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Topic:Clinical Study

Clinical studies in equine research involve the systematic investigation of health and disease in horses through structured scientific methods. These studies aim to evaluate the safety and efficacy of treatments, understand disease mechanisms, and improve veterinary care practices. Clinical studies can include randomized controlled trials, observational studies, and case-control studies. They may focus on various aspects such as pharmacokinetics, therapeutic interventions, and diagnostic techniques. This page compiles peer-reviewed research studies and scholarly articles that explore the design, implementation, and findings of clinical studies in equine medicine, providing insights into their impact on horse health and veterinary practices.
Effect of injected dexamethasone on relative cytokine mRNA expression in bronchoalveolar lavage fluid in horses with mild asthma.
BMC veterinary research    November 6, 2019   Volume 15, Issue 1 397 doi: 10.1186/s12917-019-2144-x
Bond SL, Hundt J, Léguillette R.Mild equine asthma is a common inflammatory airway disease of the horse. The primary treatment of mild equine asthma is corticosteroids. The purpose of this study was to investigate the effects of injected dexamethasone on relative IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p35, IL-17, IL-23, IFN-γ, Eotaxin-2 and TNF-α mRNA expression in bronchoalveolar lavage (BAL) fluid in healthy Thoroughbred horses (n = 6), and those with mild equine asthma (n = 7). Results: Horses with mild equine asthma had a significantly greater bronchoalveolar lavage mast cell percentage than healthy horses...
Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses.
Veterinary anaesthesia and analgesia    November 5, 2019   Volume 47, Issue 2 210-218 doi: 10.1016/j.vaa.2019.08.049
Reed RA, Knych HK, Barletta M, Sakai DM, Ruch MM, Smyth CA, Ryan CA.To compare the pharmacokinetics and pharmacodynamics of hydromorphone in horses after intravenous (IV) and intramuscular (IM) administration. Methods: Randomized, masked, crossover design. Methods: A total of six adult horses weighing [mean ± standard deviation (SD))] 447 ± 61 kg. Methods: Horses were administered three treatments with a 7 day washout. Treatments were hydromorphone 0.04 mg kg IV with saline administered IM (H-IV), hydromorphone 0.04 mg kg IM with saline IV (H-IM), or saline IV and IM (P). Blood was collected for hydromorphone plasma concentration at multiple time points for ...
Serum protein concentrations and protein fractions in clinically healthy Italian Heavy Draft Horses using agarose gel electrophoresis.
Veterinary clinical pathology    November 3, 2019   Volume 48, Issue 4 677-682 doi: 10.1111/vcp.12793
Miglio A, Morelli C, Maresca C, Felici A, Di Gianbattista A, Antognoni MT.Serum protein electrophoresis (SPE) reference intervals (RIs) have been evaluated in different horses, but no specific values are shown for equine breeds as previously described in other species (dogs, cats), and no studies have been performed on SPE in draft horses. Objective: This study aimed to determine RIs for SPE in heavy draft horses (Italian Heavy Draft Horse-IHDH) living in central Italy. A comparison between different physiologic states (pregnancy and no pregnancy) and ages (foals and adults) was executed. Methods: Blood samples were collected from 215 apparently healthy horses (mare...
Skin Disorders of the Donkey and Mule.
The Veterinary clinics of North America. Equine practice    November 2, 2019   Volume 35, Issue 3 493-514 doi: 10.1016/j.cveq.2019.08.006
Knottenbelt DC.Skin disease in donkeys is less common than in horses, but is easily overlooked. Little published material exists on this important area of equine medicine. Skin tumors continue to challenge veterinarians working with donkeys. This article outlines the main disease entities that the author has encountered, although there are many other diseases and disorders that occur in different parts of the world that are not yet appreciated. When investigating a skin disease, a logical and comprehensive clinical approach should always be made; many conditions are similar in clinical presentation or are co...
Evaluation of allogeneic freeze-dried platelet lysate in cartilage exposed to interleukin 1-β in vitro.
BMC veterinary research    November 1, 2019   Volume 15, Issue 1 386 doi: 10.1186/s12917-019-2118-z
Camargo Garbin L, McIlwraith CW, Frisbie DD.Platelet-rich plasma (PRP) as well as other platelet-derived products have been used as a potential disease-modifying treatment for musculoskeletal diseases, such as osteoarthritis (OA). The restorative properties of such products rely mainly on the high concentrations of growth factors, demonstrating encouraging results experimentally and clinically. Yet, the autologous blood-derived nature of the PRP product lead to limitations that precludes it's widespread use. The main limitations for PRP use are; product variability, the need for minimum laboratory settings in most cases, and the need fo...
Relaxing effects of clenbuterol, ritodrine, salbutamol and fenoterol on the contractions of horse isolated bronchi induced by different stimuli.
Research in veterinary science    October 31, 2019   Volume 128 43-48 doi: 10.1016/j.rvsc.2019.10.022
Pozzoli C, Bertini S, Poli E, Placenza G, Menozzi A.β-adrenoceptor agonists are considered the most effective drugs to counteract bronchoconstriction in horses with asthma, but only clenbuterol is commonly employed in clinical practice. We evaluated the effects of different selective β agonists: clenbuterol, ritodrine, salbutamol, and fenoterol on the contractions of isolated bronchial muscle of horses induced by electrical field stimulation (EFS), carbachol, histamine, and KCl. All β agonists reduced the amplitude of contraction induced by the different stimuli but with variable efficacy and potency. Fenoterol and salbutamol were more effec...
Cutaneous Leishmaniosis caused by Leishmania martiniquensis in a Horse in Florida.
Journal of comparative pathology    October 31, 2019   Volume 173 13-18 doi: 10.1016/j.jcpa.2019.09.011
Menezes RC, Campos MP, Popielarczyk M, Kiupel M.We report a new case of cutaneous leishmaniosis caused by Leishmania (Mundinia) martiniquensis in a horse in Florida, USA. A 10-year-old neutered male Quarter horse was presented with multifocal to coalescing, raised, ulcerated and oozing, non-healing wounds on both pinnae of several weeks' duration. After a few months, the lesions regressed spontaneously. Biopsies of the lesions were performed with microscopical findings of epidermal hyperplasia with multifocal ulceration and focally extensive, dermal pyogranulomatous inflammation with numerous intact and degenerate neutrophils being surround...
Inter- and Intra-Rater Reliability of Soft Tissue Palpation Scoring in the Equine Thoracic Epaxial Region.
Journal of equine veterinary science    October 31, 2019   Volume 83 102812 doi: 10.1016/j.jevs.2019.102812
Merrifield-Jones M, Tabor G, Williams J.Back pain is a significant factor for horses and is challenging for professionals to diagnose, with assessment frequently using subjective tools such as manual palpation. Reliable and valid objective measures are required and use of a pressure algometer (PA) has been investigated as an assessment tool; however, it has limitations, and other more realistic methods may be better suited for the task. The aim of the study was to establish inter- and intra-rater reliability for PA, FlexiForce Sensor (FFS), and manual palpation for equine epaxial soft tissue, measuring mechanical nociception thresho...
The mule (Equus mulus) as a recipient of horse (Equus caballus) embryos: Comparative aspects of early pregnancy with mares.
Theriogenology    October 30, 2019   Volume 145 217-225 doi: 10.1016/j.theriogenology.2019.10.029
Camargo CE, Rechsteiner SF, Macan RC, Kozicki LE, Gastal MO, Gastal EL.The aim of this study was to compare the embryonic and early fetal development of horse embryos between recipient mules and mares from day 10-60 of pregnancy, in addition to hormonal (eCG and progesterone), ovarian, and uterine characteristics for approximately 4 months. Embryo donor mares (n = 5) and two groups of recipients (acyclic mules, n = 7; cyclic mares, n = 7) were used. Donor mares were monitored daily by transrectal ultrasonography and inseminated using fresh semen. Cyclic recipient mares were synchronized with the donor's ovulation using PGF2α and deslorelin acetate. M...
Enteroinsular axis response to carbohydrates and fasting in healthy newborn foals.
Journal of veterinary internal medicine    October 30, 2019   Volume 33, Issue 6 2752-2764 doi: 10.1111/jvim.15641
Rings LM, Swink JM, Dunbar LK, Burns TA, Toribio RE.The enteroinsular axis (EIA) comprises intestinal factors (incretins) that stimulate insulin release after PO ingestion of nutrients. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the main incretins. The EIA has not been investigated in healthy neonatal foals but should be important because energy demands are high in healthy foals and dysregulation is frequent in sick foals. Objective: To evaluate the EIA response to carbohydrates or fasting in newborn foals. We hypothesized that incretin secretion would be higher after PO versus IV carbohydrate adm...
