| 1. |
- Heap, Graham A., et al.
(författare)
-
HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants
- 2014
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:10, s. 1131-1134
-
Tidskriftsartikel (refereegranskat)abstract
- Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 x 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the H LA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.
|
|
| 2. |
|
|
| 3. |
- Thompson, Robin N., et al.
(författare)
-
Key questions for modelling COVID-19 exit strategies
- 2020
-
Ingår i: Proceedings of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8452 .- 1471-2954. ; 287:1932
-
Tidskriftsartikel (refereegranskat)abstract
- Combinations of intense non-pharmaceutical interventions (lockdowns) were introduced worldwide to reduce SARS-CoV-2 transmission. Many governments have begun to implement exit strategies that relax restrictions while attempting to control the risk of a surge in cases. Mathematical modelling has played a central role in guiding interventions, but the challenge of designing optimal exit strategies in the face of ongoing transmission is unprecedented. Here, we report discussions from the Isaac Newton Institute 'Models for an exit strategy' workshop (11-15 May 2020). A diverse community of modellers who are providing evidence to governments worldwide were asked to identify the main questions that, if answered, would allow for more accurate predictions of the effects of different exit strategies. Based on these questions, we propose a roadmap to facilitate the development of reliable models to guide exit strategies. This roadmap requires a global collaborative effort from the scientific community and policymakers, and has three parts: (i) improve estimation of key epidemiological parameters; (ii) understand sources of heterogeneity in populations; and (iii) focus on requirements for data collection, particularly in low-to-middle-income countries. This will provide important information for planning exit strategies that balance socio-economic benefits with public health.
|
|
| 4. |
- Dutoit, Andrea P, et al.
(författare)
-
Cardiac baroreflex sensitivity is not correlated to sympathetic baroreflex sensitivity within healthy, young humans.
- 2010
-
Ingår i: Hypertension. - 1524-4563. ; 56:6, s. 1118-1123
-
Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to evaluate the relationship between the cardiac and sympathetic baroreflex sensitivities within healthy, young humans. The sensitivities of the cardiac and sympathetic baroreflexes were compared in 53 normotensive individuals (28 men and 25 women; age: 24.0 ± 0.9 years; body mass index: 24.0 ± 0.3 cm/kg², mean ± SEM). Heart rate, arterial blood pressure, and peroneal muscle sympathetic nerve activity were recorded under resting conditions (heart rate: 58 ± 1 bpm; systolic blood pressure: 126 ± 2 mm Hg; diastolic blood pressure: 72 ± 1 mm Hg; mean arterial blood pressure: 89 ± 1 mm Hg; muscle sympathetic nerve activity: 18 ± 1 bursts per min) and during rapid changes in blood pressure induced by sequential boluses of nitroprusside and phenylephrine. Cardiac and sympathetic baroreflex sensitivities were analyzed using the slopes of the linear portions of the muscle sympathetic nerve activity-diastolic blood pressure and R-R interval-systolic blood pressure relationships, respectively. When individual cardiac baroreflex sensitivity was compared with sympathetic baroreflex sensitivity, no correlation (R-R interval: r = -0.13; heart rate: r = 0.21) was observed when studied as a group. Analysis by sex unveiled a correlation in women between the cardiac and sympathetic baroreflex sensitivities (R-R interval: r = -0.54; P = 0.01; no correlation with hazard ratio: r = 0.29). No relationship was found in men (R-R interval: r = 0.17; heart rate: r = 0.12). These results indicate that, although both cardiac and sympathetic efferents function in baroreflex control of arterial pressure, there is no correlation in their sensitivities within healthy normotensive humans. However, sex-stratified data indicate that sex-based differential correlations might exist.
|
|
| 5. |
|
|
| 6. |
- Hart, Emma C, et al.
(författare)
-
Baroreflex control of muscle sympathetic nerve activity: a nonpharmacological measure of baroreflex sensitivity.
- 2010
-
Ingår i: American journal of physiology. Heart and circulatory physiology. - : American Physiological Society. - 1522-1539 .- 0363-6135. ; 298:3
-
Tidskriftsartikel (refereegranskat)abstract
- The sensitivity of baroreflex control of sympathetic nerve activity (SNA) represents the responsiveness of SNA to changes in blood pressure. In a slightly different analysis, the baroreflex threshold measures the probability of whether a sympathetic burst will occur at a given diastolic blood pressure. We hypothesized that baroreflex threshold analysis could be used to estimate the sensitivity of the sympathetic baroreflex measured by the pharmacological modified Oxford test. We compared four measures of sympathetic baroreflex sensitivity in 25 young healthy participants: the "gold standard" modified Oxford analysis (nitroprusside and phenylephrine), nonbinned spontaneous baroreflex analysis, binned spontaneous baroreflex analysis, and threshold analysis. The latter three were performed during a quiet baseline period before pharmacological intervention. The modified Oxford baroreflex sensitivity was significantly related to the threshold slope (r = 0.71, P < 0.05) but not to the binned (1 mmHg bins) and the nonbinned spontaneous baroreflex sensitivity (r = 0.22 and 0.36, respectively, P > 0.05), which included burst area. The threshold analysis was also performed during the modified Oxford manipulation. Interestingly, we found that the threshold analysis results were not altered by the vasoactive drugs infused for the modified Oxford. We conclude that the noninvasive threshold analysis technique can be used as an indicator of muscle SNA baroreflex sensitivity as assessed by the modified Oxford technique. Furthermore, the modified Oxford method does not appear to alter the properties of the baroreflex.
|
|
| 7. |
- Hart, Emma C, et al.
(författare)
-
Hysteresis in the sympathetic baroreflex: role of baseline nerve activity.
- 2011
-
Ingår i: The Journal of physiology. - : Wiley. - 1469-7793 .- 0022-3751. ; 589:Pt 13, s. 3395-404
-
Tidskriftsartikel (refereegranskat)abstract
- Sympathetic baroreflex sensitivity (BRS) is greater during decreasing compared to increasing diastolic blood pressure (DBP) in young men and women. In older men and women there is no difference in sympathetic BRS to increasing and decreasing DBP. We investigated whether the sensitivity of the central nervous system to increasing and decreasing DBP is dependent upon baseline muscle sympathetic nerve activity (MSNA). We hypothesised that the difference in sympathetic BRS between falling and rising segments of DBP would be positively related to baseline MSNA in 30 young men, 21 young women, 14 older men and 14 postmenopausal women. MSNA was measured using peroneal microneurography and BRS was measured using the spontaneous baroreflex threshold technique. On average, sympathetic BRS was greater during decreasing compared to increasing DBP in young men (P <0.05) and women (P <0.05). In older men and women, mean sympathetic BRS was similar in response to increasing and decreasing DBP. The difference (delta) between the falling and rising BRS correlated with baseline MSNA in young (r =0.58, P <0.05) and older men (r =0.66, P <0.05) and postmenopausal women (r =0.74, P <0.05). Thus, all men, and older women, with higher BRS to falling DBP had lower baseline MSNA. This relationship was not observed in young women (r =0.14, P >0.05). In summary, baseline MSNA plays a role in determining sympathetic BRS to falling and rising DBP in young and older men and postmenopausal women, but not in young women. This relationship is consistent with a decreased potential for sympathoexcitation in people with higher resting MSNA. Furthermore, the lack of relationship in young women suggests important contributions of sex hormones to differential responses of MSNA to falling and rising pressures.
|
|
| 8. |
- Hart, Emma C., et al.
(författare)
-
Sex, ageing and resting blood pressure: Gaining insights from the integrated balance of neural and haemodynamic factors
- 2012
-
Ingår i: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 590, s. 2069-2079
-
Tidskriftsartikel (refereegranskat)abstract
- Young women tend to have lower blood pressure, and less risk of hypertension, compared to young men. As people age, both blood pressure and the risk of hypertension increase in both sexes; this occurs most strikingly in women after menopause. However, the mechanisms for these influences of sex and age remain incompletely understood. In this review we are specifically interested in the interaction between neural (sympathetic nerve activity; SNA) and haemodynamic factors (cardiac output, blood pressure and vascular resistance) and how these change with sex and age. While peripheral vascular SNA can vary 7- to 10-fold among normotensive young men and women, it is reproducible in a given individual. Surprisingly, higher levels of SNA are not associated with higher blood pressures in these groups. In young men, high SNA is associated with higher total peripheral vascular resistance (TPR), and appears to be balanced by lower cardiac output and less peripheral vascular responsiveness to adrenergic stimulation. Young women do not exhibit the SNA-TPR relationship. Recent evidence suggests that β-adrenergic vasodilatation offsets the vasoconstrictor effects of α-adrenergic vasoconstriction in young women, which may contribute to the generally lower blood pressures in this group. Sympathetic nerve activity increases with age, and in groups over 40, levels of SNA are more tightly linked to levels of blood pressure. The potentially protective β-adrenergic effect seen in young women appears to be lost after menopause and probably contributes to the increased blood pressure and increased risk of hypertension seen in older women. © 2012 The Authors. The Journal of Physiology. © 2012 The Physiological Society.
|
|
| 9. |
|
|
| 10. |
|
|
