Anti-allergic action of anti-malarial drug artesunate in experimental mast cell-mediated anaphylactic models.

BACKGROUND: Allergy is an acquired hypersensitivity reaction of the immune system mediated by cross-linking of allergen-specific IgE-bound high-affinity IgE receptors, leading to immediate mast cell degranulation. Artesunate is a semi-synthetic derivative of artemisinin, an active component of the medicinal plant Artemisia annua. Artesunate is a clinically effective anti-malarial drug and has recently been shown to attenuate allergic asthma in mouse models. This study investigated potential anti-allergic effects of artesunate in animal models of IgE-dependent anaphylaxis. METHODS: Anti-allergic actions of artesunate were evaluated in passive cutaneous anaphylaxis and passive systemic anaphylaxis mouse models, and in ovalbumin-induced contraction of bronchial rings isolated from sensitized guinea pigs. Direct mast cell-stabilizing effect of artesunate was examined in RBL-2H3 mast cell line and in mature human cultured mast cells. Anti-allergic signaling mechanisms of action of artesunate in mast cells were also investigated. RESULTS: Artesunate prevented IgE-mediated cutaneous vascular hyperpermeability, hypothermia, elevation in plasma histamine level, and tracheal tissue mast cell degranulation in mice in a dose-dependent manner. In addition, artesunate suppressed ovalbumin-mediated guinea pig bronchial smooth muscle contraction. Furthermore, artesunate concentration-dependently blocked IgE-mediated degranulation of RBL-2H3 mast cells and human culture mast cells. Artesunate was found to inhibit IgE-induced Syk and PLCγ1 phosphorylation, production of IP(3) , and rise in cytosolic Ca(+2) level in mast cells. CONCLUSIONS: We report here for the first time that artesunate possesses anti-allergic activity by blocking IgE-induced mast cell degranulation, providing a foundation for developing artesunate for the treatment of allergic asthma and other mast cell-mediated allergic disorders.

Unilateral electronegative ERG of non-vascular aetiology.

BACKGROUND: Full field and pattern electroretinograms (ERG, PERG) are performed to assess generalised retinal function and macular function, respectively. An (electro) negative full field ERG usually describes an ISCEV standard maximal response in which the b-wave is smaller than a normal or minimally reduced a-wave and indicates dysfunction that is post-phototransduction. The most common cause of a unilateral negative ERG is central retinal artery occlusion (CRAO) or birdshot chorioretinopathy (BCR). This study examines the clinical and electrophysiological features of patients with unilateral negative ERG who do not have CRAO or BCR. METHODS: 12 patients were ascertained with a unilateral negative ERG in whom a vascular aetiology and BCR were excluded. Most presented with symptoms of central retinal dysfunction. In 11 of the 12 patients additional long duration photopic stimuli were used to test cone system ON and OFF responses. RESULTS: All 12 patients had unilateral electronegative bright flash full field ERGs indicating total or relative preservation of rod photoreceptor function, but dysfunction post-phototransduction. Seven of these patients had non-specific inflammatory changes in the eye with the negative ERG. Six patients, including five with inflammatory signs, had involvement of the cone ON response with complete preservation of cone OFF responses. A further three patients showed evidence of cone ON response abnormality with less severe OFF response involvement. CONCLUSION: The ERGs in this heterogeneous group of patients predominantly showed post-phototransduction involvement of the ON pathways. Sparing of the cone OFF response was often observed. The majority of patients had signs of previous inflammation and it is speculated that these highly unusual unilateral changes may be mediated via an autoimmune mechanism.

Multifocal electroretinogram in children on atropine treatment for myopia.

AIM: To assess retinal function by multifocal electroretinogram (mfERG) in children on atropine eye drops for the treatment of myopia. METHODS: mfERGs were recorded in children receiving atropine eye drops (n = 48) once daily for 2 years and in those receiving placebo eye drops (n = 57) for a similar time. All recordings were performed between the second and third month of cessation of atropine/placebo treatment by a masked investigator. The amplitude and implicit time of the first order kernel (k1) and first slice of the second order kernel (k21) of mfERG responses were used to study the outer and inner retinal function, respectively. RESULTS: There was no significant reduction in k1 response amplitudes of the atropine group compared to that of the placebo group (N1, p = 0.181; P1, p = 0.150). No significant difference in the k1 response implicit times between the groups was found (N1, p = 0.767; P1, p = 0.849). The differences in the k21 amplitudes and implicit times between the groups were not statistically significant (k21 amplitude, p = 0.058; k21 implicit time, p = 0.156). CONCLUSIONS: Daily atropine usage over 2 years for the treatment of myopia has no significant effect on retinal function as demonstrated by recordings of mfERG.

