Radiotherapy for oral cancer decreases the cutaneous expression of host defence peptides.

INTRODUCTION: Bacterial resistance against antibiotics has become an increasing challenge in the treatment of cutaneous infections. Consequences can be severe, especially in infected wounds following previous local radiotherapy. Certain endogenous peptide antibiotics, the host defence peptides (HDPs), exhibit broad-spectrum antimicrobial activity and promote wound healing. Their use as supplements to conventional antibiotics is a current topic of discussion; however, knowledge of their quantities in healthy and compromised tissue is a prerequisite for such discussion. To date, no data concerning HDP quantities in irradiated skin are available. METHODS: Expression profiles of the genes encoding HDPs, namely human beta-defensin-1 (DEFB1, hBD-1), beta-defensin-2 (DEFB4A, hBD-2), beta-defensin-3 (DEFB103, hBD-3) and S100A7, were assessed in samples of non-irradiated and irradiated neck. RESULTS: A reduction in the expression of all of the examined genes was observed in irradiated skin when compared with non-irradiated skin (statistically significant in the case of S100A7, P = 0.013). Immunohistochemistry revealed differences in HDP distribution with respect to the epithelial layers. CONCLUSION: The study demonstrates a significant reduction in HDP gene expression in neck skin as a result of radiotherapy. These findings might represent a starting point for novel treatments of cutaneous infections in irradiated patients, such as topical supplementation of synthetic HDP.

New skeletal tuberculosis cases in past populations from Western Hungary (Transdanubia).

The distribution, antiquity and epidemiology of tuberculosis (TB) have previously been studied in osteoarchaeological material in the eastern part of Hungary, mainly on the Great Plain. The purpose of this study is to map the occurrence of skeletal TB in different centuries in the western part of Hungary, Transdanubia, and to present new cases we have found. Palaeopathological analysis was carried out using macroscopic observation supported by radiographic and molecular methods. A large human osteoarchaeological sample (n=5684) from Transdanubian archaeological sites ranging from the 2nd to the 18th centuries served as a source of material. Spinal TB was observed in seven individuals (in three specimens with Pott's disease two of which also had cold abscess) and hip TB was assumed in one case. The results of DNA for Mycobacterium tuberculosis were positive in seven of the eight cases identified by paleopathology, and negative in the assumed case of hip TB. However, the molecular results are consistent with highly fragmented DNA, which limited further analysis. Based on the present study and previously published cases, osteotuberculosis was found in Transdanubia mainly during the 9th-13th centuries. However, there are no signs of TB in many other 9th-13th century sites, even in those that lie geographically close to those where osteotuberculous cases were found. This may be due to a true absence of TB caused by the different living conditions, way of life, or origin of these populations. An alternative explanation is that TB was present in some individuals with no typical paleopathology, but that death occurred before skeletal morphological features could develop.

First experiences with pudendal nerve stimulation in fecal incontinence: a technical report.

Sacral nerve stimulation (SNS) is an established treatment for refractory lower urinary tract and bowel dysfunction. In some urological patients, SNS does not have satisfactory results. Pudendal nerve stimulation (PNS) has recently been proposed for these patients and successfully tested. Given the sometimes unsatisfactory results after SNS in fecal incontinence (FI), we tested PNS on patients suffering from FI. We used the device and implantation technique described by Spinelli et al. By making a slight change in the device, we developed a quick and easy-to-use method for successful PNS implantation, based on electrophysiological response. We present the results of a feasibility study, in which we tested the effectiveness of PNS with our modified implantation technique on 2 patients, with very satisfactory early results in a 4-month follow-up.

Cannabis use in patients with multiple sclerosis.

