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Biomedical subjects

R Wolf

Publications and source records attributed to R Wolf.

At least 19 recordsLinked to original sources

Effects of dipeptidyl peptidase IV on the satiety actions of peptide YY.

AIMS/HYPOTHESIS: Dipeptidyl peptidase IV (DP IV) inhibitors are currently being developed to prolong the biological activity of insulinotropic peptides as a novel approach in the treatment of diabetes. We hypothesised that DP IV inhibition could attenuate the satiety actions of peptide YY (PYY) by altering the conversion of PYY(1-36) to PYY(3-36). MATERIALS AND METHODS: The effects of PYY delivered by osmotic mini-pumps were assessed in rats treated with a DP IV inhibitor and in a rat model deficient in DP IV. RESULTS: Pharmacological levels of total PYY were found in the circulation after the exogenous administration of PYY(3-36). While both PYY(1-36) and PYY(3-36) reduced food intake in normal rats, PYY(1-36) was ineffective in rats deficient in DP IV. When re-fed after a 24-h fast, DP IV-deficient rats exhibited higher food intake and weight gain than normal rats. Moreover, unlike controls, there was no postprandial increase in PYY levels in DP IV-deficient rats. Despite these findings, administration of a DP IV inhibitor, Pro-boroPro, did not alter the acute anorectic effects of exogenous PYY(1-36) in normal rats. This could be the result of the protection of other appetite regulatory peptides or the generation of PYY(3-36) by remaining DP IV activity or other dipeptidyl peptidases. CONCLUSIONS/INTERPRETATION: Although DP IV inhibition with Pro-boroPro attenuated the generation of PYY(3-36), our results indicate that short-term DP IV inhibition does not eliminate the satiety actions of exogenously administered PYY(1-36) at the doses tested.

Animals↗

Caudate blood flow and volume are reduced in HIV+ neurocognitively impaired patients.

OBJECTIVE: To evaluate the effects of HIV-associated neurocognitive impairment on caudate blood flow and volume. METHODS: The authors performed continuous arterial spin labeled MRI on 42 HIV+ patients (23 subsyndromic and 19 HIV neurosymptomatic) on highly active antiretroviral therapy and 17 seronegative controls. They compared caudate blood flow and volume among groups. RESULTS: A stepwise decrease in both caudate blood flow and volume was observed with increasing HIV-associated neurocognitive impairment. Compared with seronegative controls, baseline caudate blood flow was reduced in HIV+ neurosymptomatic patients (p = 0.001) with a similar decreasing trend for subsyndromic HIV+ patients (p = 0.070). Differences in caudate volume were observed only for neurosymptomatic HIV+ patients compared with controls (p = 0.010). A Jonckheere-Terpstra test for trends was significant for both caudate blood flow and volume for each of the three subgroups. Pearson product moment correlation coefficients were not significant between caudate blood flow and volume for each group. CONCLUSIONS: Decreasing trends in caudate blood flow and volume were associated with significantly increasing HIV-associated neurocognitive impairment (HNCI), with the greatest decreases observed for more severely impaired patients. However, reductions in caudate blood flow and volume were poorly correlated. Changes in residual caudate blood flow may act as a surrogate biomarker for classifying the degree of HNCI.

AIDS Dementia Complex↗

An image quality comparison of standard and dual-side read CR systems for pediatric radiology.

An objective analysis of image quality parameters was performed for a computed radiography (CR) system using both standard single-side and prototype dual-side read plates. The pre-sampled modulation transfer function (MTF), noise power spectrum (NPS), and detective quantum efficiency (DQE) for the systems were determined at three different beam qualities representative of pediatric chest radiography, at an entrance detector air kerma of 5 microGy. The NPS and DQE measurements were realized under clinically relevant x-ray spectra for pediatric radiology, including x-ray scatter radiations. Compared to the standard single-side read system, the MTF for the dual-side read system is reduced, but this is offset by a significant decrease in image noise, resulting in a marked increase in DQE (+40%) in the low spatial frequency range. Thus, for the same image quality, the new technology permits the CR system to be used at a reduced dose level.