Comparison of electrical thresholds for evoking movements from sensori-motor areas of the cat cerebral cortex and its relation to motor training.

Motor maps and electrical thresholds for evoking movements from motor areas of the cerebral cortex were evaluated in normal cats by using intracortical microstimulation techniques. Stainless steel chambers were implanted over craniotomies in adult cats trained to perform reaching and retrieval movements with their forelimbs. Prehensile motor training was continued and movement performance monitored for about 6-10 weeks during which the cortex was progressively explored with sharp tungsten electrodes inserted into cortical gyri (anterior and posterior sigmoid, and coronal) and the banks of sulci (cruciate, presylvian and coronal). Twice weekly, under light general anaesthesia, 3-4 tracks were made in either hemisphere till about 50 tracks were made in each hemisphere. Mean thresholds for evoking forelimb movements from different cytoarchitectonic areas (4gamma, 4delta, 6agamma and 3a) were compared and no consistent or significant differences were observed between the different areas. In the animals (4/6) which used either forelimb to perform the tasks, there were no consistent differences in the mean thresholds for evoking forelimb movements from the two hemispheres. However, in 2 animals, which used their right forelimbs predominantly or exclusively to perform all the tasks, mean thresholds for evoking forelimb movements was significantly higher in areas 4gamma and 6agamma of the left hemisphere (compared to the right); no consistent differences in the mean thresholds for evoking hindlimb or facial movements were observed between the two hemispheres. These findings suggest that ICMS thresholds for evoking forelimb movements may be similar in different sensorimotor areas of the cat cerebral cortex, and these thresholds could be influenced by motor training.

Gyrate atrophy of the choroid: two cases.

INTRODUCTION: Gyrate atrophy of the choroid (GA) is a rare, inherited choroidal dystrophy that results in progressive deterioration in peripheral and night vision. This is the first documentation of GA in Singapore. CLINICAL PICTURE: This report illustrates 2 cases of a sibling pair from a consanguineous union, presenting with the classical clinical features and biochemical abnormality of this condition. TREATMENT AND OUTCOME: One patient was treated with pyridoxine replacement and a low protein diet. However, his condition failed to improve. The other patient was left untreated. CONCLUSION: Treatment was ineffective for the first patient. As yet, there is no proven treatment of GA.

Age-related macular degeneration: what's new.

INTRODUCTION: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed western world, accounting for approximately 50% of all cases of registered blindness. The rising prevalence of this disease in Asia seems to parallel the same trend in the developed world. Because of the socio-economic impact of this disorder, much attention has been paid to elucidating the underlying pathogenic mechanisms, as well as seeking alternative forms of treatment. This review discusses the latest advances in AMD diagnosis, treatment and prophylaxis. METHODS: Medline search with emphasis on randomised controlled clinical trials and large case-control series. Only articles cited on the Index Medicus were included in this review. RESULTS: Recent advances in the diagnosis and treatment of AMD include conventional argon laser photocoagulation, photodynamic therapy (PDT), radiation therapy, surgical options and gene therapy. CONCLUSIONS: There have been numerous advances in the management of AMD and exciting new research applications have emerged. The introduction of exciting new modalities, such as PDT, has revolutionised the approach to treating CNVM and their effects on central vision. However, there has been no breakthrough in achieving satisfactory outcomes with the available techniques for treating occult neovascular lesions. As results of large prospective randomised clinical trials evaluating new treatment alternatives become available, a treatment algorithm for neovascular AMD will emerge that best minimises visual loss and may even result in visual improvement.

The incidence of negative ERG in clinical practice.

INTRODUCTION: A negative electroretinogram (ERG) is one in which there is a selective reduction in amplitude of the b-wave, such that it does not exceed that of the a-wave. The purpose of this study was to determine the incidence and clinical causes of negative ERGs at a tertiary referral centre. In addition, interesting and previously unreported aetiologies are described. PATIENTS AND METHODS: Retrospective review of all ERGs done at Moorfields Eye Hospital from November 1995 to December 1998 under ISCEV standard conditions. Many patients had photopic ON- and OFF-response recording in addition to conventional ISCEV Standard ganzfeld ERG. RESULTS: A total of 2,640 ERGs were performed during the study period. 128 cases (4.8%) showed a negative ERG. The causes, where a firm clinical diagnosis was possible, include X-linked juvenile retinoschisis, congenital stationary night blindness, central retinal artery occlusion, birdshot chorioretinopathy and melanoma-associated retinopathy (MAR). Unilateral negative ERG waveforms with normal fundal appearances were seen in 7 patients. Photopic ON- responses could be selectively affected. CONCLUSIONS: The incidence of negative ERGs over a 34-month period presenting to a large tertiary centre was almost 5%. The presence of a negative ERG may be instrumental in demonstrating the site of visual dysfunction, with many cases showing minimal or no fundus abnormality. ON- and OFF-response recording yielded additional information regarding photopic post-receptoral/phototransduction function.

