Topical resiquimod dosing regimens in patients with multiple actinic keratoses: a multicentre, partly placebo-controlled, double-blind clinical trial.

BACKGROUND: Topical immune response modifiers are established for actinic keratosis (AK) treatment and efforts are underway to make further improvements to their efficacy and safety. OBJECTIVES: To investigate the optimal dosing regimens of the Toll-like receptor 7/8 agonist resiquimod in terms of efficacy, safety and tolerability. METHODS: In a multicentre, partly placebo-controlled, double-blind clinical trial, we randomized 217 patients with AK lesions to 0·03% resiquimod gel once-daily application three times per week for 4 weeks or seven times within 2 weeks or five times for 1 week (arms 1/2/3) followed by a treatment-free interval of 8 weeks and one repetition of the cycle. In two additional arms (arms 4/5), patients applied either resiquimod gel 0·01% or 0·03% three times per week up to a biological end point defined by skin erosion or for a maximum duration of 8 weeks. Clearance was assessed clinically and histologically. RESULTS: Complete clinical clearance ranged from 56% to 85% with the highest rate observed in arm 2. Resiquimod 0·03% gel was more effective than 0·01% gel. Clearance rates in arms 1/2/3 were comparable and higher than with placebo and were reached with 24, 14 and 10 gel applications, respectively. Overall, 128 patients (59%) experienced treatment-related adverse reactions. CONCLUSIONS: Resiquimod 0·03% gel is more effective than 0·01% gel. From the perspectives of safety and tolerability, the lower concentration and shorter duration are preferable. The clinical response in arms 2/3 was reached with fewer gel applications. The dosing regimens that used the biological end point (arms 4/5) proved equally efficacious as predefined treatment durations and may therefore be suitable for personalized AK treatment.

Medical, psychological and socio-economic implications of chronic hand eczema: a cross-sectional study.

BACKGROUND: Hand eczema (HE) is a common skin disease with major medical psychological and socio-economic implications. Onset and prognosis of HE are determined by individual as well as environmental factors. So far, most epidemiological data on HE have been reported from Scandinavian and recently German studies. OBJECTIVE: To investigate the characteristics and medical care of patients with chronic HE (CHE) in Switzerland, and identify risk factors. METHODS: In this cross-sectional study, data from patients with chronic HE were obtained by means of medical history, dermatological examination and patient questionnaires. Multiple logistic regression analysis was applied to identify risk factors for high severity and dermatology life quality index (DLQI). RESULTS: In seven dermatology departments, 199 patients (mean age 40.4 years, 50.8% female) with CHE (mean duration 6.6 years) were enrolled. Moderate to severe HE was reported by 70.9% of patients, and was associated with age <30 or >50 years, localization of lesions and pruritus. Because of the CHE, 37.3% of patients were on sick leave over the past 12 months, 14.8% had changed or lost their job. Practically all patients applied topical therapy, 21% were treated with alitretinoin, and 21% with psoralen plus UVA light (PUVA). The effects on the health-related quality of life was moderate to large in 33.7% and 39.4% of CHE patients, respectively. Factors associated with a high impact on DLQI (mean 9.7 ± 5.8) were female sex, lesions on back of the hands and pruritus as well as mechanical skin irritation and wearing gloves. CONCLUSION: In agreement with recent studies, the Swiss data demonstrate the high impact of CHE on medical well-being, patient quality of life and work ability. As it is associated with an intense use of health care services, high rate of sick leave, job loss and change, CHE may cause a high socio-economic burden.

Is drug allergy less prevalent than previously assumed? A 5-year analysis.