Child↗

Influence of cassette type on the DQE of CR systems.

In our recent paper by Monnin et al. [Med. Phys. 33, 411-420 (2006)], an objective analysis of the relative performance of a computed radiography (CR) system using both standard single-side (ST-VI) and prototype dual-side read (ST-BD) plates was reported. The presampled modulation transfer function (MTF), noise power spectrum (NPS), and detective quantum efficiency (DQE) for the systems were determined at three different beam qualities representative of paediatric chest radiography, at an entrance detector air kerma of 5 microGy. Experiments demonstrated that, compared to the standard single-side read system, the MTF for the dual-side read system was slightly reduced, but a significant decrease in image noise resulted in a marked increase in DQE (+40%) in the low spatial frequency range. However, the DQE improvement for the ST-BD plate decreased with increasing spatial frequency, and, at spatial frequencies above 2.2 mm(-1), the DQE of the dual-side read system was lower than that of the single-side one.

Equipment Design↗

Cardiac risk of coronary patients after reintegration into occupations with heavy physical exertion.

The job related reintegration of patients with coronary artery disease (CAD) is a central part of cardiac rehabilitation. However, specific occupational demands like jobs with heavy physical exertion (> 6 METs) could increase the cardiovascular risk because the relative risk for acute myocardial infarction (MI) and cardiac death is temporarily elevated after vigorous exertion ("hazard period"). Thus, in 2001 any male patient with proven CAD who performed a job with heavy exertion until the occurrence of an index event (MI/ACS, any interventional or surgical revascularization measure) received a questionnaire after an average of 20 months. Complete data were available in 108 from 119 included patients (90.8%), aged 51.8+/-7.8 years. Ejection fraction was 61.5+/-13.1% and the functional capacity at the time of hospital discharge averaged 130.1+/-31.2 W. 75% of the patients had a previous MI and 59.3% underwent bypass surgery. During follow-up the previous job with heavy exertion was performed over a cumulated time of 74 years. The aim of the study was to compare the observed and the expected incidence of MI and cardiac death with and without job performance. The expected ("basal") risk for MI and cardiac death without heavy physical exertion was determined from pooled study results and assumed to be 5.2% per year. The combined risk due to performing an occupation with strenuous exertion can be calculated from time periods with and without working hours and amounts to 11.9%. There could be expected 0.119 . 74=8.8 cardiac events related to the job. In contrast, 5 MIs (4 NSTEMI, 1 STEMI) were observed (6.8%). The relative risk for an expected event compared to the basal risk without heavy exertion was 2.3 (95% CI: 0.7-7.4). The relative risk for the observed cardiac events amounts to 1.3 (95% CI: 0.4-4.8). The lower observed risk is probably due to the high grade of physical fitness in this patient group. In spite of several limitations, our study showed no convincing evidence for increasing the cardiac risk of patients with CAD performing occupations with heavy physical exertion. Because of the importance of this prognostic finding, a representative and prospective study is strongly required.

Coronary Artery Disease↗

Towards a medically approved technology for alginate-based microcapsules allowing long-term immunoisolated transplantation.

The concept of encapsulated-cell therapy is very appealing, but in practice a great deal of technology and know-how is needed for the production of long-term functional transplants. Alginate is one of the most promising biomaterials for immunoisolation of allogeneic and xenogeneic cells and tissues (such as Langerhans islets). Although great advances in alginate-based cell encapsulation have been reported, several improvements need to be made before routine clinical applications can be considered. Among these is the production of purified alginates with consistently high transplantation-grade quality. This depends to a great extent on the purity of the input algal source as well as on the development of alginate extraction and purification processes that can be validated. A key engineering challenge in designing immunoisolating alginate-based microcapsules is that of maintaining unimpeded exchange of nutrients, oxygen and therapeutic factors (released by the encapsulated cells), while simultaneously avoiding swelling and subsequent rupture of the microcapsules. This requires the development of efficient, validated and well-documented technology for cross-linking alginates with divalent cations. Clinical applications also require validated technology for long-term cryopreservation of encapsulated cells to maintaining a product inventory in order to meet end-user demands. As shown here these demands could be met by the development of novel, validated technologies for production of transplantation-grade alginate and microcapsule engineering and storage. The advances in alginate-based therapy are demonstrated by transplantation of encapsulated rat and human islet grafts that functioned properly for about 1 year in diabetic mice.

