Acupuncture of chronic headache disorders in primary care: randomised controlled trial and economic analysis.

OBJECTIVES: To determine the effects of a policy of using acupuncture, compared with a policy of avoiding acupuncture, on headache in primary care patients with chronic headache disorders. The effects of acupuncture on medication use, quality of life, resource use and days off sick in this population and the cost-effectiveness of acupuncture were also examined. DESIGN: Randomised, controlled trial. SETTING: General practices in England and Wales. PARTICIPANTS: The study included 401 patients with chronic headache disorder, predominantly migraine. INTERVENTIONS: Patients were randomly allocated to receive up to 12 acupuncture treatments over 3 months or to a control intervention offering usual care. MAIN OUTCOME MEASURES: Outcome measures included headache score; assessment of Short Form 36 (SF-36) health status and use of medication at baseline, 3 months and 12 months; assessment of use of resources every 3 months; and assessment of incremental cost per quality-adjusted life-year (QALY) gained. RESULTS: Headache score at 12 months, the primary end-point, was lower in the acupuncture group than in controls. The adjusted difference between means was 4.6. This result was robust to sensitivity analysis incorporating imputation for missing data. Patients in the acupuncture group experienced the equivalent of 22 fewer days of headache per year. SF-36 data favoured acupuncture, although differences reached significance only for physical role functioning, energy and change in health. Compared with controls, patients randomised to acupuncture used 15% less medication, made 25% fewer visits to GPs and took 15% fewer days off sick. Total costs during the 1-year period of the study were on average higher for the acupuncture group than for controls because of the acupuncture practitioners' costs. The mean health gain from acupuncture during the year of the trial was 0.021 QALYs, leading to a base-case estimate of GBP9180 per QALY gained. This result was robust to sensitivity analysis. Cost per QALY dropped substantially when the analysis incorporated likely QALY differences for the years after the trial. CONCLUSIONS: The study suggests that acupuncture leads to persisting, clinically relevant benefits for primary care patients with chronic headache, particularly migraine. It is relatively cost-effective compared with a number of other interventions provided by the NHS. Further studies could examine the duration of acupuncture effects beyond 1 year and the relative benefit to patients with migraine with compared to tension-type headache. Trials are also warranted examining the effectiveness and cost-effectiveness of acupuncture in patients with headache receiving more aggressive pharmacological management.

The management of low-flow priapism with the immediate insertion of a penile prosthesis.

OBJECTIVE: To evaluate the outcome of patients undergoing the immediate insertion of a penile prosthesis as a treatment for acute low-flow priapism. PATIENTS AND METHODS: Eight patients presenting with low-flow priapism with a mean duration of 91 h (range 32-192) were prospectively evaluated. All had failed conservative management with the instillation of alpha-adrenergic agents, and four had already undergone shunt procedures elsewhere. Immediate management consisted of the insertion of a malleable prosthesis in six patients and an inflatable prosthesis in two. One of the malleable prostheses was subsequently changed to an inflatable device. RESULTS: There were no early complications, with all patients being satisfied with the end result, and seven having sexual intercourse. One patient developed a penile deformity after surgery, cause by fibrosis around one inflatable cylinder. All patients have maintained their penile length. CONCLUSIONS: Prolonged low-flow priapism results in a variable degree of cavernosal fibrosis and a subsequent loss of penile length. The delayed insertion of a penile prosthesis can be difficult, with high complication rates. The immediate insertion of a penile prosthesis in patients with prolonged low-flow priapism is simple and maintains penile length. This should always be offered to the patient at initial presentation, as the complication rate is low and the subsequent outcome excellent.

Inter-individual variation in urothelial DNA repair gene expression in vitro.

DNA repair efficiency may play a significant role in individual susceptibility to bladder cancer, the third most common cancer in Europe. Bladder cancer arises from the urothelial cell layer which lines the urinary tract. As DNA repair gene expression levels should reflect DNA repair capacity, we investigated the expression of genes from the base excision, nucleotide excision and mismatch repair pathways in normal human urothelial (NHU) cells in vitro. RNA was extracted from six independent NHU cell lines and expression of 26 DNA repair genes was determined by ribonuclease protection assay. The results show that all the genes analysed were detected in NHU cells in vitro with a similar expression pattern in most cell lines. However, there was some variation between cell lines, with one expressing base excision repair genes very strongly, but another having weak expression of mismatch repair genes. These results suggest that DNA repair genes are constitutively expressed by NHU cells and that there is some inter-individual variation. Prospective studies are required to determine whether these differences in gene expression may play a role in susceptibility to bladder cancer.