INTRODUCTION: Little is known about the extent and patterns of cannabis use in people with multiple sclerosis (MS). METHODS: MS patients attending neurology outpatient clinics at two hospitals in London and one in Kent, UK completed a questionnaire. RESULTS: Questionnaires were completed by 254/337 (75%) MS patients. Forty-three per cent had used cannabis at some stage (ever users). Of these, 68% (75/110) had used cannabis to alleviate symptoms of MS (MS-related cannabis use). Forty-six (18%) had used cannabis in the last month (current users), of whom 12% (31/254) had used it for symptom relief. Being married or having a long-term partner, tobacco smokers and increasing disability were independent risk factors for MS-related cannabis use. Compared to patients who could walk unaided, cannabis use was more likely in those who were chair-bound (adjusted OR 2.47; 1.10-5.56) or only able to walk with an aid (adjusted OR 1.56; 0.90-3.60). Pain and spasms were common reasons for cannabis use. Seventy-one per cent of individuals who had never used cannabis said they would try the drug if it were available on prescription. CONCLUSION: A large proportion of MS patients had tried cannabis for symptom control, however current use was small. A subgroup with greater disability appears to derive some symptomatic benefit.

Non-prescribed drug use during methadone treatment by clinic- and community-based patients.

We investigated the efficacy of methadone maintenance treatment in clinic-based (n = 10) and community-based (n = 10) patients by studying the relationships between dose, plasma concentrations of methadone and non-prescribed drug-use using logistic regression. We found that clinic-based patients had significantly reduced odds of having a urine sample test positive for illicit drugs when compared to community-based patients (OR = 0.20; 95% confidence interval 0.10-0.38: p < 0.001). There was no relationship between either methadone dose or plasma methadone concentration and testing positive for non-prescribed drugs (including cocaine, cannabis, amphetamine, ecstasy, benzodiazepines). We looked specifically at the misuse of opiate drugs. Location was again important and clinic-based patients had significantly reduced odds of having a urine sample test positive for opiate drugs (OR = 0.36, 95% confidence interval 0.18-0.71: p approximately 0.004). Opiate drug use in our patients was also significantly related to plasma methadone concentration, increasing noticeably when the drug concentration < 0.48 nmol/L (p approximately 0.04). We found no relationship between methadone dose and odds of having a positive urine drug test in either clinic- or community-based patients.

Effects of cyclosporin A on resident and passenger immune cells of normal human skin and UV-induced erythema reactions.

Cyclosporin A (CyA) has proved effective in various dermatological diseases, but its mechanisms of action within the skin are still ill-defined. In order to characterize more clearly the cellular targets of CyA we examined its effects on skin immune cells in normal and UVB- and PUVA-irradiated skin by means of a three-step immunoperoxidase reaction and immunofluorescence double-labelling technique. The CyA-induced depletion of epidermal Langerhans cells equals that seen with UVB or PUVA alone. CyA alone has no effect on the number and distribution of dermal cells. CyA modulates the UV irradiation-induced changes by: (i) inhibiting the UVB- and PUVA-induced ICAM-1 expression by keratinocytes and (ii) suppressing the PUVA-induced upregulation of CD11a expression by macrophages (72 +/- 12% of Ki-M8+ macrophages express CD11a with PUVA, compared with 20 +/- 5% with CyA + PUVA, P < 0.001). Neither treatment affected ICAM-1 expression by endothelial cells. In addition, CyA increases PUVA minimal phototoxicity dose from 10 +/- 2.6 J/cm2 (PUVA alone) to 15.3 +/- 3.1 J/cm2 (CyA + PUVA), (P < 0.001). In conclusion, the effects of CyA on the skin include a down-modulation of the PUVA-erythema reaction, associated with a direct or indirect modulation of adhesion molecule expression.

Cyclosporin A suppresses ICAM-1 expression by papillary endothelium in healing psoriatic plaques.

To analyze the mode of action of Cyclosporin A (CsA) in psoriasis, we examined the phenotypic profile of resident and passenger skin cells in seven psoriatic patients before and after 2 weeks of CsA treatment using a large panel of monoclonal antibodies in a three-step immunoperoxidase technique. For comparison, skin biopsies from psoriatic patients receiving psoralen + UVA (PUVA) therapy were examined. Although both treatment protocols were equally effective in inducing resolution of psoriatic lesions, the phenotypic changes induced by CsA differed greatly from those seen after PUVA. In CsA-treated patients there was a dramatic reduction in the ICAM-1 expression by papillary endothelial cells, but density, pattern, and phenotype of infiltrating inflammatory cells remained essentially unchanged. In contrast, PUVA therapy had no visible effect on ICAM-1 expression by papillary endothelial cells, but resulted in a significant reduction of the hemopoietic resident and infiltrating mononuclear cells within the epidermis. These results favor, but do not prove, the assumption that the CsA regimen chosen in this study exerts its anti-psoriatic effect primarily at the level of the keratinocyte, i.e., by inhibiting events leading to keratinocyte proliferation as well as by interfering with the secretion of mediators responsible for ICAM-1 expression by papillary endothelial cells.