Alginates↗

Real-time 3-D dark-field microscopy for the validation of the cross-linking process of alginate microcapsules.

Alginate-based microencapsulation is a promising method for long-term maintenance of cellular and membrane function of the cells and tissue fragments required for in vitro and in vivo biosensors, for tissue engineering and particularly for immunoisolation of non-autologous transplants. Microcapsules of high mechanical strength and optimum permeability can be produced by injection of BaCl2 crystals into alginate droplets before they come into contact with external Ba2+. A key requirement is that the system parameters (number of crystals, speed of the crystal stream etc.) are properly adjusted according to the mannuronic and guluronic acid ratio and the average molecular mass of the alginate as well as to the diameter of the microcapsules. Robust, reliable, rapid and low-cost validation tools are, therefore, needed for assurance of the microcapsule quality. Here, we describe a novel three-dimensional (3-D) dark-field microscopy that allows the real-time measurement of the number and spatial distribution of the injected Ba2+ ions throughout the microcapsules after treatment with sulphate. This novel method requires only a conventional microscope equipped with three polarising filters and a double aperture stop. In contrast to confocal laser scanning microscopy images, peripherally attached BaSO4 precipitates can clearly be distinguished from internal ones. The data also demonstrate that several steps of the alginate gelling process must be improved before such immunoisolation can be used in patients.

Alginates↗

Rosiglitazone plus metformin is effective and well tolerated in clinical practice: results from large observational studies in people with type 2 diabetes.

This study investigated the efficacy during daily practice of rosiglitazone (RSG) added to metformin (MET) in poorly controlled type 2 diabetes mellitus. Two post-marketing observational studies were conducted in Germany over 6 months. RSG (4 mg/day titrated to 8 mg/day as required) was added to existing MET in 11,014 subjects. Subjects were maintained on diet and exercise. Addition of RSG to MET significantly reduced median HbA 1c by 1.3% (8.1 vs. 6.8%; p < 0.0001) and median fasting blood glucose (FBG) by 47.0 mg/dl (171.0 vs. 124.0 mg/dl; p < 0.0001) after 6 months. The proportion of subjects achieving HbA(1c) targets of < or = 6.5 and < or = 7.0% increased from 3.5 to 38.8% and from 13.5 to 63.7%, respectively. Mean systolic and diastolic blood pressure decreased by 7 and 3 mmHg, respectively (p < 0.0001). Mean weight decreased by 1.7 kg and was constant or reduced in most (74.1%) subjects. Addition of RSG to MET significantly reduces median HbA 1c and FBG in clinical practice and is generally well tolerated.

Aged↗

Impetigo herpetiformis with hyperparathyroidism.

Impetigo herpetiformis, first described by Hebra, is a rare pustular disorder that primarily affects pregnant women and it is often complicated by an increased risk of spontaneous abortion. A commonly associated hypocalcemia often appears with hypoparathyroidism. Here we report a case of complicated impetigo herpetiformis without hypocalcemia paired with a compensatory hyperparathyroidism.

Adult↗

Induction of uterine prostaglandin H synthase 2 by estradiol following fetal adrenalectomy.