BACKGROUND: Rashes are a frequent conundrum in clinical practice as they may be reactive, drug induced or disease specific. Identification of the culprit drug is important as re-exposure may be harmful or even life-threatening and unnecessary avoidance of 'innocent' drugs leads to limitations of treatment options. OBJECTIVE: To objectify the cause of suspected cutaneous drug reactions in a large patient population. METHOD: Over 5years (2006-10), 612 patients with suspected cutaneous drug reactions were evaluated. Histology was assessed. About 200 patients were invited for complete work-up with skin tests (prick/intracutaneous testing and scratch/patch as indicated) and, if necessary, lymphocyte transformation tests (LTT). In special cases, drug provocation tests were conducted. RESULTS: A total number of 141 cases with suspected drug reaction underwent full work-up (age 6-86years; 75% female, 25% male). In 107 cases (76%) a drug was identified whereas 34 (24%) were reactive rashes or had other causes. Mostly, cutaneous drug reactions were maculopapular rashes, urticaria/angio-oedema; less frequently, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, systemic drug-related intertriginous and flexural exanthema, toxic epidermal necrolysis and fixed drug eruptions were present. Of all the cutaneous drug reactions investigated, 39·8% were caused by antibiotics, 21·2% by anti-inflammatories, 7·6% by contrast media and 31·4% by others (oral antidiabetics, antimycotics, antipsychotics, antiepileptics and others). CONCLUSION: Clinical assessment overestimates the role of drug allergies in cutaneous reactions. Assessment of suspected drug reactions can be greatly improved by thorough evaluation including dermatological and allergological work-up with skin testing and assays such as LTT.

Contact dermatitis induced by glatiramer acetate.

Glatiramer acetate (Copaxone(®)) is an immunomodulatory polypeptide used in patients with relapsing-remitting multiple sclerosis. It represents a safe treatment option with mild side effects. In this study, we look at a 39-year-old woman who received glatiramer acetate as subcutaneous injections for two months and developed contact dermatitis. The drug had to be stopped, and treatment with topical prednisone was initiated. Prick/scratch testing was negative but the lymphocyte transformation test was highly positive for glatiramer acetate. This is the first report on contact dermatitis induced by glatiramer acetate injections. The treatment consisted of local topical steroids and cessation of the drug.

[Swiss clinical practice guidelines for skin cancer in organ transplant recipients]. / Recommandations suisses pour la prise en charge des cancers cutanés chez les patients transplantés d'organe.

Swiss clinical practice guidelines for skin cancer in organ transplant recipients Transplant patients have increased over the last decades. As a consequence of long-term immunosuppression, skin cancer, in particular squamous cell carcinoma (SCC), has become an important problem. Screening and education of potential organ transplant recipients (OTRs) regarding prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, OTRs should be seen yearly by a dermatologist to ensure compliance with sun avoidance as well as for treatment of precancerosis and SCC. Early removal is the best treatment for SCC. Reduction of immunosuppression, switch to mTOR inhibitors and chemoprevention with acitretin may reduce the incidence of SCC. The dermatological follow-up of OTRs should be integrated into a comprehensive post-transplant management strategy.

Development of stereopsis and cortical binocularity in human infants: electrophysiological evidence.

Dynamic random-dot stereograms and correlograms were used to elicit visually evoked brain potentials from human infants, and these potentials were compared with potentials evoked by classical checkerboard pattern reversal. The results indicate that infants begin to produce stereoscopically evoked potentials at the age of 10 to 19 weeks, several weeks after showing classical checkerboard-evoked potentials, and suggest that the onset of cortical binocularity precedes stereopsis.

Swiss clinical practice guidelines for skin cancer in organ transplant recipients.

Patients with a solid organ transplant have increased in numbers and in individual survival in Switzerland over the last decades. As a consequence of long-term immunosuppression, skin cancer in solid organ recipients (SOTRs) has been recognized as an important problem. Screening and education of potential SOTRs about prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, SOTRs should be seen by a dermatologist yearly for repeat education as well as early diagnosis, prevention and treatment of skin cancer. Squamous cell carcinoma of the skin (SCC) is the most frequent cancer in the setting of long-term immunosuppression. Sun protection by behaviour, clothing and daily sun screen application is the most effective prevention. Cumulative sun damage results in field cancerisation with numerous in-situ SCC such as actinic keratosis and Bowen's disease which should be treated proactively. Invasive SCC is cured by complete surgical excision. Early removal is the best precaution against potential metastases of SCC. Reduction of immunosuppression and switch to mTOR inhibitors and potentially, mycophenolate, may reduce the incidence of further SCC. Chemoprevention with the retinoid acitretin reduces the recurrence rate of SCC. The dermatological follow-up of SOTRs should be integrated into the comprehensive post-transplant care.

Changes in phasic femoral artery flow induced by various stimuli: a study with percutaneous pulsed Doppler ultrasound.

