Combined mediator blockade or topical steroid for treating the unified allergic airway

BACKGROUND: Asthma and allergic rhinitis are manifestations of a single unified allergic airway, for which the best treatment is uncertain. OBJECTIVE: To compare the anti-inflammatory efficacy in the unified allergic airway of combined oral mediator antagonism and combined topical steroid. METHODS: Subjects with asthma and perennial allergic rhinitis entered a randomized double blind crossover study comparing montelukast 10 mg and cetirizine 10 mg to extra-fine inhaled beclomethasone 400 mcg/day and intranasal beclomethasone 200 mcg/day, each taken once daily for 2 months, after 2-week placebo washouts. Measurements were made after each washout and randomized treatment, comprising: methacholine PC20, exhaled and nasal nitric oxide, blood eosinophils and eosinophilic cationic protein, symptoms, lung and nasal function tests. RESULTS: Seventeen patients completed per protocol. For PC20 and exhaled nitric oxide, only combined topical steroid produced improvements (P < 0.005) from placebo baseline. Combined steroid was superior by a 0.93 (95% CI 0.14-0.93, P < 0.05) doubling dilution difference for PC20 and a 0.99 (95% CI 0.9-15.1, P < 0.01) doubling difference for exhaled nitric oxide. Both treatments attenuated eosinophils and eosinophilic cationic protein, and reduced nasal symptoms (P < 0.05). Only steroid improved nasal nitric oxide (P=0.05) and asthma symptoms (P < 0.05). Neither treatment affected lung or nasal function tests. CONCLUSION: Combined topical steroid and combined mediator antagonism both attenuated systemic inflammation in the unified allergic airway, but only the former reduced bronchial and nasal inflammatory markers. The relevance of this to exacerbations and airway remodelling needs to be defined.     

Significance of abnormal sonographic findings in postmenopausal women with and without bleeding

ObjectiveWe sought to determine the incidence of cancer and to compare pathologic outcomes in bleeding and non-bleeding postmenopausal patients who underwent hysteroscopy.MethodsWe conducted a retrospective chart review of 294 postmenopausal women with abnormal uterine bleeding and 142 postmenopausal women without symptoms who underwent hysteroscopy. An 11 mm cut-off for asymptomatic women was applied to determine whether this endometrial thickness threshold would differentiate women with and without endometrial cancer in the asymptomatic group.ResultsIn symptomatic patients, 14 were found to have endometrial cancer and 10 were found to have endometrial hyperplasia. In the asymptomatic group, two women (1. 4%) were found to have endometrial cancer with average thickness 17 . 5 mm, and one (0 . 71%) was found to have endometrial hyperplasia . Logistic regression models showed the risk of a bleeding patient developing endometrial cancer at an endometrial thickness of 4 mm was the same as the risk in a non-bleeding patient at a thickness of 15 mm.ConclusionAsymptomatic postmenopausal women have a low risk of having significant endometrial pathology . Cancer was approximately four times more prevalent in women with bleeding than in women with no bleeding     

Applying the Verona coding definitions of emotional sequences (VR-CoDES) in the dental context involving patients with complex communication needs: An exploratory study

Objective

The VR-CoDES has been previously applied in the dental context. However, we know little about how dental patients with intellectual disabilities (ID) and complex communication needs express their emotional distress during dental visits. This is the first study explored the applicability of the VR-CoDES to a dental context involving patients with ID.

Methods

Fourteen dental consultations were video recorded and coded using the VR-CoDES, assisted with the additional guidelines for the VR-CoDES in a dental context. Both inter- and intra-coder reliabilities were checked on the seven consultations where cues were observed.

Results

Sixteen cues (eight non-verbal) were identified within seven of the 14 consultations. Twenty responses were observed (12 reducing space) with four multiple responses. Cohen's Kappa were 0.76 (inter-coder) and 0.88 (intra-coder).

Conclusion

With the additional guidelines, cues and responses were reliably identified. Cue expression was exhibited by non-verbal expression of emotion with people with ID in the literature. Further guidance is needed to improve the coding accuracy on multiple providers’ responses and to investigate potential impacts of conflicting responses on patients.

Practice implications

The findings provided a useful initial step towards an ongoing exploration of how healthcare providers identify and manage emotional distress of patients with ID.     