Estimation of glomerular filtration rate by plasma clearance of iohexol in healthy horses of various ages.
Journal of veterinary internal medicine    October 30, 2019   Volume 33, Issue 6 2765-2769 doi: 10.1111/jvim.15642
Plasma clearance of iohexol is a reliable method to assess the glomerular filtration rate (GFR). The relationship between aging and GFR in horses is unclear. To compare GFR estimated by iohexol clearance in horses of different ages. Twenty-one clinically healthy horses were enrolled. Prospective study. Groups: (A) composed by 8 young horses (≤14 years old) with serum creatinine <1.5 mg/dL, (B) by 7 aged horses (≥20 years old) with serum creatinine <1.5 mg/dL, and (C) by 6 aged horses (≥20 years old) with serum creatinine ≥1.5 mg/dL. Iohexol was injected (75.5 mg/kg) through...
Ex vivo evaluation of an alternative technique for resection of the proximal manica flexoria in horses.
Veterinary surgery : VS    October 30, 2019   Volume 49, Issue 2 401-408 doi: 10.1111/vsu.13336
Noguera Cender A, Mählman K, Lischer CJ.To describe and evaluate an alternative technique for tenoscopic resection of the manica flexoria (MF). Methods: Descriptive study. Methods: Equine cadaver forelimbs and hind limbs (n = 36). Methods: Three surgeons varying in experience resected the MF in 12 limbs. The procedure was divided into six steps, including resection of the lateral/medial borders of the MF with a hook knife and resection of the proximal border with a micro scalpel. Outcomes compared between surgeons included completeness of resection, appearance of the margins of resection, appearance of the resected MF, collateral da...
Exercise Induced Laryngeal Obstruction in Humans and Equines. A Comparative Review.
Frontiers in physiology    October 30, 2019   Volume 10 1333 doi: 10.3389/fphys.2019.01333
Fretheim-Kelly ZL, Halvorsen T, Clemm H, Roksund O, Heimdal JH, Vollsæter M, Fintl C, Strand E.Dynamic obstructions of the larynx are a set of disorders that occur during exercise in equines and humans. There are a number of similarities in presentation, diagnosis, pathophysiology and treatment. Both equines and humans present with exercise intolerance secondary to dyspnea. During laryngoscopy at rest, the larynx appears to function normally. Abnormalities are only revealed during laryngoscopy at exercise, seemingly triggered by increased ventilatory demands, and quickly resolve after cessation of exercise. Lower airway disease (asthma being the most prevalent condition), cardiac diseas...
Superovulation, embryo recovery, and pregnancy rates from seasonally anovulatory donor mares treated with recombinant equine FSH (reFSH).
Theriogenology    October 29, 2019   Volume 142 291-295 doi: 10.1016/j.theriogenology.2019.10.030
Roser JF, Etcharren MV, Miragaya MH, Mutto A, Colgin M, Losinno L, Ross PJ.The effectiveness of different treatments with recombinant equine FSH to stimulate follicular growth, multiple ovulations and embryo production in seasonally anovulatory mares was evaluated. During mid-winter season (July-August in Argentina, South America) forty light breed donor mares, presenting follicles <10 mm in diameter and no CL at ultrasound examination (deep-anestrus), were randomly assigned (n = 10/group) to one of the following treatments: Group 1: twice daily intramuscular (IM) injections of 0.65 mg reFSH (AspenBio Pharma, CO), Group 2: once daily IM injection of 1.3 mg ...
Impact of alpha-tocopherol deficiency and supplementation on sacrocaudalis and gluteal muscle fiber histopathology and morphology in horses.
