Respiratory tract symptoms in multi-day trail runners - a focus on allergy.

Thesis (M.Med.Sc.)-University of KwaZulu-Natal, Westville, 2012.Introduction: Respiratory tract symptoms (RTS), common in athletes during heavy training and after events, result in impaired readiness for events and race times. Since the 1980’s exercise immunologists have investigated the aetiological factors surrounding the development of exercise induced RTS in order to develop effective preventative strategies. A number of theories have been put forward and explored, such as increased susceptibility to infection, ‘run-away’ inflammatory response and reactivation of prior viral infection. It has been suggested that the mechanisms producing exercise induced inflammation could potentiate allergic responses in sensitized individuals and recently allergic response has been proposed as a potential contributor to exercise induced RTS. Certainly allergic reactions can produce a range of respiratory symptoms; however the relationship between allergic sensitization, allergic reaction and the incidence of post-exercise RTS has not been well defined. Objectives: The primary objective of this study was to document the incidence of RTS for two weeks before and two weeks after a three-day trail run and relate these to the general systemic and salivary immunological profile as well as atopic status of the participants. The secondary objective was to validate the use of the Phadiatop® assay as a predictor of allergy-associated post-race RTS in trail runners. Study Design and Methods: The study formed part of a larger, descriptive field study examining the physiological responses of trail runners during the Three Cranes Challenge, a multi-day 95 km event divided into three stages, in Karkloof, KwaZulu-Natal. Outcome measures examined included self- reported RTS over a 31 day period (pre, during and post race), as well as pre-race Phadiatop® status, salivary IgA (sIgA) concentrations and changes in concentrations of serum IgE (sIgE), cortisol, high sensitivity C-Reactive Protein (hs-CRP) and differential leukocyte counts. The haematological and salivary parameters were obtained at 8 time points before, during and after the event. A convenience sample of 22 individuals was used and two separate analyses were conducted on the data. The inclusion criteria of the first analysis were met by 14 participants. In this analysis, the incidence of RTS was related to each participant’s general immunological profile. Sixteen of the subjects met the inclusion criteria for the second analysis, in which their Phadiatop® status was related to their sIgE and blood eosinophil and basophil concentrations in order to establish the validity of the Phadiatop® assay in predicting the development of allergy–associated postexercise RTS in trail runners. Results: In the first analysis, 78.6 % (n=11) of subjects met the criteria for positive diagnosis of upper respiratory symptoms (URS) during the two week post-race period. In four subjects (36.4 %), URS appeared to be of inflammatory origin, but these were not linked to systemic markers of an allergic response. Of the URS positive subjects, six (54.5 %) presented with markers of infection, three (27.3 %) with markers of a de novo infection and three (27.3%) with a profile suggestive of reactivation of previous infection. Of those presenting with markers of infection 66.7 % (n=4) had concomitantly elevated levels of IgE suggestive of allergic response. There was, however, no evidence of isolated allergic reaction independent of other causes amongst the symptomatic subjects. In the second analysis, 75% (n=12) of runners presented with post-race RTS and seven of these were Phadiatop® positive. In four of the Phadiatop® positive RTS subjects, symptoms appeared to be of allergic origin. Although total IgE concentrations were significantly higher (p< 0.01) in Phadiatop® positive group, there was no significant difference between the eosinophil and basophil concentrations or post-race RTS of the positive and negative groups (p>0.05). Of the four subjects who did not develop RTS, three were Phadiatop® positive. Conclusion: Respiratory tract symptoms in trail runners have a multi-factorial aetiology. A link between concurrent markers of an allergic response and infection is common in symptomatic trail runners. The Phadiatop® assay does not accurately predict the incidence of allergic postexercise RTS in trail runners

Bottom-Up Preparation Techniques for Nanocrystals of Lipophilic Drugs

# The Author(s) 2010. This article is published with open access at Springerlink.com KEY WORDS bottom-up. large-scale production. nanocrystal. solubilit

Psychosocial sequelae in 29 children with giant congenital melanocytic naevi

Giant congenital melanocytic naevus (GCMN) may be expected to affect psychosocial functioning of children and their parents due to deviant appearance and painful treatment. To obtain insight into clinical aspects and psychosocial functioning of those suffering from GCMN, 29 children diagnosed with GCMN syndrome or single GCMN received a dermatological examination, were interviewed, and their mothers and teachers completed standardized questionnaires on the child's competence and behavioural/emotional problems and their own adjustment. Social problems were reported for 30% of the patients and behavioural/emotional problems for 25.9%. There was no correlation between visibility of the naevus, treatment or child age and psychological problems. Mothers reported considerable psychosocial burden. It is concluded that children with GCMN are at increased risk of social and behavioural/emotional problems, and mothers suffer considerable psychological impact of their child's condition

CLSM as Quantitative Method to Determine the Size of Drug Crystals in a Solid Dispersion