In sheep, fetal cortisol stimulates the conversion of progesterone to estradiol in late gestation initiating labor. It is unclear whether an intact fetal hypothalamic-pituitary-adrenal (HPA) axis is required to induce the estradiol-triggered subsequent endocrine changes including enhanced intrauterine prostaglandin (PG) synthesis associated with the onset of labor. We have shown that maternal estradiol administration stimulates PG H synthase (PGHS)-2 expressions in pregnant ovine intra-uterine tissues. The current study was undertaken to determine whether the fetal adrenal mediates estradiol's stimulation of the intrauterine PGHS-2 in pregnant sheep. Placenta, myometrium, and endometrium were collected from two groups of ewes at 123-127 d of gestational age (dGA) after fetal adrenalectomy and vehicle treatment (ADX; n = 5); or fetal ADX and maternal estradiol administration (5 mg twice a day for 2 d, ADX+E2, n = 5). PGHS-2 mRNA and protein were analyzed by Northern and Western Blot analyses in both groups and presented as the ratios to beta actin mRNA for Northern and G protein beta subunit for Western blot analysis. Fetal plasma cortisol was measured by radioimmunoassay. Data were analyzed by Student's t test. Fetal plasma cortisol levels were low in ADX and ADX+ E2 groups (<6 ng/mL). The cervix of all ADX+E2 treated ewes was dilated at necropsy. Three out of five ADX+ E2-treated ewes delivered within 48 h. The cervix was closed in all fetal ADX ewes at necropsy. PGHS-2 mRNA and protein increased (p < 0.05) in myometrium and endometrium, but not placenta in ADX+E2-treated ewes compared with ADX group. These data provide the first in vivo evidence for estradiol upregulation of intrauterine PGHS-2 in late gestation in the absence of an intact fetal HPA axis. Thus, the fetal adrenal is not required to mediate estradiol's stimulation of uterine PGHS-2 expression associated with the onset of labor.

Adrenal Glands↗

Treatment of psoriasis with light and heat energy (LHE): a preliminary study.

In psoriasis the earliest observable electron microscopic changes are in the papillary dermis vasculature. Selective photothermolysis of the dermal vasculature using a 585-nm pulsed-dye laser (PDL) for the treatment of psoriasis was reported more than a decade ago. Although clinically effective, the pulsed-dye laser has limited practicality because of small spot size (5-10 mm) and lack of cost effectiveness. The objective of this study is to evaluate the safety and efficacy of a novel Light and Heat Energy (LHE) selective-photothermolysis system for the treatment of psoriasis. This system delivers controlled heat simultaneously with the light pulse; it has a large beam spot (55 x 22 mm) and is sufficiently cost effective to be widely used. Thirteen patients, seven with plaque psoriasis, five with palmoplantar psoriasis, and one with guttate psoriasis participated in a controlled study. Patients received two therapy regimens in parallel: LHE plus salicylic acid or salicylic-acid cream alone as control. Treatments were applied twice weekly spread evenly over 4-6 weeks. In most cases a fluence of 8.6 J/cm2 was applied. Efficacy of the treatment was assessed using the psoriasis-severity index (PSI) calculated from the investigator's overall assessment of the plaque's erythema, scaling, and induration. PSI was evaluated at baseline, at every other treatment visit, and during two follow-up visits scheduled 1 and 5 weeks following the last treatment. In eleven patients who completed the treatment regimen, the average global PSI score for the treated sites was reduced by 65 percent. In contrast, the control sites average global PSI score was reduced by only 7.4 percent. Six patients (55 %) had a significant improvement of 70-percent reduction or above in their PSI score, ten patients (91 %) had a 50 percent or above reduction; only one patient had a poor response (12.5 % reduction in global PSI). Erythema was reported in all cases and resolved within 24-48 hours. Six cases of burns were resolved within 2 days to 2 weeks following appropriate remedy. No cases of dyspigmentation were encountered. Light and Heat Energy (LHE) selective photothermolysis combined with salicylic acid appears to be a practical modality for the treatment of mild to moderate psoriasis. Patients experience discomfort that is only mild. There is no convalescence downtime. Clinical results obtained are similar to those reported with the pulsed-dye laser; however, this new system seems more suitable to be widely adopted as a treatment modality. Further followup is required to determine whether remission periods will be as long as those reported for treatment with the pulsed-dye laser.

