Impact of maternal topiramate ingestion on ossification of skull and appendicular bones in rat fetuses.

The skull and appendicular bones are derived from different embryological sources during their development. The impact of prenatal exposure of topiramate on ossification of these bones is not adequately studied. The goal of this study was to assess the ossification patterns of the craniofacial bones and bones of the forelimbs and hindlimbs in 20-day-old rat fetuses after maternal exposure to topiramate at doses equivalent to human therapeutic doses. Three groups of Sprague-Dawley pregnant rats were used: control, topiramate 50mg/kg/day (T50) and topiramate 100mg/kg/day (T100). Topiramate was given by oral gavage from day 6 to day19 of gestation. Ossification was evaluated in the bones of 20 days fetuses after staining with Alizarin red. Results showed a significant reduction in complete ossified centers of the metacarpal, metatarsal and craniofacial bones in topiramate-exposed fetuses at both doses when compared to the control group. Also, a significant decrease in the length of ossified part of the long bones of the forelimbs and hindlimbs in topiramate-exposed fetuses at both doses was noted when compared to the control group. Crown-rump length and fetal weight were significantly decreased in topiramate treated groups compared to the control group. In all examined groups, there was a positive correlation between the crown-rump length and the lengths of humerus and femur. No abnormalities in the ossified bones and no significant changes in their ossification pattern were observed between the treated groups. In conclusion, prenatal administration of topiramate in doses equivalent to human therapeutic doses delayed ossification and development of craniofacial and appendicular bones in rat fetuses and their effects are not dose dependent at doses investigated. The implications of these findings in women who require topiramate therapy in pregnancy merit further evaluation.

Checklist-based active learning in anatomy demonstration sessions during the COVID-19 pandemic: Perception of medical students.

Human anatomy is an essential component of the medical curricula. Anatomy education has been significantly affected during the COVID-19 pandemic. The aim of this study was to explore student's perceptions on a blended learning approach using Checklist-based Active Learning in Anatomy Demonstration Sessions (CALADS) as a method in comparison to the two previously used methods; namely face-to-face Structured Problem-Related Anatomy Demonstrations (SPRAD) and online anatomy learning. A comparative, cross-sectional, survey-based study was conducted. The survey was composed of 13 questions that explored preference of learning anatomy in demonstration sessions of 4th year pre-clerkship students who have had their anatomy learning through face-to-face SPRAD in year 2 (before the COVID-19 pandemic), online in year 3 (during the COVID-19 pandemic), and CALADS method in year 4. Descriptive statistics were used, and the level of significance was set at P<0.05. The survey exhibited high internal consistency (Cronbach's α=0.953). Validity of the survey was established through exploratory factor analysis. The preferred method for more than half of the students was the CALADS method. Face-to-face SPRAD came next and lastly came the online method. However, more students preferred the online method in comparison to face-to-face method for "learning radiological anatomy". There were no statistically significant differences between male and female students regarding any of the survey questions. CALADS method, as a hybrid, student-centered, interactive learning method of learning practical anatomy, was preferred by pre-clerkship students as a more effective method in understanding anatomy than face-to-face and online learning methods.

Learning anatomy before and during COVID-19 pandemic: Students' perceptions and exam performance.

The objective of our study was to explore the impact of COVID-19 pandemic on learning anatomy and to compare the students' perceptions of "face-to-face" and "online" anatomy teaching, and to assess their impact on student's performance. We used a descriptive, cross-sectional, questionnaire-based study that focused on a single cohort of undergraduate medial students who attended anatomy demonstrations, at the College of Medicine and Medical Sciences, Arabian Gulf University (CMMS-AGU), both pre-pandemic (face-to-face) during 2019-2020 and the pandemic (online) during 2020-2021. Students who participated in this study responded in favor of face-to-face demonstrations for better understanding of the spatial orientation of body organs and systems, the visualization of the anatomical relations between structures, understanding the difficult anatomical structures, understanding the clinical correlations, and making them more confident about their practical exams. On the other hand, students were in favor of online demonstrations for retaining key information, confidence levels on discussing anatomy learning needs, effective utilization of demonstration time, and lower stress associated with the online learning. Regarding anatomy exam scores, statistically significant difference was found between mean scores of online and onsite exams in one of the two analyzed multiple choice questions tests. However, there was a statistically significant difference between the mean scores of objective structured practical examination of online and onsite exams in the two analyzed tests. Furthermore, the majority of the students who participated in the survey prefer a mixture of both face-to-face and online anatomy demonstrations during the pandemic and also in the post-COVID-19 era.