PURPOSE: To test whether confocal laser scanning microscopy (CLSM) can be used as an analytical tool to determine the drug crystal size in a powder mixture or a crystalline solid dispersion. METHODS: Crystals of the autofluorescent drug dipyridamole were incorporated in a matrix of crystalline mannitol by physical mixing or freeze-drying. Laser diffraction analysis and dissolution testing were used to validate the particle size that was found by CLSM. RESULTS: The particle size of the pure drug as determined by laser diffraction and CLSM were similar (D(50) of approximately 22 μm). CLSM showed that the dipyridamole crystals in the crystalline dispersion obtained by freeze-drying of less concentrated solutions were of sub-micron size (0.7 μm), whereas the crystals obtained by freeze-drying of more concentrated solutions were larger (1.3 μm). This trend in drug crystal size was in agreement with the dissolution behavior of the tablets prepared from these products. CONCLUSION: CLSM is a useful technique to determine the particle size in a powder mixture. Furthermore, CLSM can be used to determine the drug crystal size over a broad size distribution. A limitation of the method is that the drug should be autofluorescent

Controlled Crystallization of the Lipophilic Drug Fenofibrate During Freeze-Drying: Elucidation of the Mechanism by In-Line Raman Spectroscopy

We developed a novel process, “controlled crystallization during freeze-drying” to produce drug nanocrystals of poorly water-soluble drugs. This process involves freeze-drying at a relatively high temperature of a drug and a matrix material from a mixture of tertiary butyl alcohol and water, resulting in drug nanocrystals incorporated in a matrix. The aim of this study was to elucidate the mechanisms that determine the size of the drug crystals. Fenofibrate was used as a model lipophilic drug. To monitor the crystallization during freeze-drying, a Raman probe was placed just above the sample in the freeze-dryer. These in-line Raman spectroscopy measurements clearly revealed when the different components crystallized during freeze-drying. The solvents crystallized only during the freezing step, while the solutes only crystallized after the temperature was increased, but before drying started. Although the solutes crystallized only after the freezing step, both the freezing rate and the shelf temperature were critical parameters that determined the final crystal size. At a higher freezing rate, smaller interstitial spaces containing the freeze-concentrated fraction were formed, resulting in smaller drug crystals (based on dissolution data). On the other hand, when the solutes crystallized at a lower shelf temperature, the degree of supersaturation is higher, resulting in a higher nucleation rate and consequently more and therefore smaller crystals. In conclusion, for the model drug fenofibrate, a high freezing rate and a relatively low crystallization temperature resulted in the smallest crystals and therefore the highest dissolution rate

A cross-sectional study on fatigue, anxiety, and symptoms of depression and their relation with medical status in adult patients with Marfan syndrome:Psychological consequences in Marfan syndrome

Marfan syndrome (MFS) is a connective tissue disorder affecting the cardiovascular, ocular, and skeletal system, which may be accompanied by psychological features. This study aimed to determine the prevalence of fatigue, anxiety, and symptoms of depression in MFS patients, and to assess the degree to which sociodemographic and clinical variables are associated with fatigue and psychological aspects. The prevalence of fatigue, anxiety, and symptoms of depression were assessed in two cohorts of MFS patients and compared with healthy controls. The checklist individual strength (CIS), and hospital anxiety and depression scale (HADS) questionnaires were utilized. Medical status was assessed (family history of MFS, aortic root dilatation >40 mm, previous aortic surgery, aortic dissection, chronic pain, skeletal involvement, and scoliosis). Severe fatigue was experienced by 37% of the total MFS cohort (n = 155). MFS patients scored significantly higher on the CIS questionnaire, concerning severe fatigue, as compared with the general Dutch population (p < 0.0001). There were no differences in HADS anxiety or depression scores. In older MFS patients, with a more severe cardiovascular phenotype, chronic pain, and a higher unemployment rate, significantly more symptoms of depression were observed, when compared with the general population (p = 0.027) or compared with younger MFS patients (p = 0.026). Multivariate analysis, showed that anxiety was associated with chronic pain (p = 0.022) and symptoms of depression with unemployment (p = 0.024). MFS patients report significantly more severe fatigue as compared with the general population. Since the cause of fatigue is unclear, more research may be needed. Psychological intervention, for example, cognitive behavioral therapy, may contribute to a reduction in psychological symptoms

Symmetric dithiodigalactoside: strategic combination of binding studies and detection of selectivity between a plant toxin and human lectins

Thioglycosides offer the advantage over O-glycosides to be resistant to hydrolysis. Based on initial evidence of this recognition ability for glycosyldisulfides by screening dynamic combinatorial libraries, we have now systematically studied dithiodigalactoside on a plant toxin (Viscum album agglutinin) and five human lectins (adhesion/growth-regulatory galectins with medical relevance e.g. in tumor progression and spread). Inhibition assays with surface-presented neoglycoprotein and in solution monitored by saturation transfer difference NMR spectroscopy, flanked by epitope mapping, as well as isothermal titration calorimetry revealed binding properties to VAA (Ka: 1560 ± 20 M-1). They were reflected by the structural model and the affinity on the level of toxin-exposed cells. In comparison, galectins were considerably less reactive, with intrafamily grading down to very minor reactivity for tandem-repeat-type galectins, as quantitated by radioassays for both domains of galectin-4. Model building indicated contact formation to be restricted to only one galactose moiety, in contrast to thiodigalactoside. The tested lycosyldisulfide exhibits selectivity between the plant toxin and the tested human lectins, and also between these proteins. Therefore, glycosyldisulfides have potential as chemical platform for inhibitor design

Tissue-specific suppression of thyroid hormone signaling in various mouse models of aging

DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNAdamaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging