Since the present study is a large population insurance registrybased cohort study and the temporal sequence between migraine and HS is ordered, this enabled us to establish a temporal association between migraine and HS. Such a temporal relationship is essential for establishing a causal connection. However, several limitations should be acknowledged. First, the diagnosis of migraine, HS, and AbMole Nilotinib (monohydrochloride monohydrate) medical comorbidities in our study was determined by the ICD codes from the NHI claim database and there may be concern about the diagnostic accuracy. However, the Bureau of the NHI has formed different audit committees that randomly sample the claim data from every hospital and review charts on a regular basis to verify the diagnostic validity and quality of care. Accordingly, the NHI claim database is an established research database and has been used in various biomedical research fields. In addition, we used case ascertainment algorithms that required at least two ambulatory medical care visits with a principal diagnosis code of migraine to validate the diagnosis, which might be expected to provide adequate diagnostic accuracy. Second, migraine is often underrecognized and therefore the non-migraine group in our study may include some unrecognized migraineurs. Nevertheless, such potential misclassification is expected to weaken the association between migraine and HS. Therefore, the positive association between migraine and hemorrhagic stroke may be underestimated in our study when considering the potential under-diagnosis of migraine in the non-migraine group. Third, because most of the diagnostic codes of migraine in the NHI claim database were encoded using only the 3-digit ICD-9CM category number without the subcategory number, the information regarding migraine subtypes was incomplete. Nevertheless, our subgroup analysis showed a consistently increased risk of HS in the MA, MO, and MU subgroups, further support for an association between both MA and MO and a higher risk of HS. Fourth, due to the inherent limitations of the NHI database, information was lacking regarding lifestyle factors, such as smoking, alcohol consumption, and obesity, which may affect the interpretation of our findings. Finally, most inhabitants of Taiwan are of Chinese ethnicity and it is uncertain whether our findings can be generalized to other ethnic groups. Multiple sclerosis is a disease that affects the central nervous system. The animal model used to study MS is experimental autoimmune encephalomyelitis that mimics many of the clinical and pathological features of MS. Gironi et al. found a reduction in b-endorphin levels in peripheral blood mononuclear cells from patients with clinically inactive MS. In 1973, endorphins were identified and these peptides were not only shown to act in an antinociceptive manner but also in ameliorating synovitis associated with rheumatoid arthritis and down-regulation of the inflammatory process. b-endorphine is a 31 amino acid opioid peptide synthesized primarily by the arcuate nucleus of the hypothalamus. A second b-endorphin system is found in the anterior pituitary where b-endorphin is co-released with ACTH into the bloodstream and exerts its effects on different target organs. Studies in humans and animals indicated that BE exerted a physiological inhibitory effect on immune function and BE has been shown shift the immune response from Th1 to Th2 response.