Effects of mitogen-activated protein kinase kinase inhibitor PD 098059 on antigen challenge of guinea-pig airways in vitro.

1. It has been shown that activation of protein tyrosine kinases is the earliest detectable signalling response to FcepsilonRI cross-linking on mast cell. Following tyrosine kinase activation, a family of mitogen-activated protein kinases (MAPKs) was found to be activated as well. The present study examined the role of MAPK signalling cascade in in vitro model of allergic asthma using a specific MAPK kinase inhibitor PD 098059. 2. Guinea-pigs were passively sensitized with IgG antibody raised against ovalbumin (OA). Effects of PD 098059 on OA-induced anaphylactic contraction of isolated bronchi and release of histamine and peptidoleukotrienes from chopped lung preparations were studied. 3. PD 098059 (10-50 microM) produced only minor reduction of maximal OA-induced bronchial contraction. In contrast, the rate of relaxation of OA-induced bronchial contraction was markedly faster in the presence of PD 098059 than the vehicle control in a concentration-dependent manner. 4. These observations corroborate well with the inability of PD 098059 (5-50 microM) to substantially block the OA-induced release of histamine and with marked inhibition of OA-induced release of peptidoleukotrienes from lung fragments in the presence of PD 098059. Exogenous arachidonic acid-induced release of peptidoleukotrienes from lung fragments was not blocked by PD 098059. 5. In immunoblotting study, we found that p42MAPK was constitutively expressed in guinea-pig bronchi. However, treatment with OA, histamine or LTD4 did not cause activation of p42MAPK. These findings together with the lack of inhibitory effects of PD 098059 on bronchial contraction induced by histamine or LTD4 suggest that histamine- and LTD4-induced bronchial contractions are not mediated by p42MAPK activation. 6. Taken together, our findings show that inhibition of MAPK signalling cascade by PD 098059 significantly reduced the OA-triggered release of peptidoleukotrienes leading to rapid relaxation of anaphylactic bronchial contraction. On the other hand, p42MAPK did not play a role in histamine- or LTD4-induced bronchial smooth muscle contraction suggesting that PD 098059 exerts its inhibitory effects on OA-induced bronchial contraction primarily through inhibition of peptidoleukotrienes release from mast cells.

Anaemia--more than meets the eye.

Anaemia is a commonly encountered medical condition, although associated ophthalmic manifestations are not often sought or recognised. The authors present a case report of a patient with severe vitamin B12 deficiency anaemia with florid retinal changes classical of anaemic retinopathy. A review of the ocular involvement in anaemia is also presented.

Using the phacoemulsification crescent knife in dacryocystorhinostomy.

Dacryocystorhinostomy is an effective treatment for nasolacrimal duct obstruction. Most techniques employ a conventional blade or knife in making the incision of the nasal mucosa and lacrimal sac. The authors describe the use of a phacoemulsification crescent knife for this purpose. This technique can be effective and at the same time safer and easier to perform.

Effects of tyrosine kinase inhibitors on antigen challenge of guinea pig lung in vitro.

The present study was conducted to examine the effects of two protein tyrosine kinase inhibitors, genistein and tyrphostin 47, on an in vitro model of allergic asthma. Guinea pigs were sensitized with purified IgG raised against ovalbumin (OA). Isolated sensitized bronchial rings contracted in response to OA in a concentration-dependent manner, maximum contraction being achieved at 1 microg/ml. Genistein and tyrphostin 47 concentration-dependently (10-100 microM) inhibited OA-induced anaphylactic contraction of the bronchi, as well as release of histamine and peptidoleukotrienes from chopped lung preparations. Genistein, but not tyrphostin 47, significantly suppressed bronchial contraction to leukotriene D4 at 50 microM and to histamine at 100 microM. Daidzein, an inactive congener of genistein, did not alter OA-induced anaphylactic contraction. However, it slightly reduced bronchial contraction to leukotriene D4 and the OA-stimulated release of peptidoleukotrienes. The inhibitory effects were significantly weaker than those of genistein. Taken together, our results show that tyrphostin 47 inhibited anaphylactic contraction mainly by preventing mast cell degranulation, whereas genistein exerted inhibitory effects partly by blocking mast cell degranulation and partly by attenuating leukotriene D4-induced bronchial contraction. These findings suggest that protein tyrosine kinase inhibitors have a therapeutic potential as mast cell stabilizers in the treatment of allergic diseases such as bronchial asthma.