Adult↗

[Drug therapy of acute manias. A retrospective data analysis of inpatients from 1997 to 1999].

The aim of the present retrospective chart analysis was to compare published treatment algorithms with the treatment patterns of 90 consecutive inpatients suffering from acute mania or hypomania at the Department of General Psychiatry, University of Vienna, from 1997 to 1999. Treatment strategies during the first 14 days and on discharge as well as sociodemographic and illness related data were evaluated. The results of our study reflect that international guidelines were not included in daily practice from 1997 to 1999 with regard to the usage pattern of atypical antipsychotics versus typical neuroleptics. Also, recommendations have not been taken into account about monotherapy with a mood stabilizer as first-line treatment for acute mania (polypharmacia was the predominant treatment scheme) and the advice to taper off benzodiazepines (at discharge).

Acute Disease↗

Gene expression in actinic keratoses: pharmacological modulation by imiquimod.

BACKGROUND: Actinic keratoses (AKs) are premalignant lesions that can progress into squamous cell carcinoma. Imiquimod, which belongs to the new class of immune-response modifiers, was recently shown to be effective in the treatment of AKs. The underlying mechanisms are not fully understood. OBJECTIVES: To study the expression of individual genes in uninvolved skin and AKs before therapy and to elucidate the way in which the expression of these genes is influenced by imiquimod therapy. METHODS: We treated 13 patients with AK with imiquimod and compared gene expression before, during (five patients) and after (eight patients) therapy with that in uninvolved skin. We analysed genes coding for inflammatory cytokines or their receptors, adhesion molecules, anti-apoptotic proteins, p53 and toll-like receptors (TLRs) by reverse-transcriptase polymerase chain reaction. RESULTS: Comparing uninvolved skin and untreated AK, we found significant differences in the expression of interleukin (IL)-6, hurpin, TLR7 and TLR8. During imiquimod therapy, we detected a further upregulation of interferon-alpha, IL-6, IL-10 receptor 1 and TLR7. In contrast, two anti-apoptotic genes, hurpin and HAX-1, were downregulated. We did not detect significant differences in gene expression for p53, tumour necrosis factor-alpha and alpha- and beta-catenins. Clinically, the upregulated expression of the proinflammatory cytokines correlated with the local inflammation induced by imiquimod. CONCLUSIONS: Our results indicate that specific differences in gene expression are detectable between AK and uninvolved skin. Imiquimod influenced the expression of most genes analysed in this study. This work extends previous findings on the effects of imiquimod on gene regulation in AKs.

Aged↗

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.

Breast↗

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.

Journal Article↗

[Cardiac risk in men with angiographically normal coronary arteries or minimal coronary arteriosclerosis].