Journal of veterinary internal medicine    October 29, 2019   Volume 33, Issue 6 2770-2779 doi: 10.1111/jvim.15643
Bookbinder L, Finno CJ, Firshman AM, Katzman SA, Burns E, Peterson J, Dahlgren A, Ming-Whitfield B, Glessner S, Borer-Matsui A, Valberg SJ.A subset of horses deficient in alpha-tocopherol (α-TP) develop muscle atrophy and vitamin E-responsive myopathy (VEM) characterized by mitochondrial alterations in the sacrocaudalis dorsalis medialis muscle (SC). Objective: To quantify muscle histopathologic abnormalities in subclinical α-TP deficient horses before and after α-TP supplementation and compare with retrospective (r)VEM cases. Methods: Prospective study; 16 healthy α-TP-deficient Quarter Horses. Retrospective study; 10 retrospective vitamin E-responsive myopathy (rVEM) cases . Methods: Blood, SC, and gluteus medius (GM) biops...
Colic surgery: keeping it affordable for horse owners.
The Veterinary record    October 28, 2019   Volume 185, Issue 16 505-507 doi: 10.1136/vr.l6062
Archer DC.No abstract available
Nonsurgical and surgical management of metacarpo/metatarsophalangeal joint dorsal chip fracture in the Thoroughbred racehorse.
Equine veterinary journal    October 28, 2019   Volume 52, Issue 3 399-403 doi: 10.1111/evj.13185
Ramzan PHL, Wylie CE.Arthroscopy is considered the treatment of choice for dorsal osteochondral chip fractures of the metacarpo/metatarsophalangeal (MCP/MTP) joints in the racehorse; however, there is no published research on non-surgical management of this injury. Objective: To compare clinical features, intra-articular medication use and return to racing in Thoroughbred racehorses with non-surgically (non-SX) or surgically (SX) managed MCP/MTP dorsal chip fracture. Methods: Retrospective observational study conducted between 2006 and 2014. Methods: Radiographs of Thoroughbred racehorses were reviewed to identify...
Application of embryo biopsy and sex determination via polymerase chain reaction in a commercial equine embryo transfer program in Argentina.
Reproduction, fertility, and development    October 28, 2019   Volume 31, Issue 12 1917-1925 doi: 10.1071/RD19228
Riera FL, Roldán JE, Espinosa JM, Fernandez JE, Ortiz I, Hinrichs K.Embryo biopsy for fetal sexing has clinical application, but few reports are available of its use within an active embryo transfer program. We evaluated results on biopsy of 459 embryos over one breeding season. There were no significant differences in pregnancy rate between biopsied and non-biopsied embryos (72% vs 73%) or for biopsied embryos recovered at the centre (73%) compared with those shipped overnight (72%). However, the pregnancy rate decreased significantly in shipped embryos biopsied ≥20h after collection. Overall, 86% of biopsies provided a sex diagnosis. The likelihood of a po...
BEVA primary care clinical guidelines: Analgesia.
Equine veterinary journal    October 28, 2019   Volume 52, Issue 1 13-27 doi: 10.1111/evj.13198
Bowen IM, Redpath A, Dugdale A, Burford JH, Lloyd D, Watson T, Hallowell GD.Primary care guidelines provide a reference point to guide clinicians based on a systematic review of the literature, contextualised by expert clinical opinion. These guidelines develop a modification of the GRADE framework for assessment of research evidence (vetGRADE) and applied this to a range of clinical scenarios regarding use of analgesic agents. Key guidelines produced by the panel included recommendations that horses undergoing routine castration should receive intratesticular local anaesthesia irrespective of methods adopted and that horses should receive NSAIDs prior to surgery (ove...
Investigation into pathophysiology of naturally occurring palatal instability and intermittent dorsal displacement of the soft palate (DDSP) in racehorses: Thyro-hyoid muscles fatigue during exercise.
PloS one    October 25, 2019   Volume 14, Issue 10 e0224524 doi: 10.1371/journal.pone.0224524
Cercone M, Olsen E, Perkins JD, Cheetham J, Mitchell LM, Ducharme NG.Exercise induced intermittent dorsal displacement of the soft palate (DDSP) is a common cause of airway obstruction and poor performance in racehorses. The definite etiology is still unclear, but through an experimental model, a role in the development of this condition was identified in the dysfunction of the thyro-hyoid muscles. The present study aimed to elucidate the nature of this dysfunction by investigating the spontaneous response to exercise of the thyro-hyoid muscles in racehorses with naturally occurring DDSP. Intramuscular electrodes were implanted in the thyro-hyoid muscles of nin...
