from the number of MEDLINE-listed and clinical trial-type articles for January 1, 1966, through December 31, 1996. METHODS: Systematic literature searches of the MEDLINE database, using the expanded terms "alternative medicine," "traditional medicine," "acupuncture," "homeopathy," and "chiropractic," were conducted in January 1998 to evaluate the number of all articles. The number of clinical trial-type articles on the above was obtained by conducting searches for those indexed as 1 or more of the following publication types: clinical trial; clinical trial phase 1, 2, 3, or 4; controlled clinical trial; metaanalysis; randomized controlled trial; and limited to "human" trials only. RESULTS: Articles indexed as alternative medicine formed a small proportion (0.4%) of the total number of MEDLINE-listed articles throughout the period studied. From 1966 through 1996, the total number of articles listed in MEDLINE rose significantly to a peak of 400000 additions per annum in 1996 (r = 0.97; P<.001). By contrast, the number of articles indexed under alternative medicine rose progressively only from 1972 through 1986 and since then has been relatively stable at around 1500 additions per annum. For this period, the proportion of clinical trial-type alternative medicine articles was low (mean, 2.1% per annum) but increased significantly from 1987 through 1996, reaching around 10% of the total in 1996 (r = 0.79; P<.001). Patterns of growth in the number of publications for individual therapies have varied during the period studied, and clinical trial-type articles form only a small part of any increase. CONCLUSIONS: Interest in and awareness of complementary medicine among orthodox health care professionals has increased in the past 30 years. The increase in the number and proportion of reports of clinical trials indicates an increasing level of original research activity in complementary medicine and suggests a trend toward an evidence-based approach in this discipline. The cumulative number of clinical trial-type articles is small, however, and more high-quality original research in complementary medicine is required.

Randomized, double-blind trial of chitosan for body weight reduction.

BACKGROUND: Overweight and obesity is a prevalent and costly threat to public health. Compelling evidence links overweight and obesity with serious disorders such as cardiovascular diseases and diabetes. Dietary regimen are notoriously burdened with poor compliance. Chitosan is promoted in the US and other countries as an oral remedy to reduce fat absorption and has now been incorporated as a major constituent into several over-the-counter remedies. The primary aim of this study is to investigate the clinical effectiveness of oral chitosan for body weight reduction. METHODS: Thirty-four overweight volunteers were included in a randomized placebo-controlled double-blind trial. Subjects were assigned to receive either four capsules of chitosan or indistinguishable placebo twice daily for 28 consecutive days. Measurements were taken at baseline, after 14 and 28d of treatment. Subjects maintained their normal diet and documented the type and amount of food consumed. Adverse effects were assessed and compliance monitored. RESULTS: Data from 30 subjects were entered into an intention-to-treat analysis. After four weeks of treatment, body mass index, serum cholesterol, triglycerides, vitamin A, D, E and beta-carotene were not significantly different in subjects receiving chitosan compared to those receiving placebo. Vitamin K was significantly increased after four weeks in the chitosan group compared with placebo (P<0.05). Compliance was 91.5% and 96.0% for chitosan and placebo groups respectively. CONCLUSION: The above data suggest that chitosan in the administered dosage, without dietary alterations, does not reduce body weight in overweight subjects. No serious adverse effects were reported.

Different standards for reporting ADRs to herbal remedies and conventional OTC medicines: face-to-face interviews with 515 users of herbal remedies.