House dust mite sublingual immunotherapy is safe in patients with mild-to-moderate, persistent asthma: a clinical trial.

BACKGROUND: The safety of allergen immunotherapy (AIT) in asthma has not always been sufficiently documented; accordingly, fear of asthma exacerbations has made physicians somewhat reluctant to prescribe AIT in this context. In a double-blind, placebo-controlled, randomized clinical trial, house dust mite (HDM) sublingual AIT was found to be efficacious in moderate, persistent asthma. The trial's safety results are now reported in detail. METHODS: Asthmatic adults were randomized 2 : 1 to twelve months of daily treatment with a sublingual solution of Dermatophagoides pteronyssinus and Dermatophagoides farinae extracts or a placebo. Adverse events (AEs) at least possibly related to the investigational product were classified by the investigators as adverse drug reactions (ADRs). RESULTS: Overall, the patients in the safety analysis set (n = 484; active treatment: n = 322; placebo: n = 162) had mostly well-controlled, persistent asthma [mild in 290 patients (59.9%), moderate in 183 (37.8%) and severe in 11 (2.3%)]. No treatment-related serious AEs were reported. A total of 87.0% and 75.9% of the patients in the active and placebo groups, respectively, experienced at least one AE (mostly mild), and 78.9% and 48.1% experienced an ADR (mostly mild or moderate oral reactions). The incidence of asthma exacerbations (symptoms requiring a short course of oral corticosteroids) during the study was similar in the active treatment group (3.7%) and the placebo group (4.3%). There were no significant intergroup differences or intragroup changes over time in respiratory AEs, lung function or asthma-related quality of life. CONCLUSIONS: HDM sublingual AIT was safe and well tolerated in adult patients with mild-to-moderate, persistent asthma (ClinicalTrials.gov: NCT00660452).

House dust mite sublingual immunotherapy is safe and appears to be effective in moderate, persistent asthma.

BACKGROUND: The efficacy and safety of sublingual immunotherapy in house dust mite-induced asthma have yet to be firmly established. We report the results of a double-blind, placebo-controlled, randomized clinical trial performed in mainland China. METHODS: After a three-month baseline period, 484 asthmatic adults were randomized 2 : 1 to 12 months of daily treatment with either an aqueous, standardized, 300 index of reactivity mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae extracts or a placebo. The primary efficacy criterion was well-controlled asthma for at least 16 of the last 20 weeks of treatment. RESULTS: In the active (n = 308) and placebo (n = 157) groups, well-controlled asthma was achieved by 85.4% and 81.5% of the patients, respectively (P = 0.244). A subsequent post hoc analysis by asthma severity revealed significant clinical benefits in actively treated subjects with moderate, persistent asthma at baseline [401-800 µg budesonide/day (n = 175)], with greater achievement of well-controlled asthma (80.5% and 66.1% for the active treatment and placebo groups, respectively; P = 0.021) and totally controlled asthma (54.0% and 33.9%, respectively, P = 0.008), a higher percentage of patients with an asthma control questionnaire score < 0.75 (56.6% and 40.0%, respectively; P = 0.039) and a greater mean reduction in inhaled corticosteroid use (218.5 µg and 126.2 µg, respectively; P = 0.004). The active vs placebo differences in disease control and corticosteroid use were not significant for mild, persistent asthma. No treatment-related serious adverse events were reported. CONCLUSIONS: Sublingual mite allergen immunotherapy was well tolerated in adult asthmatics and effectively controlled disease in patients with moderate (but not mild) persistent asthma (ClinicalTrials.gov: NCT00660452).