Oxygen free radicals and the penis.

Penile erection is dependent upon vascular smooth muscle relaxation in erectile tissue and penile arteries, the principal mediator of relaxation being nitric oxide (NO). Evidence from basic scientific studies indicates that oxidative stress mediated through the superoxide radical (superoxide) and other reactive oxygen species (ROS) may be central to impaired cavernosal function in erectile dysfunction (ED). Increased inactivation of NO by superoxide results in impaired penile NO transmission and smooth muscle relaxation. Furthermore, propagation of endothelial dysfunction by ROS may result in chronic impairment of penile vascular function, a process analogous to early atherogenesis. Indeed, ED and atherosclerosis are closely linked through shared risk factors. Given our current understanding of ED pathophysiology, antioxidants may be of benefit in both the short- and long-term. Evidence supporting the paradigm of antioxidant therapy for the prevention or treatment of ED is presented herein.

Human and rabbit cavernosal smooth muscle cells express Rho-kinase.

Rho-kinase is an enzyme involved in the Ca2+-sensitizing pathway in smooth muscle cells. Inhibition of this enzyme has been recently demonstrated to elicit penile erection by relaxing cavernosal smooth muscle. We aimed to investigate the presence and activity of Rho-kinase in human cavernosal smooth muscle. Primary culture of smooth muscle cells from human and rabbit penile corpus cavernosum was developed, and cells showed characteristic myocyte morphology and alpha-actin immunoreactivity. The presence of Rho-kinase was demonstrated by indirect immunofluorescence and Western blotting. A specific inhibitor of Rho-kinase, Y-27632, inhibited in a concentration-dependent manner the kinase activity of the protein immunoprecipitated with anti-Rho-kinase antibody. These results demonstrate for the first time expression and activity of Rho-kinase in human penile cavernosal smooth muscle cells and suggest that these cells can provide a cellular model for the study of enzymes involved in Ca2+-sensitizing pathways.

Y-27632, an inhibitor of Rho-kinase, antagonizes noradrenergic contractions in the rabbit and human penile corpus cavernosum.

We have examined the effect of an inhibitor of Rho-kinase, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y-27632), on the contractions elicited by noradrenergic nerve stimulation and by phenylephrine in the human and rabbit penile corpus cavernosum. In both tissues, after treatment with scopolamine (10 microM) and N(G)-nitro-L-arginine methyl ester (L-NAME; 300 microM), electrical field stimulation (EFS) elicited noradrenergic contractions. These contractions were inhibited by Y-27632 in a concentration-dependent manner. The compound caused concentration-dependent relaxation of phenylephrine-contracted tissues, which were treated with scopolamine (10 microM), guanethidine (10 microM) and L-NAME (300 microM). These results suggest that Rho-kinase is involved in noradrenergic contractile pathway in the cavernosal smooth muscle of the penis.

Prevalence of complementary therapy use by women with breast cancer. A population-based survey.

The study measured the prevalence and costs of complementary therapy use by women diagnosed with breast cancer in the South Thames NHS region. A postal questionnaire was sent to a sample of 1023 women from the Thames Cancer Registry who had been diagnosed with breast cancer in the previous 7 years. Just over a fifth (22.4%) had consulted a complementary practitioner in the previous 12 months. Almost one third (31.5%) had done so since diagnosis. Almost pound17000 had been spent on visits in the previous year. The women using complementary medicine after diagnosis were slightly younger, more educated and more likely to have used complementary medicine before their diagnosis than non-complementary medicine users. In conclusion, significant numbers of women are visiting complementary therapists for health reasons following a breast cancer diagnosis. The out of pocket costs per user, with notable exceptions, are modest. Use of practitioners of complementary therapies following diagnosis is a significant and possibly growing phenomenon.

Analysis of gene mutations and clastogenicity following short-term treatment with azathioprine in MutaMouse.