Re-evaluation of the pharmacokinetics of xylazine administered to Thoroughbred horses.
Journal of veterinary pharmacology and therapeutics    October 25, 2019   Volume 43, Issue 1 6-12 doi: 10.1111/jvp.12820
Habershon-Butcher J, Cutler C, Viljanto M, Hincks PR, Biddle S, Paine SW.Xylazine is widely used worldwide as a short-acting sedative in general equine and racing practice. In the UK, although it has a legitimate use during training, equine anti-doping rules state it is a prohibited substance on race day. The aim of the study was to produce a detection time (DT) to better inform European veterinary surgeons so that xylazine can be used appropriately under regulatory rules. Previous publications have various limitations pertaining to analysis method, particularly for plasma and limited length of time of sample collection. In this study, pharmacokinetic data were pro...
Single-dose pharmacokinetics of orally and rectally administered misoprostol in adult horses.
American journal of veterinary research    October 24, 2019   Volume 80, Issue 11 1026-1033 doi: 10.2460/ajvr.80.11.1026
Lopp CT, McCoy AM, Boothe D, Schaeffer DJ, Lascola K.To characterize the pharmacokinetics of a clinically relevant dose of misoprostol administered PO or per rectum (PR) to horses. Methods: 8 healthy adult horses. Methods: In a randomized 3-way crossover design, horses received a single dose of misoprostol (5 μg/kg) administered PO (with horses fed and unfed) and PR, with a minimum 3-week washout period separating the experimental conditions. Blood samples were obtained before and at various points after drug administration (total, 24 hours), and plasma concentrations of misoprostol free acid were measured. Results: Mean maximum plasma concentr...
Atrial premature depolarisations five days post electrical cardioversion are related to atrial fibrillation recurrence risk in horses.
Equine veterinary journal    October 24, 2019   Volume 52, Issue 3 374-378 doi: 10.1111/evj.13186
Vernemmen I, De Clercq D, Decloedt A, Vera L, Van Steenkiste G, van Loon G.The number of atrial premature depolarisations (APDs) is a known risk factor for atrial fibrillation (AF) recurrence in humans. Objective: To evaluate if the number of APDs over a 24-h period 5 days post cardioversion predicts AF recurrence within 1 year in horses, taking the multifactorial nature of AF into account. Methods: Retrospective case series. Methods: Eighty horses met these inclusion criteria: first AF episode, no AF recurrence within 5 days post cardioversion, cardioversion by transvenous electrical cardioversion (TVEC), 24-h ECG recording and echocardiographic examination 5 da...
Influence of digital hypothermia on lamellar events related to IL-6/gp130 signalling in equine sepsis-related laminitis.
Equine veterinary journal    October 24, 2019   Volume 52, Issue 3 441-448 doi: 10.1111/evj.13184
Dern K, Burns TA, Watts MR, van Eps AW, Belknap JK.Interleukin-6 (IL-6) is consistently increased in the digital lamellae in different studies of sepsis-related laminitis (SRL). IL-6 signalling through the gp130 receptor activates similar signalling (i.e. mTORC1-related signalling) previously reported to be activated in models of endocrinopathic laminitis. Objective: To assess the activation state of signalling proteins downstream of IL-6/gp130 receptor complex activation in an experimental model of SRL. Methods: Randomised experimental study. Methods: Lamellar phospho-(P) protein concentrations downstream of the IL-6/gp130 receptors were asse...
Use of rotational periosteal flaps in primary repair of sinofacial fractures in seven horses.
New Zealand veterinary journal    October 24, 2019   Volume 68, Issue 2 119-125 doi: 10.1080/00480169.2019.1675555
Gustafsson K, Tatz AJ, Dahan R, Kelmer G.Case history: Medical records were reviewed of horses (n = 7) undergoing surgery for fracture of one or more facial bones extending into the paranasal sinuses that was repaired primarily within 24 hours of the time of injury using a rotational periosteal flap, between April 2009 and May 2017. A kick from another horse was the cause of the injury of three horses, and one horse was injured when it collided with a tree. The cause of the injury of three horses was unknown.Clinical findings and treatment: Fractures were of the right maxillary bone in two horses, the left maxillary bone in two h...