Arginase activity in alternatively activated macrophages protects PI3Kp110δ deficient mice from dextran sodium sulfate induced intestinal inflammation

Alternatively activated or M2 macrophages have been reported to protect mice from intestinal inflammation, but the mechanism of protection has not been elucidated. In this study, we demonstrate that mice deficient in the p110δ catalytic subunit activity of class I phosphatidylinositol 3‐kinase (PI3Kp110δ) have increased clinical disease activity and histological damage during dextran sodium sulfate (DSS) induced colitis. Increased disease severity in PI3Kp110δ‐deficient mice is dependent on professional phagocytes and correlates with reduced numbers of arginase I⁺ M2 macrophages in the colon and increased production of inflammatory nitric oxide. We further demonstrate that PI3Kp110δ‐deficient macrophages are defective in their ability to induce arginase I when skewed to an M2 phenotype with IL‐4. Importantly, adoptive transfer of IL‐4‐treated macrophages derived from WT mice, but not those from PI3Kp110δ‐deficient mice, protects mice during DSS‐induced colitis. Moreover, M2 macrophages mediated protection is lost when mice are cotreated with inhibitors that block arginase activity or during adoptive transfer of arginase I deficient M2 macrophages. Taken together, our data demonstrate that arginase I activity is required for M2 macrophages mediated protection during DSS‐induced colitis in PI3Kp110δ‐deficient mice.     

Epidemiology of severe hepatitis A in Indigenous Australian children

AIMS: To describe the epidemiology of hepatitis A in Indigenous Australian children. METHODS: Analysis and mapping of national notification and hospitalisation data. RESULTS: Indigenous Australian children are at far higher risk of clinical hepatitis A than their non-Indigenous counterparts, particularly in the age group 0-4 years. Rates of hospitalisation (15.5 vs. 0.3 per 100,000) and notification (24.4 vs. 1.8 per 100,000) were higher in Indigenous children aged 0-4 years compared with other children in the same age group. In the age group 5-14 years, the rates were 4.4 per 100,000 (Indigenous) versus 0.6 per 100,000 (non-Indigenous) hospitalisations. This excess morbidity falls sharply with age. Rates were the highest in the Northern Territory, South Australia, Western Australia and North Queensland. CONCLUSIONS: Indigenous children are at risk of hepatitis A, particularly early in life. Mapping shows that rates were the highest in jurisdictions with the largest Indigenous populations. This study presents baseline data against which to measure the success of new hepatitis A vaccination programme for Indigenous Australian children which commenced in 2005.     

Autonomous histopathological regression of primary tumours associated with specific immune responses to cancer antigens

Spontaneous histopathological regression of cancer has been reported. The involvement of the immune system in such regression has been advocated, leading to the theory of immunological surveillance against cancer. A prediction of this theory is that common tumour antigens can be recognized upon repeated exposure by cell-mediated immunity, which leads to tumour regression and the subsequent appearance of tumour antigen-loss variants. However, no direct evidence has been provided in non-viral-induced experimental animal models of primary malignancy or in human primary cancer. This study examined two groups of melanoma patients where histopathological regression of the primary tumour was observed. Many of the 23 patients with multiple (> or =3) primary melanomas showed significant regression of their last melanoma (median 33%, mean 40) compared with matched melanomas from patients with a single primary melanoma (median 0%, mean 12) (p=0.0080), or compared with their first primary melanoma (p=0.0013). Regression was consistent with an 'immunization effect' seen in murine tumour transplantation studies, where inoculation with > or =3 asynchronous tumours induces transplantation rejection on subsequent challenge. A significant decrease in the expression of the melanoma common tumour antigen MART-1 in the last primary tumour from multiple melanoma patients (median 8%, mean 24) versus matched single melanoma patients (median 79%, mean 68) (p=0.0041) and in the last versus first tumour in multiple primary patients was found (p=0.0083). Metastases from 17 patients whose primary skin melanomas had completely regressed (occult primary melanoma) also showed significant MART-1 loss (median 0%, mean 11) compared with matched metastases from patients with non-regressing primary melanoma (median 51%, mean 50) (p=0.0013). MART-1 antigen-loss variants observed in the multiple primary and occult primary patients correlated with the presence of peripheral blood MART-1-specific cytotoxic T lymphocytes (CTLs) (p=0.03). No similar effects were observed with two other melanoma antigens, gp100 and CD63. Thus, in two groups of human melanoma patients, evidence is provided for histopathological tumour regression associated with cancer immune surveillance.     