The mutagenicity and clastogenicity of the immunosuppressive drug azathioprine (AZA), a multitissue rodent carcinogen and IARC-classified human carcinogen, was investigated using transgenic lacZ mice (MutaMouse). Male animals (n = 5 per group) were dosed with AZA (10, 50, 100 mg/kg p.o. daily for 5 days), vehicle (n = 10), or the positive control, chlorambucil (15 mg/kg i.p., n = 3), and killed 24 hr or 25 days after the last treatment. Micronucleus assays were performed with bone marrow (24-hr samples) or peripheral blood (24-hr and 25-day samples) and DNA was extracted from bone marrow and liver for gene mutation analysis at the transgenic lacZ locus. AZA induced 5.3-111.3-fold increases in %MNPCE (P < 0.01) in bone marrow compared with vehicle control, accompanied by 4.4-5. 6-fold increases in %MNRETs (P < 0.01) in peripheral blood. Chlorambucil caused a 14.5-fold increase in %MNRET and there was evidence of significant stem cell toxicity in both positive control and AZA treatment groups. By day 25, however, there was evidence of substantial recovery of the bone marrow as determined by the frequency of RET, and the %MNRET in all treatment groups was the same as the vehicle control. Analysis of lacZ MF showed 1.4-1.6-fold increases in AZA 24-hr bone marrow samples, increasing to approximately 2.0-fold above concurrent controls by day 25 (medium dose P < 0.05, high dose P < 0.01). For liver, there was a 2-fold increase in MF (P < 0.05) in the 24-hr sample at the highest dose only, and increases of 1.3-1.5-fold by day 25 in the medium (P < 0. 05) and high (P = 0.055) dose groups, respectively. The positive control, chlorambucil, induced 2-3-fold increases (P < 0.01) in mean MF in both bone marrow (25-day sample) and liver (24-hr and 25-day samples). These data confirm the clastogenicity of AZA in the mouse, and show that this compound induces gene mutations in bone marrow and liver, in vivo, at the highest dose and supports the view that AZA is a genotoxic carcinogen.

Advice given by health food shops: is it clinically safe?

OBJECTIVE: To determine whether health shop staff give specific therapeutic recommendations to someone who describes symptoms associated with serious pathology and to determine whether they refer this person to conventional medical care. DESIGN: Quantitative survey using participant observation. SETTING: Health food shops selling herbal, homeopathic or nutritional remedies in inner London. METHOD: A researcher visited 29 health food shops and claimed to be suffering from severe, daily headaches of recent onset. The researcher recorded on tape whether the health shop staff took diagnostic information; recommended any therapeutic intervention; asked about or recommended seeing a general practitioner (GP); asked about use of conventional drugs. Coding of the interactions was carried out independently by two researchers. RESULTS: Whereas all but two shops recommended a specific therapeutic intervention, less than one in four advised a GP consultation. Forty-two different interventions were recommended. There was little consistency in the advice given. CONCLUSION: Health food shops need to review the circumstances in which they should venture to provide advice and the basis on which they make any therapeutic recommendations. Shops selling over-the-counter herbal, homeopathic and health food products are a common feature of UK high streets. Such shops could be a useful source of health information and advice to their customers, but could also lead to harm, for example by delaying treatment of known benefit, if their recommendations were to be inaccurate or inappropriate.

A proposal for a two-dose/single-sample in vivo/in vitro rat hepatocyte unscheduled DNA synthesis assay.

We have developed a two dose/single-sample protocol for the in vivo/in vitro rat hepatocyte unscheduled DNA synthesis (UDS) assay. In order to enhance the effectiveness of grain detection by image analysis we found minor technical modifications to be beneficial. These included the use of 3% acetic acid in ethanol (or 4% aqueous paraformaldehyde) for hepatocyte fixation and 0.5% aqueous eosin for staining. Also, there was no correlation between cell viability (measured using the trypan blue method) and UDS response and, therefore, we do not reject animals from data analysis unless hepatocyte viability falls below 50%. Furthermore, we suggest that cell attachment is a more reliable indicator of toxicity than of cell viability. Therefore, our range-finding test has been modified to incorporate an extra animal per group so that hepatocyte cultures can be evaluated. Comparisons of a two-dose/single-sample protocol with the currently accepted single-dose/multiple-sample protocol demonstrated that the former was an acceptable alternative, in that responses with standard positive controls are very similar with both protocols. Furthermore, the two-dose protocol has clear advantages in that it uses fewer animals, resources and time and has better statistical discriminatory power. As a move away from the use of arbitrary values for determining the performance and outcome of assays, we use criteria based on confidence limits placed on historical data ranges. Where necessary, statistical analyses of concurrent data is performed using rank transformation followed by parametric analysis of the ranks; this combines the generality of a non-parametric methodology with the power and versatility of parametric analyses.

