Comparative immunophenotyping of monocytes from symptomatic and asymptomatic atopic individuals.

BACKGROUND: Allergy has at least two components - a genetic predisposition referred to as atopy and the progress from an atopic state to clinically apparent disease. Peripheral blood monocytes are circulating myeloid precursors of antigen-presenting cells. The expression of cell surface proteins on monocytes may therefore witness the disease status and affect the development of allergic disease. METHODS: Monocytes were isolated from atopic individuals with seasonal allergic rhinitis (n = 10), from atopic individuals sensitized to aeroallergens but without any signs of acute disease (n = 11), and from healthy nonatopic donors (n = 21). Detailed comparative phenotypic analysis of CD14(+) and FcepsilonRI(+)CD14(+) monocytes was performed by flow cytometry. RESULTS: CD14(+) monocytes from symptomatic atopic donors showed a significant increase in the cell surface intensity of the integrin adhesion molecule CD11c over monocytes from asymptomatic atopic and nonatopic donors. Asymptomatic atopic individuals showed significantly enhanced expression of FcepsilonRI on the CD14(high)CD16(dim) monocyte subset compared with this subset from symptomatic atopic and nonatopic donors. CONCLUSION: The increase in monocyte surface intensity of the adhesion molecule CD11c may be involved in the manifestation of allergic disease. FcepsilonRI on CD14(high)CD16(dim) monocytes of asymptomatic atopic donors may be of functional importance for the maintenance of clinical unresponsiveness toward allergens.

Asymptomatic atopy is associated with increased indoleamine 2,3-dioxygenase activity and interleukin-10 production during seasonal allergen exposure.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan (TRP)-catabolizing enzyme with regulatory effects on T cells. T cell inhibition is achieved through both TRP depletion and TRP metabolite accumulation in specific local tissue microenvironments. The expression of IDO activity by different types of antigen-presenting cells (APCs) has been shown to play a role in many instances of immunoregulation and tolerance induction. Induction of IDO after the engagement of the high-affinity receptor for IgE, FcepsilonRI, on atopic monocytes has been suggested to regulate T cell responses in atopic disorders. Interleukin-10 (IL-10), a cytokine known for its down-regulatory functions in the immune system, has recently been associated with the stable expression of IDO in mature tolerogenic dendritic cells. OBJECTIVE: This study was devised to understand the role of systemic IDO and IL-10 in the prevention of clinical apparent allergy. METHODS: The concentration of TRP and the break-down product kynurenine were measured by high-performance liquid chromatography in- and off-season in sera from patients with seasonal allergic rhinitis (n=12) and from clinically asymptomatic atopic patients sensitized to specific aeroallergens (n=12). Non-atopic (NA) individuals (n=12) served as control. The concentration of plasma IL-10 was determined in parallel from these donors by ELISA in- and off-season. RESULTS: In clinically unresponsive but aeroallergen-sensitized atopic individuals significantly higher systemic activity of IDO and increased plasma IL-10 levels were found during allergen exposure but not off-season compared to symptomatic atopic individuals with allergic rhinitis and NA individuals. CONCLUSION: Enhanced systemic IDO activity as well as increased systemic levels of IL-10 may contribute to the containment of allergic T cell responses and could be involved in the maintenance of a state of clinical unresponsiveness.

Pemphigus vulgaris induced by radiotherapy.

Pemphigus can be triggered or induced by many insults, such as drugs, infections, viruses and neoplasms. X-ray-induced pemphigus has been recorded only rarely in the literature. We describe the case of a woman with pemphigus vulgaris in remission, who relapsed 1 week after completion of an irradiation course for breast cancer, in the exact location of the radiation. We review the previous 15 cases from the literature and outline the common features of those cases.

Smoking can be good for you.

Smoking is without doubt one of the greatest causes of avoidable illness and death in the modern world. Most well known is the relationship between smoking and numerous cancers, cerebrovascular and cardiovascular disease. Smoking and most especially nicotine, are, however, sometimes beneficial in certain diseases, including Parkinson's, Alzheimer's, allergic alveolitis, nausea and vomiting of pregnancy, pre-eclampsia, fibroids, carcinoma of body of uterus, ulcerative colitis, pyoderma gangrenosum, aphthous stomatitis and ulceration, pemphigus, herpes simplex and acne. In the immensely justifiable enthusiasm to discredit this dangerous activity, the mechanisms behind these beneficial effects tend to have been un-discussed or ignored. It is the aim of this paper to spur interest in the reasons for these effects. If the mechanisms are elucidated, therapeutic advances may be possible.