Cyclosporin A in combination with photochemotherapy (PUVA) in the treatment of psoriasis.

Forty patients with relapsing plaque psoriasis involving more than 20% body surface were treated either with cyclosporin A (CyA) plus PUVA or the retinoid etretinate plus PUVA (RePUVA). They initially received either CyA (2 weeks) or etretinate (1 week) alone and then PUVA was given concomitantly until complete remission. The patients were monitored over a period of 6 months and any relapse recorded. With each combined treatment regimen, CyA plus PUVA and RePUVA, the patients cleared within comparable periods of time (mean treatment period of 5.3 vs. 4.7 weeks after initiation of therapy and 3.3 vs. 3.7 weeks after initiation of PUVA). However, the cumulative UVA dose required for clearance (110.9 J/cm2 vs. 62.1 J/cm2 (P less than 0.05)) and the incidence of severe and early relapses were significantly higher in the CyA cohort. Within 6 months severe relapses had occurred in 58% of CyA plus PUVA but only in 15% of RePUVA-treated patients (P less than 0.001). This suggests that the CyA plus PUVA regimen as performed in this study is less effective than RePUVA.

Photochemotherapy improves chronic cutaneous graft-versus-host disease.

We have used oral psoralen photochemotherapy (PUVA) to treat four patients with chronic graft-versus-host disease of the skin, oral mucosa, and liver, who had responded only partially to long-term immunosuppressive therapy (prednisolone, cyclosporine, azathioprine). PUVA therapy was delivered to the entire skin but not to the oral mucosa, and immunosuppressive therapy was continued in all patients. Two patients' skin lesions improved considerably; the oral lesions healed and did not recur in one. Immunosuppressive therapy could be reduced in these two patients. One patient with sicca signs did not improve. One patient had to interrupt PUVA therapy because of side effects attributed to 8-methoxypsoralen (nausea and vomiting). No flare of acute cutaneous graft-versus-host disease was noted during PUVA therapy. Chronic graft-versus-host disease of the liver did not improve in any patient.

Side-effects of psoralen photochemotherapy (PUVA).

Although psoralen photochemotherapy (PUVA) is one of the most effective forms of therapy for psoriasis, the risk of potential long-term side-effects is, as yet, not clearly determined. Chronic degenerative and pigmentary skin changes similar to those of chronic solar exposure occur after long-term PUVA treatment; PUVA also causes non-melanoma skin cancers in man, although there is, as yet, no consensus as to what cumulative phototoxic PUVA dose is carcinogenic. Long-term multicentre studies from the U.S.A. indicate a definite risk of squamous cell carcinoma for long-term PUVA-treated patients, whereas European studies reveal no overall increase in skin cancers in similar patients except for those exposed to other carcinogens. Assignment to PUVA should be based on the risk:benefit ratio for the individual patient. Careful patient selection is therefore mandatory and should be limited to those who can be monitored and controlled by informed, competent and conscientious physicians.

Treatment of psoriatic arthritis by extracorporeal photochemotherapy.

Five patients with long-standing seronegative arthritis resistant to conventional therapy and who also had psoriasis of the skin were treated with photopheresis. This mode of treatment combines a lymphocyte-enrichment procedure with 8-methoxypsoralen-photochemotherapy. There was a marked in vitro effect on treated lymphocytes, with a reduction of viability, proliferation and mitogen response. There was a slight to moderate clinical improvement in four of the five patients with regard to the strength of grip, swelling, pain, morning stiffness, the dosage of non-steroidal anti-rheumatic drugs and the radiographical changes. The skin lesions did not respond to photopheresis. Short-term side-effects were minimal and consisted of a temporary sensitivity of the eyes to light and signs of circulatory dysregulation immediately after treatment. This experimental therapy has some measurable but not dramatic effect in improving psoriatic arthropathy.

Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results.

Systemically disseminated cutaneous T-cell lymphoma is generally resistant to chemotherapy and radiotherapy. We tested a treatment involving the extracorporeal photoactivation of biologically inert methoxsalen (8-methoxypsoralen) by ultraviolet A energy to a form that covalently cross-links DNA. After oral administration of methoxsalen, a lymphocyte-enriched blood fraction was exposed to ultraviolet A (1 to 2 J per square centimeter) and then returned to the patient. The combination of ultraviolet A and methoxsalen caused an 88 +/- 5 percent loss of viability of target lymphocytes, whereas the drug alone was inactive. Twenty-seven of 37 patients with otherwise resistant cutaneous T-cell lymphoma responded to the treatment, with an average 64 percent decrease in cutaneous involvement after 22 +/- 10 weeks (mean +/- SD). The responding group included 8 of 10 patients with lymph-node involvement, 24 of 29 with exfoliative erythroderma, and 20 of 28 whose disease was resistant to standard chemotherapy. Side effects that often occur with standard chemotherapy, such as bone marrow suppression, gastrointestinal erosions, and hair loss, did not occur. Although the mechanism of the beneficial effect is uncertain, an immune reaction to the infused damaged cells may have restricted the activity of the abnormal T cells. This preliminary study suggests that extracorporeal photochemotherapy is a promising treatment for widespread cutaneous T-cell lymphoma.

Skin tumors in the European PUVA Study. Eight-year follow-up of 1,643 patients treated with PUVA for psoriasis.

In the continuation of the European PUVA Study, 1,643 patients of the original cohort of 3,175 patients enrolled in this prospective study were reevaluated for skin tumors after an average observation period of 96 months. Thirty-six patients with a total of seventy-one tumors (forty squamous cell carcinomas, twenty-three basal cell carcinomas) were observed. In contrast to the U.S. sixteen-center study, we were unable to demonstrate a clinically relevant increase in the risk of tumors induced by psoralens with ultraviolet A (PUVA), and we also failed to show a clear relationship between PUVA exposure and tumor development. Almost all patients with tumors had been exposed to various carcinogens before the initiation of PUVA. No tumors were detected in patients without such prior treatment, although 10% of the patients had received more than 3,000 joules/cm2 total cumulative phototoxic PUVA dose during the observation period. The discrepancy between the results of the U.S. study and our findings may partly be explained by a variety of factors such as a different treatment approach, a different attitude toward sun exposure, and the overall lower incidence of skin cancer in the European population.

Nonmelanoma skin tumors in long-term photochemotherapy treatment of psoriasis. An 8-year follow-up study.

Two hundred ninety-seven long-term photochemotherapy (PUVA)-treated patients from an original cohort of 418 subjects reported in 1980 were reevaluated in a second follow-up in order to determine the risk of tumor development under long-term PUVA. Within an observation period of up to 8 years (mean, 63.1 months) six patients with squamous cell carcinomas and three with basal cell carcinomas were observed. Eight of the nine tumor patients had been exposed to potential carcinogens such as arsenic and/or ionizing radiation prior to PUVA treatment. Five with squamous cell carcinomas were skin type I or II; in four of the six patients with squamous cell carcinomas the tumors were located on unexposed skin areas. The mean cumulative ultraviolet A (UVA) dose in three of the six squamous cell carcinoma patients was three times as high as that in the group of nontumor patients. The other three squamous cell carcinoma patients had lower mean doses than nontumor patients, as did the three patients with basal cell carcinomas. Although the cumulative UVA dose may eventually turn out to be relevant for PUVA carcinogenesis, our present data do not sufficiently substantiate a correlation between cumulative UVA dose and squamous cell carcinoma formation in PUVA-treated patients. This report confirms that previous exposure to carcinogens appears to be the most important factor for nonmelanoma skin tumor formation in long-term PUVA patients.