Dynamic particle image velocimetry flow analysis of the flow field immediately downstream of bileaflet mechanical mitral prostheses

New dynamic particle image velocimetry (PIV) technology was applied to the study of the flow field associated with prosthetic heart valves. Four bileaflet prostheses, the St. Jude Medical (SJM) valve, the On-X valve with straight leaflets, the Jyros (JR) valve, and the Edwards MIRA (MIRA) valve with curved leaflets, were tested in the mitral position under pulsatile flow conditions to find the effect of the leaflet shape and overall valve design on the flow field, particularly in terms of the turbulent stress distribution, which may influence hemolysis, platelet activation, and thrombus formation. Comparison of the time-resolved flow fields associated with the opening, accelerating, peak, and closing phases of the diastolic flow revealed the effects of the leaflet shape and overall valve design on the flow field. Anatomically and antianatomically oriented bileaflet valves were also compared in the mitral position to study the effects of the orientation on the downstream flow field. The experimental program used a dynamic PIV system utilizing a high-speed, high-resolution video camera to map the true time-resolved velocity field inside the simulated ventricle. Based on the experimental data, the following general conclusions can be made. High-resolution dynamic PIV can capture true chronological changes in the velocity and turbulence fields. In the vertical measuring plane that passes the centers of both the aortic and mitral valves (A-A section), bileaflet valves show clear and simple circulatory flow patterns when the valve is installed in the antianatomical orientation. The SJM, the On-X, and the MIRA valves maintain a relatively high velocity through the central orifice. The curved leaflets of the JR valve generate higher velocities with a divergent flow during the accelerating and peak flow phases when the valve is installed in the anatomical orientation. In the velocity field directly below the mitral valve and normal to the previous measuring plane (B-B section), where characteristic differences in valve design on the three-dimensional flow should be visible, the symmetrical divergent nature of the flow generated by the two inclined half-disks installed in the antianatomical orientation was evident. The SJM valve, with a central downward flow near the valve, is contrasted with the JR valve, which has a peripherally strong downward circulation with higher turbulent stresses. The On-X valve has a strong central downward flow attributable to its large opening angle and flared inlet shape. The MIRA valve also has a relatively strong downward central flow. The MIRA valve, however, diverts the flow three-dimensionally due to its peripherally curved leaflets.     

Neural connectivity between the hypothalamic supramammillary nucleus and appetite‐ and motivation‐related regions of the rat brain

The supramammillary nucleus (SuM) has an emerging role in appetite control. We have shown that the rat SuM is activated during hunger or food anticipation, or by ghrelin administration. In the present study, we characterised the connectivity between the SuM and key appetite‐ and motivation‐related nuclei in the rat. In adult wild‐type rats, or rats expressing Cre recombinase under the control of the tyrosine hydroxylase (TH) promoter (TH‐Cre rats), we used c‐Fos immunohistochemistry to visualise and correlate the activation of medial SuM (SuMM) with activation in the lateral hypothalamic area (LH), the dorsomedial hypothalamus (DMH) or the ventral tegmental area (VTA) after voluntary consumption of a high‐sugar, high‐fat food. To determine neuroanatomical connectivity, we used retrograde and anterograde tracing methods to specifically investigate the neuronal inputs and outputs of the SuMM. After consumption of the food there were positive correlations between c‐Fos expression in the SuMM and the LH, DMH and VTA (P = 0.0001, 0.01 and 0.004). Using Fluoro‐Ruby as a retrograde tracer, we demonstrate the existence of inputs from the LH, DMH, VTA and ventromedial hypothalamus (VMH) to the SuMM. The SuMM showed reciprocal inputs to the LH and DMH, and we identified a TH‐positive output from SuMM to DMH. We co‐labelled retrogradely‐labelled sections for TH in the VMH, or for TH, orexin and melanin‐concentrating hormone in the LH and DMH. However, we did not observe any colocalisation of immunoreactivity with any retrogradely‐labelled cells. Viral mapping in TH‐Cre rats confirms the existence of a reciprocal SuMM‐DMH connection and shows that TH‐positive cells project from the SuMM and VTA to the lateral septal area and cingulate cortex, respectively. These data provide evidence for the connectivity of the SuMM to brain regions involved in appetite control, and form the foundation for functional and behavioural studies aiming to further characterise the brain circuitry controlling eating behaviours.     

Incompatibility of contrast agents with intravascular medications. Work in progress

In vitro and in vivo precipitation of iodinated contrast agents when ioxaglate and papaverine are given together has been reported. To verify these reports and to investigate other medications not previously tested, the authors analyzed mixtures of contrast agents and medications in vitro with a light spectrophotometer and observed them for visible precipitates for up to 120 minutes. Previously reported incompatibilities between ionic or low-osmolality contrast media and medications were verified, and several new incompatibilities were discovered. No incompatibilities were found when the drugs tested were mixed with the new nonionic contrast media.