Co-existing sensitivity to metronidazole and isothiazolinone.

A 68-year-old woman developed allergic contact dermatitis to topical metronidazole gel as proven by positive patch tests to the gel and to metronidazole. She was also allergic to methylchloroisothiazolinone and methylisothiazolinone (MC/MI). The similarity between the two molecules and the fact that the patient reacted to the gel after the very short incubation period of 1 day (i.e. not long enough for acquiring an active sensitization) makes the possibility of a cross-reaction between these substances very plausible. As the isothiazolinones are widely used and comprise an important and relatively frequent cause of allergic contact dermatitis, a cross-reactivity with metronidazole means that perhaps there should have been more cases of metronidazole allergy is more common than the current literature suggests.

Quantification of indoleamine 2,3-dioxygenase gene induction in atopic and non-atopic monocytes after ligation of the high-affinity receptor for IgE, Fc(epsilon)RI and interferon-gamma stimulation.

Antigen-presenting cells (APCs) are crucial in regulating the outcome of T cell responses. Certain APCs are able to down-regulate T cell proliferation in vitro by inducing the enzyme indoleamine 2,3-dioxygenase (IDO) upon interferon-gamma (IFN-gamma) stimulation. IDO is the rate-limiting enzyme in the catabolism of the essential amino acid tryptophan. A lack of extracellular tryptophan creates environments in which cells become starved for this amino acid. The high-affinity receptor for IgE, Fc(epsilon)RI, is the principal receptor for the binding of specific IgE in type I-mediated allergies. We demonstrated recently that IDO is overexpressed in Fc(epsilon)RI-stimulated monocytes. In the present study, we performed quantification of IDO gene induction after treatment of atopic (Fc(epsilon)RI(high)) and non-atopic (Fc(epsilon)RI(low/-)) monocytes with IgE/anti-IgE and IFN-gamma. By quantitative PCR ELISA, we found IDO molecule induction in atopic monocytes was enhanced about 50-fold over non-atopic monocytes after ligation of Fc(epsilon)RI. Stimulation with IFN-gamma at a concentration of 100 U/ml in culture medium caused an increase in IDO gene copy numbers in atopics of about fourfold over that of non-atopics. This comparative quantification study demonstrates clearly the regulation of IDO gene expression by Fc(epsilon)RI and discloses differences thereof in atopic and non-atopic cells upon inflammatory stimuli.

A prototype device for standardized calibration of pulse oximeters II.

OBJECTIVE: There is no commonly accepted in vivo calibration method for pulse oximeters available up to now. On the basis of a prototype device for the calibration of pulse oximeters which was introduced recently, a second approach based on the same concept was tackled in order to design a reliable method for standardized calibration of pulse oximeters. METHODS: An extensive clinical database of time-resolved optical transmission spectra of patient fingers is used to simulate the behavior of patients. A device which is capable of playing back these spectroscopic data to pulse oximeters, and a database where the oxygen status measured with the reference method (Co-Oximetry) is stored, are the main parts of the concept. The playback device has an artificial finger as interface to the pulse oximeters and serves to collect light from the pulse oximeter for analysis and to playback simulated light to the pulse oximeter. The light intensity emitted by two LEDs which illuminates the pulse oximeter detector is controlled via a computer in such a way that it is the same as if the pulse oximeter light had passed the finger. The pulse oximeter display during the data playback can thus be compared to the true SaO2 of the patient. The device is tested with 4 pulse oximeters based on 100 patient spectra. RESULTS: For the four pulse oximeters used in this investigation, an Agilent Technologies CMS monitor (formerly Hewlett-Packard), an Ivy 2000 with Masimo Set technology and Nellcor N-3000 and N-395, there is good correlation between SPO2 and SaO2, and mean and standard deviation of in vivo SpO2-SaO2 and playback SpO2-SaO2 are in good agreement. For two instruments, Nellcor N3000 and Agilent CMS Monitor, a quantitative comparison between the in vivo and in vitro SpO, results was derived. A mean of the deviation playback vs. in vivo SpO2 is less than 0.5% SpO2. The error limits are comparable with the calibration error of the conventional calibration routine. The device is also capable of data playback even in situations with rapid desaturation changes, as displayed in Figure 2. For the other tested pulse oximeters the results are comparable. CONCLUSIONS: Compared to the first prototype the current version is simpler and less expensive in production. Many of previously existing problems are solved and the applicability to a large variety of pulse oximeters and sensors is given. The novel concept for the calibration of pulse oximeters is a tool for assessing the performance of pulse oximeters.