Plasma adrenocorticotropic hormone concentration in horses decreases after freezing for 60 days. Haffner JC, Neal DL, Hoffman RM, Grubbs ST.We investigated the stability of adrenocorticotropic hormone (ACTH) in plasma after freezing for different lengths of time. The plasma ACTH concentrations of 12 horses were measured on day 0 (baseline) and over time, after stimulation with thyrotropin-releasing hormone. Samples were stored at -80°C for 3, 7, 30, 60, and 90 d, or at -20°C for 3, 7, 30, and 60 d, or between ice packs at -20°C for 3 and 7 d prior to determination of ACTH concentration. ACTH concentrations were compared to baseline (non-frozen day 0 plasma) for each storage method using a mixed model with repeated measure...
Effect of hCG application at different moments of the estrous cycle on corpus luteum and uterine vascularization and serum progesterone concentration in mares.
Animal reproduction    October 24, 2019   Volume 16, Issue 2 317-327 doi: 10.21451/1984-3143-AR2018-0103
Alonso MA, Silva LA, Affonso FJ, Lemes KM, Celeghini ECC, Lançoni R, Carvalho HF, de Arruda RP.Establishment of pregnancy after embryo transfer is the ultimate goal of an embryo transfer program and increasing pregnancy rates and reducing pregnancy loss are mandatory. The utilization of treatments to improve conception rates in recipient mares has been the focus of several research groups over the last years and the results are controversial. Some studies using human chorionic gonadotrophin (hCG) found promising results. Our hypothesis was that hCG administration would cause an additional stimulation on luteal function, uterine and luteal vascularization and progesterone concentration, ...
Comparison of sperm selection techniques in donkeys: motile subpopulations from a practical point of view.
Animal reproduction    October 23, 2019   Volume 16, Issue 2 282-289 doi: 10.21451/1984-3143-AR2018-0133
Ortiz I, Dorado J, Morrell JM, Diaz-Jimenez MA, Pereira B, Consuegra C, Hidalgo M.The aim of this study was to compare the post-thaw distribution of motile sperm subpopulations, following simple or colloid centrifugation. A new analysis was used to evaluate the available number of sperm from each subpopulation after each centrifugation protocol. Frozen/thawed semen samples were divided into the following after-thawing treatments: uncentrifuged control (UDC), sperm washing (SW) and two colloid centrifugation procedures (Equipure, SLC-E, and Androcoll, SLC-A). Percentage of total and progressive motility (TM and PM), as well as sperm motility kinematics, distribution of motil...
Can we use LDL instead of egg yolk in BotuCrio® extender to cryopreserve sperm from the Mangalarga Marchador stallion?
Animal reproduction    October 23, 2019   Volume 16, Issue 2 340-347 doi: 10.21451/1984-3143-AR2019-0039
Snoeck PPDN, Pessoa THO, Pereira MGS, Bastos ICL, de Melo MIV.The objective of this study was to compare the BotuCrio extender with the Merk - egg yolk and the INRA 82 modified by the inclusion of acetamide, methyl cellulose and trehalose in substitution of glycerol for freezing equine semen. The semen was diluted after centrifugation to obtain 100 x 10 of sperm/ml in: BotuCrio (control); Merk - egg yolk or INRA 82 modified (Experiment 1). The extended semen was packaged in 0.5 ml straws, cooled and frozen in a freezing machine. The control extender was superior in preserving the motility, VCL, VSL, VAP, LIN, STR and the BCF when compared to the Merk - e...
Antigen array for serological diagnosis and novel allergen identification in severe equine asthma.
Scientific reports    October 23, 2019   Volume 9, Issue 1 15170 doi: 10.1038/s41598-019-51820-7
White SJ, Moore-Colyer M, Marti E, Hannant D, Gerber V, Coüetil L, Richard EA, Alcocer M.Severe equine asthma (sEA), which closely resembles human asthma, is a debilitating and performance-limiting allergic respiratory disorder which affects 14% of horses in the Northern Hemisphere and is associated with increased allergen-specific immunoglobulin E (IgE) against a range of environmental proteins. A comprehensive microarray platform was developed to enable the simultaneous detection of allergen-specific equine IgE in serum against a wide range of putative allergenic proteins. The microarray revealed a plethora of novel pollen, bacteria, mould and arthropod proteins significant in t...