Transcutaneous blood flow measurements were performed by means of pulsed Doppler ultrasound flowmeter in the femoral artery of healthy subjects. The pulsatile flow pattern was changed characteristically from resting state by postocclusive reactive hyperaemia, by the application of amyl nitrite, xanthinol nicotinate, and angiotensin amide. During reactive hyperaemia systolic flow was increased, diastolic reverse flow was abolished, and the forward flow continued throughout diastole. Amyl nitrite augmented thenegative flow phase and reduced mean flow, while xanthinol nicotinate decreased the negative component and augmented mean flow. Angiotensin amide produced enhancement of the average flow by elevating systolic and diastolic flow equally over the base line. In each of these interventions the changes in flow were determined mainly by variations during the diastolic flow phase.

Fluorescence spectroscopy for identification of atherosclerotic tissue.

OBJECTIVE: Vessel perforation and limited steerability of the laser light are the major limitations of laser angioplasty. To improve steerability fluorescence spectroscopy has been proposed for identification of atherosclerotic plaques. The aim was to investigate this. METHODS: Fluorescence spectroscopy with three different excitation wavelengths (325 nm, 380 nm, 450 nm) was tested in an emission range of 400 nm to 600 nm. Intensity ratios at 480/420 nm were determined in different types of blood vessels. Necropsy material from 40 patients (punch biopsies of 4 mm diameter from the coronary and carotid artery as well as from the ascending and descending aorta) was studied spectroscopically. Histological alterations of the vessel wall were assessed by a semiquantitative score (0 to 10 points): (a) normal tissue, 0 to 2 points (mean = 0.25; n = 38); (b) mild atherosclerotic lesions, 3 to 5 points (mean = 3.35; n = 39); (c) severe atherosclerotic lesions, greater than or equal to 6 points (mean = 6.75; n = 43). RESULTS: Best spectroscopic results were obtained with an excitation wavelength of 325 nm. In samples with severe atherosclerotic lesions the fluorescence spectra showed a significant reduction of the emitted wavelength intensities when compared to normal tissue. There was a clear separation of the fluorescence spectra between normal and mild as well as between normal and severe atherosclerotic lesions; normal tissue showed an increased intensity in the range from 420 nm to 540 nm, whereas atherosclerotic lesions had no or only a small peak at 480 nm. There was a significant correlation between the semiquantitative score (n = 120) and the fluorescence ratio at 480/420 nm (excitation wavelength 325 nm) with a correlation coefficient of 0.87. The spectroscopic results showed no differences between the samples taken from different types of vessels. CONCLUSIONS: Fluorescence spectroscopy allows a reliable identification of normal and atherosclerotic lesions. The close correlation between the emitted light intensity ratio at 480/420 nm and the histological alterations of the vessel wall suggests a relationship between vessel wall fluorescence and the atherosclerotic alterations of the wall.

T2 relaxation time in patients with Parkinson's disease.

Postmortem studies of patients with Parkinson's disease (PD) reveal an increase in iron concentration in the substantia nigra. Iron content in the brain is associated with decreased signal intensity on T2-weighted MRI. We measured in vivo the T2 relaxation time in 30 PD patients and 33 healthy volunteer subjects, using a 1.5-T whole-body MRI system. In comparison with healthy controls, T2 values in PD patients were reduced in the following brain regions: substantia nigra, caudate nucleus, and putamen. Due to the overlap between patients and control subjects, we could not differentiate, in a given patient, healthy from diseased state on the basis of T2 relaxation time. Our findings support the notion of increased iron deposition in the substantia nigra of patients with PD. However, the shortening of T2 values in the substantia nigra did not correlate with disease duration nor with clinical severity.

Bone loss in premenopausal and postmenopausal women. A cross-sectional and longitudinal study using quantitative computed tomography.

Trabecular and total bone densities were determined by quantitative computed tomography in patients with untreated postmenopausal osteoporosis and in normal premenopausal and postmenopausal women. A special procedure was used for precise low-dose examinations of the distal end of the radius and the distal end of the tibia. The results indicate that the trabecular bone density of the peripheral skeleton is a reliable index of postmenopausal osteoporosis. In general, osteoporotic patients could be distinguished from patients with age-related bone loss based on differences in the magnitude of the decrease in trabecular bone density. Serial determinations of trabecular bone density in individual patients indicated that trabecular bone loss in postmenopausal osteoporotic patients shows a step-wise pattern in which phases of relative stability are followed by brief phases of bone loss. Quantitative computed-tomography measurements of bone density should provide a better understanding of the pathogenesis of postmenopausal osteoporosis and be useful in the assessment of different methods of treatment.