Effect of prenatal administration of therapeutic doses of topiramate on ossification of ribs and vertebrae in rat fetuses.

There are few studies that have addressed the effects of prenatal exposure of topiramate on ossification of the bones derived from the paraxial mesoderm. This study aimed to evaluate skeletal ossification of ribs and vertebrae in 20-day-old rat fetuses after maternal exposure to two therapeutic doses of topiramate. Three groups of Sprague-Dawley pregnant rats were used: control, topiramate 50 mg/kg/day and topiramate 100 mg/kg/day treated groups. Topiramate was administered by gavage from day 6-19 of gestation. Fetuses were collected on day 20 by caesarean section. Fetal bones were stained with alizarin red and ossification was assessed. Results showed significant delayed ossification of ribs and vertebrae in topiramate-exposed fetuses at both doses and the effects were not dose dependent. In all examined groups, there was a direct correlation between the fetal weight and the number of complete ossified vertebral centers. Also, there were significant increases in skeletal abnormalities, particularly in ribs in both treated groups when compared to the control group. In conclusion, therapeutic doses of topiramate should be taken cautiously during pregnancy as they lead to fetal growth restriction and increases abnormalities of axial skeleton in rat fetuses.

Comparison between continuous or intermittent schedules of sublingual immunotherapy for house dust mites: effects on compliance, patients satisfaction, quality of life and safety.

Sublingual immunotherapy (SLIT) is indicated in the treatment of allergic rhinitis and asthma. However, an issue scantly investigated is the patients satisfaction and the consequent compliance. This study is aimed at evaluating the possible differences of SLIT administered continuously or intermittently on several parameters: clinical efficacy, Quality of Life (QoL), satisfaction, compliance and safety. Forty allergic patients were treated for 12 months. The treatment was carried out by sublingual administration of an allergen extract of a 50% mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae at 10 and 300 IR/ml concentrations. Patients were randomly treated continuously or intermittently (i.e. 2 month treatment alternate to 2 month suspension). Both schedules were significantly effective in reducing allergic symptoms and improving QoL. Compliance and satisfaction were good in both groups. Local and systemic reactions were few, self-resolving, and mild in both schedules. Intergroup analysis did not reveal any difference between the two groups regarding these parameters. In conclusion, this preliminary study provides the evidence that also intermittent SLIT is as effective and safe as traditional continuous treatment. In addition, compliance and satisfaction are super-imposable in the two groups.

Pharmacoeconomic assessment of specific immunotherapy versus current symptomatic treatment for allergic rhinitis and asthma in France.

OBJECTIVES: The therapeutic benefit of specific immunotherapy (SIT) in allergic rhinitis and asthma has been endorsed by expert consensus. This study compared the cost/efficacy (C/E) of SIT with current symptomatic treatments (CST) for allergic rhinitis and asthma. METHODS: A C/E analysis was performed using a decision tree model. The decision tree and medical and economic hypotheses were defined by a panel of experts. The perspective adopted was that of the French Social Security. The costs and efficacy of SIT and CST were compared for dust-mite and pollen allergies, in adults and children. Direct medical costs included diagnosis and follow-up, consultations, CST and SIT. End-point economic criteria were cost per stabilised patient and cost per asthma case avoided. A sensitivity analysis was performed for each model. RESULTS: In adults, the incremental costs per asthma case avoided with injectable SIT were 393 Euro and 1327 Euro for dust-mite and pollen allergy, respectively, over a 6-year period. For sublingual SIT, the costs per asthma case avoided were 3158 Euro and 1708 Euro, respectively. In children, over a 7-year period, the incremental costs per asthma case avoided with injectable SIT were 583 Euro and 597 Euro for dust-mite and pollen allergy, respectively. For sublingual SIT the incremental costs were 3938 Euro and 824 Euro. CONCLUSION: Compared to CST, SIT is a cost-effective treatment in pollen and dust-mite-induced allergic rhinitis and asthma. Sublingual SIT is an attractive option in pollen-induced rhinitis, particularly in children. SIT appears to be an economically relevant strategy compared to CST.