Relationship between blood pressure and finger photoplethysmographic waveform during oxygen desaturation test: a model fitting approach.

UNLABELLED: A modified 3-element windkessel model was applied to study the relationship between brachial arterial blood pressure and the photoplethysmographic waveform from pulse oximeters. Data were recorded from 12 healthy volunteers who underwent the oxygen desaturation study. During about 30 minutes recording period, the SpO2 value was regulated down till about 70%. After preprocessing, singular value decomposition (SVD) algorithm was then used to get the best fit of the model parameters. RESULT: the fitting error (RMSE) was 1.07 +/- 0.48 mmHg. The time constant of the model shown significant difference between the highest and the lowest saturation group.

Design and validation of a pulse oximeter calibrator.

The performance of a new calibrator for pulse oximeters is tested with five pulse oximeters from different manufacturers. The calibrator is based on time resolved transmission spectra of human fingers. Finger spectra with different arterial oxygen saturation can be selected to simulate real patients. The results obtained with this calibration device are compared with the results of conventional calibration procedures with volunteers. Beside accuracy tests the suitability for artifact simulation with the new device is discussed. The response of the five tested pulse oximeters is in good agreement with the response of the pulse oximeters connected to real patients. A test procedure for pulse oximeters similar to the conventional desaturation practice is possible; some of the typical artifacts pulse oximetry has to cope with can be simulated easily.

A prototype device for standardized calibration of pulse oximeters.

OBJECTIVE: To develop and test a method for standardized calibration of pulse oximeters. METHODS: A novel pulse oximeter calibration technique capable of simulating the behavior of real patients is discussed. It is based on an artificial finger with a variable spectral-resolved light attenuator in conjunction with an extensive clinical database of time-resolved optical transmission spectra of patients fingers in the wavelength range 600-1000 nm. The arterial oxygen saturation of the patients at the time of recording was derived by analyzing a corresponding blood sample with a CO-oximeter. These spectra are used to compute the modulation of the light attenuator which is attached to the artificial finger. This calibration method was tested by arbitrarily playing back recorded spectra to pulse oximeters and comparing their display to the value they displayed when the spectra were recorded. RESULTS: We were able to demonstrate that the calibrator could generate physiological signals which are accepted by a pulse oximeter. We also present some experience of playing back recorded patient spectra. The mean difference between the original reading of the pulse oximeters and the display when attached to the calibrator is 1.2 saturation points (displayed oxygen saturation SpO2) with a standard deviation of 1.9 saturation points. CONCLUSIONS: The tests have shown the capabilities of a spectral light modulator for use as a possible calibration standard for pulse oximeters. If some improvements of the current prototype can be achieved we conclude from the experience with the device that this novel concept for the calibration of pulse oximeters is feasible and that it could become an important tool for assessing the performance of pulse oximeters.

Computerized system to enhance the clinical diagnosis of pigmented cutaneous malignancies.

BACKGROUND: An increase in the incidence of cutaneous malignant melanoma in recent years has not been accompanied by satisfactory progress in diagnostic methods. This study was carried out to evaluate a specially designed computerized image analysis system, called Derma Vision, to aid in the differentiation between malignant and benign cutaneous pigmented lesions. METHODS: Seventy-one lesions were photographed with a digital camera and the data were analyzed by the Derma Vision system. The system assessed the variation of hues in each image, calculated the mean standard deviation of the hues, and produced a value that expressed the range of hues in the lesion. The lesions were then excised and examined histologically. The computer-assisted clinical diagnosis was correlated with the histologic diagnosis to determine the accuracy of the former. RESULTS: Derma Vision predicted the malignant character of a lesion with 92% precision, compared with 87% accuracy based only on the clinical features. CONCLUSIONS: This simple, inexpensive device can boost the accuracy of clinical diagnosis and provide a useful tool to the physician faced increasingly with having to determine whether pigmented lesions are malignant or benign.

Improvement in androgenetic alopecia in 53-76-year-old men using oral finasteride.

Twenty-eight men with AGA, aged 53-76 years (mean, 65 years), were selected to participate in this trial from a double blind, placebo controlled, multicenter study of subjects with moderate symptoms of BPH. Patients received either finasteride 5 mg or placebo daily for 24 months. Hair counts were performed at entry to the study and at 6, 12, 18, and 24 months. Hair counts were made directly on the scalp in a circular target area 1 in in diameter, located in the center of a template. The template was applied in such a way that its counting window fell on the most balding scalp area, which remained the same for each patient.11 At each hair counting session, patients were asked about side-effects and questioned about their sex life. Time trend and differences between groups were examined using a one-way (treatment) MANOVA with repeated measures (baseline, 6, 12, 18, and 24 months). Additional two-tailed t-tests were performed to compare the two groups at each point of time. P < 0.05 was considered to be significant.