Use of the rectus abdominis myocutaneous flap in treating advanced carcinomas of the penis.

OBJECTIVE: To examine the methods used to obtain skin closure after radical surgery for carcinomas of the penis, with special reference to the rectus abdominis myocutaneous flap. PATIENTS AND METHODS: Over a 20 year period, 21 patients underwent surgery for carcinomas of the penis. Seven had advanced tumours, requiring radical surgery for complete local tumour control. The resulting wounds were repaired with scrotal skin transfer in three patients and with a rectus abdominis myocutaneous flap in the other four. RESULTS: These methods of repair were a 100% reliable, all wounds being healed within 10 days. CONCLUSIONS: Scrotal skin transfer is a simple and effective method of achieving wound closure. Where removal of the scrotum is required along with curative or palliative surgery, and after ilio-inguinal lymphadenectomy, a rectus abdominis myocutaneous flap is useful for skin closure.

Parametric analysis of rank transformed data for statistical assessment of genotoxicity data with examples from cultured mammalian cells.

The utility of rank transformation followed by parametric analysis of the ranks has been assessed for determination of the statistical significance of genotoxicity data. Both nonparametric and parametric analytical methods have defects when used to assess the significance of results from routine regulatory tests. Superficially, the rank transformation method followed by parametric analysis of ranks appears to be an ideal solution. However, we considered that such a test might suffer a substantial loss of power when used to analyse normally distributed data with very low sample replication. To test this hypothesis we took 22 data sets from five 'borderline' positive compounds in mouse lymphoma treat-and-plate assays where treatment-related increases were between 1.5- and 3-fold the control and analysed these results by Dunnett's t-test using rank transformed data and weighted, untransformed data. In theory these mouse lymphoma data should show the rank transformation system at its worst in comparison with parametric methodology using weighted data. Surprisingly, the rank transformation methodology showed no loss of power and, overall, performed more consistently than the weighted data methodology. Based on this limited number of data sets, rank transformation followed by parametric analysis of ranks seems to be an approach very suitable for genotoxicity assays in general, particularly where distributions are non-normal or of uncertain form. It combines the general applicability of non-parametric methods with the power of parametric analyses. However, the methodology still requires to be further validated in use and by computer simulation.

The Klippel-Trenaunay syndrome: a rare cause of hematuria requiring nephrectomy.

The Klippel-Trenaunay syndrome is a rare disorder in which the congenital vascular anomalies can affect the urogenital tract. Several cases of hemorrhage from the urogenital system have been reported in children with this condition. We report an upper renal tract hemorrhage in an adult, which required nephrectomy. To our knowledge this condition has not been reported previously in an adult with the Klippel-Trenaunay syndrome. We discuss the condition, and its diagnosis, treatment and relevance to the urogenital tract.

Theatre footwear: a health hazard?

Theatre footwear frequently appears to be contaminated with blood. We assessed objectively the nature and degree of contamination of theatre shoes after cleaning. Two hundred pairs of theatre shoes were randomly selected from three hospitals in South East Wales. Hospital 1 (H1), 100 pairs of shoes, Hospital 2 (H2), 40, Hospital 3 (H3), 60. They were examined for general appearance, the presence of bacterial pathogens and blood, using a leuchomalachite green assay. The majority of shoes were dirty, 63% in H1, 80% in H2, and 95% in H3. Six per cent of shoes in H1, 2.5% in H2 and 0% in H3 were contaminated with staphylococcus aureus. No shoes were contaminated with pseudomonas aeruginosa. Thirty six per cent of shoes in H1, 40% in H2 and 57% in H3 were contaminated with blood. In H1 it was possible to determine the grade of staff to whom the shoes belonged. Fifty eight per cent of consultant surgeons' shoes tested positive for blood, 50% of junior surgeons, 16% of operating department assistants and none of nurses' theatre shoes. The high level of blood contamination following cleaning may pose a potential HIV or hepatitis B risk to patients, manual shoe cleaner and surgeons. We have demonstrated that current shoe cleaning practices are ineffective. We propose methods that should eliminate this risk. Procedures will need to be defined.