AIMS: To determine whether adverse drug reactions (ADRs) to herbal remedies would be reported differently from similar ADRs to conventional over-the-counter (OTC) medicines by herbal-remedy users. METHODS: Face-to-face interviews (using a structured questionnaire) with 515 users of herbal remedies were conducted in six pharmacy stores and six healthfood stores in the UK. The questionnaire focused on the likely course of action taken by herbal-remedy users after experiencing an ADR associated with a conventional OTC medicine and a herbal remedy. RESULTS: Following a 'serious' suspected ADR, 156 respondents (30.3%) would consult their GP irrespective of whether the ADR was associated with the use of a herbal remedy or a conventional OTC medicine, whereas 221 respondents (42.9%) would not consult their GP for a serious ADR associated with either type of preparation. One hundred and thirty-four respondents (26.0%) would consult their GP for a serious ADR to a conventional OTC medicine, but not for a similar ADR to a herbal remedy, whereas four respondents (0.8%) would consult their GP for a serious ADR to a herbal remedy, but not for a similar ADR to a conventional OTC medicine. Similar differences were found in attitudes towards reporting 'minor' suspected ADRs. CONCLUSIONS: Consumers of herbal remedies would act differently with regard to reporting an ADR (serious or minor) to their GP depending on whether it was associated with a herbal remedy or a conventional OTC medicine. This has implications for herbal pharmacovigilance, particularly given the increasing use of OTC herbal remedies. The finding that a high proportion of respondents would not consult their GP or pharmacist following ADRs to conventional OTC medicines is also of concern.

Protective effects of carnosine against malondialdehyde-induced toxicity towards cultured rat brain endothelial cells.

Malondialdehyde (MDA) is a deleterious end-product of lipid peroxidation. The naturally-occurring dipeptide carnosine (beta-alanyl-L-histidine) is found in brain and innervated tissues at concentrations up to 20 mM. Recent studies have shown that carnosine can protect proteins against cross-linking mediated by aldehyde-containing sugars and glycolytic intermediates. Here we have investigated whether carnosine is protective against malondialdehyde-induced protein damage and cellular toxicity. The results show that carnosine can (1) protect cultured rat brain endothelial cells against MDA-induced toxicity and (2) inhibit MDA-induced protein modification (formation of cross-links and carbonyl groups).

Laser Doppler perfusion imaging of skin blood flow using red and near-infrared sources.

At present, scanning laser Doppler imaging uses a 633-nm helium-neon laser (RED) as the only light source, but this restricts its ability to measure blood flow (i) at darkly pigmented skin and (ii) from deeper or subdermal structures. Because near-infrared (NIR) light is known to penetrate deeper into tissue and to be less absorbed than RED, two imagers were adapted to include a NIR laser diode source (one of 830 nm for UK studies; one of 780 nm for leprosy field trials) in parallel with the existing RED source. In human hands representing a range of skin pigmentations, RED scans were unobtainable at the darkest areas of skin, but intact NIR scans could be collected in all cases. In experiments at the rat knee and the dorsal human hand, NIR and RED values were similar on normal skin. Over underlying vessels, however, NIR values greatly exceeded RED values, an effect abolished by occlusion. Similarly, in patients with leprosy and in healthy controls in Spain, fingerpulp NIR values exceeded RED values to the greatest degree when thermoregulatory flow was highest, i.e., when the deeper-lying arteriovenous anastomoses were open. Over areas of experimental inflammation, NIR gave higher values and also exhibited a greater degree of spatial heterogeneity than RED. We conclude that some current limitations of laser Doppler imaging technology can be overcome by the use of NIR laser diode sources.

Laser Doppler perfusion imaging of proximal interphalangeal joints in patients with rheumatoid arthritis.

OBJECTIVE: A non-invasive imaging technique (laser Doppler perfusion imaging-LDI) based on measurement of backscattered Doppler-broadened near infra-red laser radiation was used to provide two-dimensional images of perfusion over the proximal interphalangeal (PIP) joints of a group of normal subjects compared to a group of patients with rheumatoid arthritis (RA). RESULTS: Some PIP joints of the RA group showed areas of increased perfusion whereas normal subjects showed much less variation in perfusion between joints. These hyperaemic areas arose from the underlying joint, as scans taken with a less penetrating red laser did not show such areas. CONCLUSION: Apart from its obvious dermatological uses, LDI could be employed to image hyperaemia associated with a variety of inflammatory conditions affecting subcutaneous structures.