Transdermal iontophoresis and solute penetration across excised human skin.

The potential of transdermal iontophoresis to facilitate drug delivery was evaluated by studying the transport kinetics of model compounds salicylate (anion), phenylethylamine (cation), mannitol (polar neutral compound of low molecular weight), and inulin (polar neutral compound of high molecular weight) using an excised human skin model. The transport kinetics of solutes were determined across both intact and cellophane-tape-stripped dermatomed skin both in the presence and absence of applied current to probe the mechanisms of iontophoretic delivery. Iontophoresis effectively enhanced delivery of all compounds relative to passive transport. The skin is shown to be both ion selective and size selective. On the basis of results from present work and other studies, the "aqueous pathway" of iontophoretic transport is further reinforced.

Subtraction procedure for the registration of tissue perfusion with Doppler ultrasound.

Tissue perfusion, i.e., in muscles or parenchymatous organs, is of both physiological and pathophysiological interest. The measurement of tissue perfusion is an unsolved problem. The Doppler ultrasound method is well suited to this purpose. However, measurements using this technique may be disturbed by movements or vibrations such as heart motion, muscle trembling or vibration of the subsoil (i.e. the examination table). These interfering movements produce Doppler frequencies in the same frequency range as slowly flowing erythrocytes, causing artifacts to appear in the measured data. The goal of this project was to suppress such artifacts with the help of a subtraction procedure. The mathematical theory of this subtraction procedure and its implementation in a newly developed two channel Doppler system are presented. This system was successfully tested on a phantom which is able to generate flow and movement artifacts. Preliminary measurements in the forearms of volunteers showed that movement artifacts can be at least partially suppressed.

Bone densitometry using computed tomography. Part I: selective determination of trabecular bone density and other bone mineral parameters. Normal values in children and adults.

Gamma-ray computed tomography (gamma-ray CT), using a special purpose scanner, enables in-vivo quantitative analysis of bone mineralization. Trabecular bone density (TBD), the relative amount of compact bone (bone density, BD) and the total absorption (TA) for a cross-section of the radius are determined from measurements of local linear absorption coefficients. A preliminary study of normal children (n = 49) and adults (n = 34) indicated that TBD is independent of age and sex in the age range 4 to 40 years. DB remains constant throughout childhood but increases after puberty in both women and men. TA is higher for adults than for children, and also higher for men than for women. A correlation between TA and parameters relating to body size indicates a relationship between body weight and bone mass.

Bone densitometry using computed tomography. Part II: increased trabecular bone density in children with chronic renal failure.

The method of gamma-ray computed tomography (gamma-ray CT) bone densitometry described in the preceding article provides selective determination of trabecular bone density (TBD), the relative amount of compact bone (bone density, BD), and the total absorption (TA) within a bone cross section. Seven of nine children with chronic renal failure (CRF), and selected only on the basis of their serum creatinine value (greater than 5 mg/100 ml), had increased TBD values above the normal range, whereas the other bone mineral parameters were normal. Radiographic signs of secondary hyperparathyroidism (subperiosteal erosions, cysts) were reported in the five patients with the highest TBD values, whereas the subjective diagnosis of osteosclerosis reported in three of these five and in one other patient correlated less well with the TBD increases. However, this is the first report of an objective, non-invasive documentation of the radiological finding of osteosclerosis in CRF. It also explains why methods for bone mineral measurements used previously, such as a photon absorptiometry which provides only a parameter equivalent to TA, failed to reveal increases in bone mineral content in renal osteodystrophy even when signs of osteosclerosis were present. Thus, gamma-ray CT helps to document objectively the degree of osteosclerosis and its location.

The microvasculature of the small-intestinal mucosa of the rat: quantification of hemodynamic effects of topically applied cimetidine, ranitidine, somatostatin, and vasopressin.

The influence of topically administered cimetidine, ranitidine, somatostatin, and vasopressin on microvessels of the jejunal villus of the rat was investigated by means of an in vivo videomicroscopy technique. For all substances a dose-response curve concerning the change of vessel diameters was obtained. All four drugs induced a significant vasoconstriction at the capillary level. Maximum vasoconstriction was achieved with vasopressin. These results strongly suggest the presence and possibly importance of H2 receptors in the intestinal vascular bed of the rat.