Treatment of outflow tract obstruction due to benign prostatic hyperplasia with the pollen extract, cernilton. A double-blind, placebo-controlled study.

Whilst prostatectomy remains the "gold standard" for the treatment of outflow tract obstruction due to benign prostatic hyperplasia, medical treatment--if only for symptomatic relief--appears to be an attractive alternative. Most of the pharmacological agents in use block the hormonal or the sympathetic neurological pathways that influence prostate growth and function. All of these drugs are known to have side effects. Sixty patients with outflow obstruction due to benign prostatic hyperplasia (BPH) were entered into a double-blind, placebo-controlled study to evaluate the effect of a 6-month course of the pollen extract, Cernilton. There was a statistically significant subjective improvement with Cernilton (69% of the patients) compared with placebo (30%). There was a significant decrease in residual urine in the patients treated with Cernilton and in the antero-posterior (A-P) diameter of the prostate on ultrasound. However, differences in respect of flow rate and voided volume were not statistically significant. It is concluded that Cernilton has a beneficial effect in BPH and may have a place in the treatment of patients with mild or moderate symptoms of outflow obstruction.

The use of historical data for identifying biologically unimportant but statistically significant results in genotoxicity assays.

The definition of a negative result is a problem in genetic toxicology. Here we suggest that a result may be considered biologically unimportant (negative) if it falls within the limits of variation usually found in the negative controls of the particular test. To determine 'usual' variation, we have set 95% confidence limits on three indices of variation, calculated from historical values for duplicate negative control data from several genotoxicity tests. These tests showed four characteristic types of response and the appropriate index of variability was determined for each. Where there was little test-to-test variation in true mean (micronucleus test and metaphase analysis), confidence limits set on the overall distribution of negative controls were the best index of variability. In other assays (Ames, yeast and mouse lymphoma), there was considerable test-to-test variation so that differences between, or ratios of, the members of control duplicates were the preferred measure of variability. This approach can define what is biologically unimportant in terms of the test system. However, no inference can be drawn as to potential importance. Thus the main use is the removal of the positive 'label' from statistically significant results which fall within the usual range of spontaneous variation for the assay under consideration.

Treatment of chronic prostatitis and prostatodynia with pollen extract.

Chronic abacterial prostatitis and prostatodynia are notoriously difficult both to diagnose and to treat. These patients tend to have received several courses of antibiotics, antiinflammatory agents or adrenergic blockade and various other therapeutic manoeuvres with little success. The pollen extract, Cernilton, is reported to be effective in the treatment of this condition and we present the results of an open trial with Cernilton in a group of 15 patients with chronic prostatitis and prostatodynia. In 13 patients there was either complete and lasting relief of symptoms or a marked improvement; 2 patients failed to respond. Cernilton was found to be effective in the treatment of chronic prostatitis and prostatodynia. Its precise mode of action is not known, although experimental studies suggest that it has anti-inflammatory and anti-androgenic properties.

Optimization of metabolic activation for four mutagens in a bacterial, fungal and two mammalian cell mutagenesis assays.

The optimum concentrations of Aroclor-induced rat liver S9 microsomal fraction for the mutagenic activity of the four standard mutagens 2-aminofluorene (2-AF), acriflavine (ACR), benzo[a]pyrene (BP) and cyclophosphamide (CP) were determined in four mutation assays. The four assays were the Ames test using Salmonella typhimurium strain TA100, cycloheximide resistance in the yeast Saccharomyces cerevisiae, the mouse lymphoma TK assay and the human peripheral lymphocyte cytogenetic assay. BP was the only mutagen to be most active at comparable S9 concentrations, of approximately 1%, for all four assays. The optimum S9 concentrations for each of the remaining three mutagens varied substantially between the four assays. ACR was a potent direct-acting mutagen in both mammalian cell assays. The mouse lymphoma TK assay results showed similar optimal values of 1.5% S9 or below for each of the four test agents. The assay with the largest variation of optimal S9 values for the four mutagens was the Ames test in strain TA100, although it also had the widest peaks of activity over the range of S9 concentrations tested. It is likely that the diversity of findings is due to a variety of metabolites affecting the different genetic endpoints that are measured in these assays. Thus from these results it is not possible for bacterial optimization data to be related to other routine in vitro systems. The use of more than one concentration of S9 would contribute useful information.