It is accepted that the assessment of the global cardiac risk for the occurrence of a coronary event is basically for preventive strategies. In a retrospective study, we have estimated the initial 10-year risk in 54 consecutive men (mean age 53.1 years) without clinically coronary artery disease (CAD) by using the PROCAM Score Scheme and the FRAMINGHAM Scoring System. All individuals underwent coronary angiography for diagnostic reasons. Inclusion criteria were angiographically normal coronary arteries or coronary vessels with minimal arteriosclerosis (luminal diameter reduction <35%). The extent of initial coronary arteriosclerosis was estimated semiquantitatively by the number of wall changed vessel segments S (proximal, medial, distal) of the 3 large epicardial coronary arteries. Individuals were divided into 3 risk categories with a 10-year risk/PROCAM <5% (gr. I), 5-20% (gr. II) and >20% (gr. III). The mean 10-year risk/PROCAM and FRAMINGHAM of the entire group was 14.0 and 14.1%, respectively. The number of vessel segments with minimal arteriosclerosis averaged S=2.6. There was a significant linear relation between the number of arteriosclerotic segments, grouped by S=0, 1-2, 3-4, >4 and the mean corresponding 10-year risk/PROCAM (r=0.97; p<0.025). The mean 10-year risk/PROCAM and FRAMINGHAM in gr. I was 2.1+/-1.1 and 5.1+/-3.5%, in gr. II 11.1+/-4.4 and 14.5+/-7.1% and in gr. III 25.4+/-3.3 and 20.4+/-6.2%, respectively (gr. I vs II vs III: p<0.005). In gr. I an average of S=0.8+/-1.4 segments, in gr. II of S=2.4+/-1.8 and in gr. III of S 4.1+/-1.8 vessel segments revealed initial coronary arteriosclerosis (gr. I vs II vs III: p<0.01 <0.0025, respectively). In 42 of the 54 men (78%) there were 10-year follow-up data regarding sudden cardiac death, fatal and non-fatal myocardial infarction available. Thirty-two men of the follow-up group (78%) showed no cardiac event (gr. A, mean age 53.3+/-8.3 years). In 10 men (23.8%, 95% CI 19.7-32.5%) a fatal or non-fatal event occurred (gr. B, mean age 55.6+/-7.5 years). At the beginning of the study, the 10-year risk/PROCAM and FRAMINGHAM in gr. A was 12.0+/-9.3 and 14.1+/-8.0%, respectively. In gr. B the estimated 10-year risk was 18.7+/-8.0% (gr. A vs B: p<0.025) and 17.6+/-7.6%, respectively (gr. A vs B: p=ns). No cardiac event occurred in the low risk group <5% (mean 2.4+/-1.2%). In 23.8% (95% CI 19.2-36.8%) of the group with mild or moderate risk (5-20%, mean 10.4+/-4.1%) and in 38.5% (95% CI 29.5-53.1%) of the high risk group (>20%, mean 25.6+/-3.3%) a fatal or non-fatal event occurred. The total cardiac mortality was 7.1% (95% CI 6.6-15.1%). Our study indicates that men mean aged 53 years without clinical CAD and with a high 10-year risk (>20%), judged by the PROCAM Score Scheme, have a high probability of subclinical coronary arteriosclerosis and for the occurrence of a cardiac event. Thus, a strict distinction between primary and secondary prevention does not seem to be justified any more.

Adult↗

The role of central parts of the brain in the control of sound production during courtship in Drosophila melanogaster.

The question of the roles of the two main parts of the insect brain, the mushroom bodies and the central complex, in controlling motor coordination and triggering a variety of behavioral programs, including sound production, remains controversial. With the aim of improving our understanding of this question, we studied the parameters of songs used by five-day-old males during courtship for fertilized wild-type females (Canton-S, C-S) over 5-min periods at 25 degrees C; males were of two wild-type Drosophila melanogaster lines (Berlin and C-S). Berlin males lacking mushroom bodies because of treatment with hydroxyurea during development (chemical removal of the mushroom bodies) were used, along with two mutants with defects in the mushroom bodies (mbm1 and mud1), two mutants with defects in the central complex (ccbKS127 and cexKS181), and mutant cxbN71 with defects in both the mushroom bodies and the central complex. The experiments reported here showed that courtship songs in males lacking mushroom bodies were virtually identical to those of wild-type males. The main parameters of pulsatile song in mutants mbm1 and mud1 (interpulse interval and train duration) were insignificantly different from those of the songs of wild-type flies, though the stability of the pulse oscillator was the same. Flies of these lines were no different from wild-type flies in terms of courtship success (percentage of copulating pairs in 10-min tests). Conversely, the songs of mutants with defects in the central complex differed from those of wild-type males. Firstly, there was degradation of the stability of the pulse oscillator and interpulse intervals were very variable. In addition, pulses were often significantly longer and appeared multicyclic, as in the well-known cacophony mutant, while the mean train duration was significantly shorter. Males of the line cexKS181 usually courted very intensely, though abnormal sounds were generally emitted. Mutants cexKS181 and ccbKS127 were significantly less successful in courtship than wild-type flies. These data show that the central complex appears to play a very important role in controlling song, while the mushroom bodies are not related to this function.

Animal Communication↗

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.

Aged↗