Immune mechanisms of allergen-specific sublingual immunotherapy.

Sublingual immunotherapy has been shown in some clinical studies to modulate allergen-specific antibody responses [with a decrease in the immunoglobulin E/immunoglobulin G4 (IgE/IgG4) ratio] and to reduce the recruitment and activation of proinflammatory cells in target mucosa. Whereas a central paradigm for successful immunotherapy has been to reorient the pattern of allergen-specific T-cell responses in atopic patients from a T helper (Th)2 to Th1 profile, there is currently a growing interest in eliciting regulatory T cells, capable of downregulating both Th1 and Th2 responses through the production of interleukin (IL)-10 and/or transforming growth factor (TGF)-beta. We discuss herein immune mechanisms involved during allergen-specific sublingual immunotherapy (SLIT), in comparison with subcutaneous immunotherapy. During SLIT, the allergen is captured within the oral mucosa by Langerhans-like dendritic cells expressing high-affinity IgE receptors, producing IL-10 and TGF-beta, and upregulating indoleamine dioxygenase (IDO), suggesting that such cells are prone to induce tolerance. The oral mucosa contains limited number of proinflammatory cells, such as mast cells, thereby explaining the well-established safety profile of SLIT. In this context, second-generation vaccines based on recombinant allergens in a native conformation formulated with adjuvants are designed to target Langerhans-like cells in the sublingual mucosa, with the aim to induce allergen-specific regulatory T cells. Importantly, such recombinant vaccines should facilitate the identification of biological markers of SLIT efficacy in humans.

Safety of various dosage regimens during induction of sublingual immunotherapy. A preliminary study.

BACKGROUND: Sublingual immunotherapy (SLIT) has been demonstrated to be a viable alternative to injection immunotherapy. Administration of high doses of allergens to ensure efficacy has been shown to be well tolerated. The aim of the present study was the first step to address the issue of fast-induction regimens using various induction SLIT regimens in paediatric and adult patients. METHODS: Sixty-four patients (age range 5-46 years) with grass pollen rhinoconjunctivitis were enrolled in an 8-month double-blind, placebo-controlled trial of SLIT. Sixty-three patients were randomized to four groups and evaluated at the end of the study. One group received placebo (n = 16) and the other three groups (n = 47) received five grass pollen extracts according to three different induction regimens: regimen 1 starting with 3 IR tablets (n = 15), regimen 2 starting with 10 IR (n = 16) and regimen 3 starting with 30 IR (n = 16). The maintenance phase was made with sublingual-swallow drops at the same concentration of 300 IR/ml for all the patients. Adverse events were recorded on diary cards. RESULTS: During induction phase, 25/47 patients in the SLIT groups had adverse reactions in comparison to 2/16 patients in the placebo group (p < 0.05). The rate of adverse reactions was 33.3% (11.8-61.6) (95% CI) for regimen 1, 31.3% (11.0-58.7) for regimen 2, 43.8% (19.8-70.1) for regimen 3 and 12.5% (1.6-38.3) for placebo. Fifty-seven reactions were local reactions involving the oral region (54 SLIT, 3 placebo) and 13 were systemic reactions (all in the SLIT groups). 11/13 reactions were mild (gastrointestinal disorders, rhinoconjunctivitis), 1/13 consisted of moderate asthma and 1/13 consisted of severe abdominal pain. No urticaria, angioedema or life-threatening events were observed. CONCLUSIONS: These preliminary data showed that various induction regimens for SLIT are generally well tolerated and could allow a fast build-up phase of SLIT.

Immunotherapy with a calcium phosphate-adsorbed five-grass-pollen extract in seasonal rhinoconjunctivitis: a double-blind, placebo-controlled study.