Sympathetic vasomotor dysfunction in leprosy patients: comparison with electrophysiological measurement and qualitative sensation testing.

Testing of skin vasomotor reflexes (VRs) by laser Doppler flowmetry (LDF) is now a recognised method of measuring peripheral dysautonomia. To assess its specificity as an indicator of impairment to unmyelinated autonomic fibres, VR testing at the fingerpulp was compared with standard qualitative sensation (QST) and with sensory electrophysiological (SNVC) measurements in 39 Iranian leprosy patients. There was a significant relationship between VR and SNCV values (but not QST): these were jointly measurable in 38.5% of fingers, and jointly absent in 35.3% of fingers which also showed significantly reduced LDF perfusion and skin temperatures. However, in 10.3% of fingers, predominantly index and otherwise apparently healthy, VRs were absent but SNCV present, suggesting early sub-clinical autonomic impairment. In a further 16% of fingers, predominantly ulnar and with poor microcirculation, intact (though impaired) VRs could be recorded despite the absence of SNCV responses, suggesting sparing or regeneration of these fibres. This evidence suggests that where there is heterogeneity of nerve damage a combination of VR and electrophysiological testing can indicate the functional status of distinct fibre types.

Perfusión Doppler con laser ionfrarrojo y cercano al rojo en manos de pacientes de lepra en España

Se ha empleado una nueva técnica de perfusión Doppler con láser a las longitudes de onda, rojo (663 nm) y cercano al rojo (780 nm) para obtener imágenes del flçujo sanguíneo de los dedos de pacientes de lepra y vonluntarios sanos en el Sanatorio de Fontilles. La técnica permite medir el flujo en las estructuras dérmicas y subdérmicas y podría ser útil para localizar deterioro microcirculatorio. Se pueden medir niveles muy elevados de riego en la pulpa de los dedos a la temperatura ambiente de Fontilles (23-6.ºC), ya debido a una abundante anastomosis arteriovenosa, desempeñan un papel termorregulador. Sin embargo en muchos pacientes, incluyendo los que no presentan un compromiso clínico en las manos, el riego sanguíneo y temperaturas cutáneas estaban significativamente reducidas, confirmando hallazgos previos en pacientes de lepra en India e Iran. Los hallazgos preliminares indican que estas disminuciones de riego no están localizadas a una región anatómica pero pueden afectar todos los dedos evaluados de un individuo sugiriendo un deterioro más generalizado de la función termoregulatoria. Mientras que esto puede implicar un mecanismo central, también se podría explicar por una vasculitis sub-cutánea continua de los dedos. Nuestros trabajos anteriores indicando una asociación entre pérdida de sensación y reducción del flujo sanguíneo, también sugieren factopres neurales como una depleción de neuropéptidos sensorilaes.

Effects of treatment on the histopathology of leprosy.

AIMS: To identify the histological changes in leprosy skin lesions over the first few weeks after the start of leprosy treatment and to examine their relationship to reversal reaction. METHODS: Sequential skin biopsy during treatment with multiple drug therapy. In this study, a series of 28 patients was studied, from whom two or more biopsies were taken at two week intervals. Fourteen patients had paucibacillary leprosy (PBL) and 14 had multibacillary leprosy (MBL). RESULTS: In most cases, granuloma fraction and bacterial index fell during treatment, the bacterial index being less sensitive than the granuloma fraction. Since the biopsies were fixed in buffered formalin and processed through to paraffin wax, little immunohistochemistry was feasible. However, there was strong evidence of immune activation, with increased expression of HLA-DR in the granulomas of MBL and PBL cases: the epidermis also expressed HLA-DR in several patients. Such changes may reflect gamma IFN production from granuloma lymphocytes. Patients with reversal reaction often showed HLA-DR expression on admission which decreased with corticosteroid treatment. CONCLUSIONS: The results suggest that activation of cell mediated immunity in leprosy lesions occurs during treatment with multiple drug therapy and may not be restricted to those with clinical evidence of reversal reaction.