Paraneoplastic pemphigus associated with pancreatic carcinoma.

A case of paraneoplastic pemphigus associated with pancreatic carcinoma is presented. The histopathological and immunological features of the case, which are consistent with and differ from the accepted diagnostic criteria, are discussed.

Diclofenac: a new trigger of pemphigus vulgaris?

Many drugs have been shown to induce pemphigus, including thiol and nonthiol drugs. We present a case of pemphigus vulgaris where a nonsteroidal anti-inflammatory medication, diclofenac in suppositories and topical gel preparations, is suspected of having triggered the disease. The temporal relationship between drug and outbreak of disease together with the positive migration inhibition factor test to diclofenac point to the possible involvement of this drug in triggering pemphigus vulgaris.

Cost-benefit analysis of diabetic eye disease.

Diabetic retinopathy is the main cause of blindness in adults 25-74 years of age in Western countries. At 100% diagnosability and 100% treatability, with laser photocoagulation vision can be retained in at least one eye in 73% of patients with proliferative retinopathy and in 67% of patients with diabetic maculopathy. The cost-benefit analysis draws a comparison of the costs incurred through benefits granted to a blind diabetic and those incurred through proper screening, examination and treatment to avoid blindness as much as possible. These calculations are valid for the State of Tyrol in Austria. The anticipated annual costs for blindness are thus ATS 19,000,000, of which ATS 14,600,000 could be avoided through an optimal screening, examination and therapy program. The maximum costs for examination and therapy amount to ATS 10,700,000, thus giving a minimum saving of ATS 3,900,000 in favor of preventive medicine.

Effects of adenosine deaminase inhibition on active uptake and metabolism of adenosine in astrocytes in primary cultures.

The use of a relatively specific adenosine deaminase inhibitor, 2'-deoxycoformycin (1.0 microM), has revealed an active transport of adenosine into astrocytes in primary cultures. The abolishment of part of the metabolic degradation and of a concentration gradient, which may favour influx, did not lead to a decreased total uptake. The concentration of labelled, i.e. exchangeable adenosine rose to become several fold higher than in the medium. Thus, as previously shown in neurons, the uptake of adenosine into astrocytes occurs by an active and concentrative process. As a result of the increase in the adenosine concentration when the inhibitor was present, evidence for an increased phosphorylation to the nucleotides (i.e. ATP, ADP, AMP) was obtained. This is in contrast to previous findings in neurons where the incorporation of labelled adenosine into these compounds was decreased in the presence of 2'-deoxycoformycin. This difference may suggest that the salvage pathway from inosine to adenine nucleotides is crucial for nucleotide synthesis in neurons, but not in astrocytes.

Adenosine metabolism in neurons and astrocytes in primary cultures.

Metabolic fate of [8-14C]adenosine was studied in primary cultures of either astrocytes or neurons from the mouse brain. In astrocytes the main metabolic route was the formation of nucleotides. Thus, synthesis of adenosine triphosphate (ATP) amounted to about 0.2 nmol X min-1 X mg-1 protein. The deamination occurred less rapidly. The total rate of formation of inosine was difficult to establish because a considerable amount of labeled inosine accumulated in the medium. The initial incorporation of radioactivity into inosine in the medium was extremely rapid, probably because of the action of an ectoenzyme. However, the labeling of inosine in the medium also continued to increase slowly throughout the incubation, maybe as a result of release of intracellularly formed inosine. The total inosine formation rate during the incubation amounted to at most 0.1 nmol X min-1 X mg-1. Hypoxanthine was formed at a corresponding rate but was released to a lesser extent. In neurons much less label was incorporated into ATP. The major metabolite was inosine, formed intracellularly at a rate of 0.2 nmol X min-1 X mg-1. In addition, there was an immediate rapid labeling of inosine (and to a lesser extent hypoxanthine) in the medium, again suggesting the action of an ectoenzyme. Neither neurons nor astrocytes released a measurable amount of nucleotides to the medium. The cellular differences in adenosine metabolism are probably of relevance for the interpretation of adenosine metabolism in brain in situ. The ectoenzyme may be of importance for rapid termination of the neuromodulator activity of adenosine, and the rapid nucleotide formation in astrocytes is in agreement with a high metabolic activity of these cells.