BACKGROUND: Calcium phosphate-adsorbed allergen extracts are used for subcutaneous immunotherapy to avoid the use of aluminium adjuvants. OBJECTIVES: A double-blind, placebo-controlled study was performed in order to confirm the safety and assess the efficacy of a standardized five-grass-pollen extract adsorbed onto calcium phosphate for specific immunotherapy (IT). METHODS: Twenty-nine patients with seasonal rhinoconjunctivitis were randomized to receive either the active preparation (16 patients) or placebo (13 patients), in a 1-year study. During the increasing dose phase, an extract ranging from 0.1 IR per ml to 50 IR per ml was administered at a rate of one subcutaneous injection per week until a maintenance dose was reached. The patients were assessed by symptom diary and rescue medications during seasonal exposure and specific nasal and skin reactivity before and after IT. Immunological parameters (specific IgE and IgG4 antibodies) were assessed before, during and after IT. RESULTS: The overall symptoms score (mean AUC) was not significantly different between the IT group and the placebo group during grass-pollen exposure (49.6 vs. 56, respectively). The total medication score (mean AUC) was significantly lower in the IT group than in the placebo group (11 vs. 41, P < 0.01, Mann-Whitney U-test). The cumulative symptom/medication score was significantly lower in the IT group than in the placebo group (64.5 vs. 102.3, P < 0.05, U-test). A significant increase in nasal reactivity threshold was observed after IT in the IT group (21. 4 IR/mL before IT vs. 63.4 IR/mL after IT, P < 0.01, Wilcoxon), whereas no significant changes were observed in the placebo group (31.0 IR/mL before IT vs. 37.7 IR/mL after IT). IT induced a significant reduction in grass pollen cutaneous reactivity in the actively treated group (P < 0.001). A significant increase in serum-specific IgG4 antibody response was observed in the IT group (3.1% before IT vs. 10.1% after IT, P < 0.001). Nine patients in the IT group developed moderate immediate systemic reactions vs. two patients in the placebo group. CONCLUSION: Specific immunotherapy with calcium phosphate-adsorbed standardized grass pollen extract was safe and effective for the treatment of patients with seasonal allergic rhinoconjunctivitis.

Safety and efficacy of specific immunotherapy with standardized allergenic extracts adsorbed on aluminium hydroxide.

Specific immunotherapy (SIT) with standardized allergenic extracts is the only specific treatment of allergic patients. In order to evaluate the safety, side effects, and efficacy of SIT with standardized extracts adsorbed to aluminium hydroxide manufactured by Stallergènes S.A., a prospective multicenter open study was performed in Switzerland. Fifteen patients suffering from seasonal or perennial rhinoconjunctivitis with or without asthma were included in the trial and received a total of 442 injections with standardized mix of grass pollens (n = 8) or house dust mites (n = 7) over one year. Low incidence of local reactions was noted (7%). Subcutaneous nodules (granuloma) following injections were not recorded. Only a few systemic reactions (one mild rhinitis, one mild asthma attack, one worsening of eczema) were recorded. No anaphylactic reactions requiring adrenaline were recorded. No admission to the hospital was required. Global appreciation of the physicians and the patients after the first year of treatment showed a good efficacy of SIT: Only two patients (13%) did not improve. A worsening of the symptoms was not observed. In order to assess the efficacy, skin reactivity and conjunctival reactivity to allergen challenge were compared before and after one year of treatment as well as immunologic parameters (such as specific IgE, specific IgG4) in blood samples. A significant decrease in skin reactivity (p = .001) and in conjunctival reactivity (p = .01) was observed. Specific IgE level decreased for both types of allergens but to a significantly greater extent for grass pollen allergen (p = .03). Specific IgG4 level increased significantly for grass (p = 0.01) and for mites (p = 0.04). Specific immunotherapy appears to be a valuable tool in the efficient management of the allergic respiratory diseases.

Cetirizine inhibits bradykinin-induced cutaneous wheal and flare in atopic and healthy subjects.

BACKGROUND: Kinins are vasoactive mediators involved in allergic reactions. When applied on the skin or in the nose, bradykinin (BK) elicits inflammation that is poorly affected by previous H1-blockade. The aim of this study was to compare the possible effect of cetirizine (an H1-antagonist) on wheal and flare responses to BK, histamine, and compound 48/80 in atopic and healthy subjects. METHODS: In a randomized, double-blind, crossover study, eight atopic and eight healthy subjects received cetirizine (10 mg/day) or placebo for 3 days before cutaneous tests. Intradermal tests (IDT) and prick tests (PT) were performed with BK (20 nmol/ml for IDT and 20 micromol/ml for PT), histamine (100 microg/ml IDT and 100 mg/ml PT), and compound 48/80 (100 microg/ml IDT and 100 mg/ml PT) as positive controls and saline as negative control. The skin responses were monitored by measurement of wheal and flare areas. RESULTS: BK, histamine, and 48/80 induced wheal and flare reactions in all placebo-treated subjects. Histamine elicited larger wheal and flare reactions than BK and 48/80. IDT with BK induced four- to six-fold larger wheal and flare reaction than PT. No differences in BK-induced wheal and flare were observed between atopic and healthy subjects. In atopic subjects, cetirizine induced a significant reduction of flare reactions after the BK test (80% for IDT, and 94% for PT [P<0.01]). Moreover, cetirizine reduced significantly BK-induced wheals by 70% for IDT (P<0.01) and 65% for PT (P<0.01). A similar inhibiting effect of cetirizine was also observed in healthy subjects. CONCLUSIONS: These findings showed that the wheal and flare reactions induced by BK challenge were markedly inhibited by previous intake of cetirizine. The mechanism by which this effect is mediated cannot be established at present.

House-dust-mite sublingual-swallow immunotherapy (SLIT) in perennial rhinitis: a double-blind, placebo-controlled study.

BACKGROUND: The safety and efficacy of sublingual-swallow immunotherapy (SLIT) in rhinitis caused by house-dust mite were evaluated in a double-blind, placebo-controlled study including 75 patients for 24 months. METHODS: Patients received either placebo or SLIT with a standardized Dermatophagoides pteronyssinus (D.pt.) - D. farinae (D.f) 50/50 extract. The mean cumulative dose was 90,000 IR, equivalent to 2.2 mg of Der p 1 and 1.7 mg of Der f I. Symptom and medication scores were assessed throughout the study. Exposure to house-dust mite, skin sensitivity, and serum specific IgE and IgG4 were assessed before starting treatment and after 12 and 24 months. RESULTS: Seventy-two patients (36 active-36 placebo) were eligible for intent-to-treat analysis. Thirty-six patients dropped out of the study. The number of patients who dropped out due to lack of efficacy was eight out of 37 (21.6%) in the active treatment group compared to 15 out of 38 (39.5%) in the placebo group (chi-square=2.81, P=0.09). Total symptom and medication scores decreased significantly after 12 and 24 months (P<0.05) of treatment in both groups, but no significant difference was observed between the active and placebo groups. After 24 months, the number of patients with high levels of indoor allergenic load decreased significantly in both groups compared to baseline data (P=0.01). Specific IgE (D.pt. and D.f.) increased significantly in the active treatment group after 12 and 24 months, while no change was observed in the placebo group. Specific IgG4 levels were not significantly modified in either group. Two patients in each group reported mild adverse effects. No severe adverse effects were reported. CONCLUSIONS: We conclude that SLIT in rhinitis caused by house-dust mite was safe, but there was a lack of consistent clinical benefit compared to placebo, probably due to the impact of the allergen avoidance measures that lowered the allergen burden.

Cetirizine inhibits bradykinin-induced cutaneous wheal and flare in atopic and healthy subjects.

BACKGROUND: Kinins are vasoactive mediators involved in allergic reactions. When applied on the skin or in the nose, bradykinin (BK) elicits inflammation that is poorly affected by previous H1-blockade. The aim of this study was to compare the possible effect of cetirizine (an H1-antagonist) on wheal and flare responses to BK, histamine, and compound 48/80 in atopic and healthy subjects. METHODS: In a randomized, double-blind, crossover study, eight atopic and eight healthy subjects received cetirizine (10 mg/day) or placebo for 3 days before cutaneous tests. Intradermal tests (IDT) and prick tests (PT) were performed with BK (20 nmol/ml for IDT and 20 micromol/ml for PT), histamine (100 microg/ml IDT and 100 mg/ml PT), and compound 48/80 (100 microg/ml IDT and 100 mg/ml PT) as positive controls and saline as negative control. The skin responses were monitored by measurement of wheal and flare areas. RESULTS: BK, histamine, and 48/80 induced wheal and flare reactions in all placebo-treated subjects. Histamine elicited larger wheal and flare reactions than BK and 48/80. IDT with BK induced four- to sixfold larger wheal and flare reaction than PT. No differences in BK-induced wheal and flare were observed between atopic and healthy subjects. In atopic subjects, cetirizine induced a significant reduction of flare reactions after the BK test (80% for IDT, and 94% for PT [P < 0.01]). Moreover, cetirizine reduced significantly BK-induced wheals by 70% for IDT (P < 0.01) and 65% for PT (P < 0.01). A similar inhibiting effect of cetirizine was also observed in healthy subjects. CONCLUSIONS: These findings showed that the wheal and flare reactions induced by BK challenge were markedly inhibited by previous intake of cetirizine. The mechanism by which this effect is mediated cannot be established at present.

Nephrotoxicity of low-dose methotrexate in guinea pigs: an ultrastructural study.

The nephrotoxicity of low-dose methotrexate (MTX) and the rescue effect of leucovorin were studied by electron-microscopic examination of the kidney of guinea pigs. One group received MTX as a single weekly dose of 10 mg/kg, i.p.; a second group received a similar dose divided into three equal fractions. The third group received MTX rescued with an equal dose of leucovorin. The distal convoluted tubule showed cell swelling, fragmentation of the endoplasmic reticulum and loss of mitochondrial cristae and matrix. Leucovorin minimized these changes. The proximal tubule and the glomerulus were not affected. Low-dose MTX induced a nephrotoxicity in the distal convoluted tubule which could be minimized by leucovorin. Mild myelosuppression was also observed.

The superficial ulnar artery: development and surgical significance.

The upper limbs of 72 formalin-fixed human cadavers were examined by dissection for arterial anomalies. In one subject, the ulnar artery was noted to be a branch of the second part of the axillary artery on both right and left sides. It ran a superficial course in the arm, crossed the elbow immediately subjacent to the median cubital vein, and continued its course in the forearm in a subcutaneous position. In the hand it played a dominant role in the formation of the superficial palmar arch. The anomalous ulnar artery was of a smaller caliber than both the radial and common interosseous arteries. Although superficial ulnar arteries have been reported in the literature, the combination of bilateral superficial ulnar arteries originating from the axillary arteries appears to be rare. The developmental and surgical significance of the findings are discussed.

[Skin reactions to bradykinin]. / La réactivité cutanée à la bradykinine.

A large series of experiments carried out in animals and humans suggest that histamine release is not involved in the leakage phenomenon induced by bradykinin (BK) challenge. These experiments comprise in vitro studies on skin and bronchial human mast cells and in vivo studies on guinea pig airways and human skin using mepyramine, chlorpheniramine and terfenadine as reference H1-anti-histamines. Nevertheless, it has been shown recently that the H1 antagonist cetirizine 10 mg p.o. markedly inhibits skin reactions induced by BK challenge (intradermal injection of 212 micrograms BK in 10 microL saline and prick test with a solution of 21.2 micrograms/microL). In a guinea pig model, this drug also inhibited the bronchospasm induced by increasing concentrations of BK given by iv route (0.25 to 2 micrograms/Kg) and aerosol (3 to 300 micrograms/Kg). This inhibition was similar to the one obtained with the specific BK antagonist HOE 140 (15 pM/Kg). New data in the literature suggest the existence of various pharmacological mediators possibly involved in the BK-induced reaction: neuromediators, nitric oxyde and PAF. They also suggest that this reaction presents itself as a well defined sequence of pharmacological events. Since we could show that there is no binding of cetirizine to a human recombinant B2 receptor in vitro, some hypotheses are raised in order to explain this unexpected inhibiting effect of cetirizine.