Background and purpose
Edema formation, inflammation and increased blood-brain barrier permeability contribute to poor outcomes after intracerebral hemorrhage (ICH). This study examined the therapeutic effect of Dimethyl fumarate (DMF), a fumaric acid ester that activates nuclear factor erythroid-2 related factor 2 (Nrf2) and Nrf2 heterodimerization effector musculo-aponeurotic fibrosacoma-G (MAFG) in a murine ICH model.
Methods
Male CD-1 mice (n=176) were subjected to intrastriatal infusion of bacterial collagenase (n=120), autologous blood (n=18) or sham surgery (n=30). After ICH, animals either received vehicle, Dimethyl fumarate (10mg or 100mg/kg) or casein kinase 2 inhibitor (E)-3-(2,3,4,5-tetrabromophenyl)acrylic acid (TBCA). Thirty-eight mice also received scrambled siRNA or MAFG siRNA 24 hours before ICH. Brain water content and neurological function were evaluated.
Results
Dimethyl fumarate reduced Evans blue extravasation, decreased brain water content, and improved neurological deficits at 24 and 72 hours after ICH. Casein kinase 2 inhibitor TBCA and MAFG siRNA prevented the effect of Dimethyl fumarate on brain edema and neurological function. After ICH, ICAM-1 levels increased and Casein kinase 2 levels decreased. Dimethyl fumarate reduced ICAM-1 but enhanced Casein kinase 2 levels. Again, Casein kinase 2 inhibitor TBCA and MAFG siRNA abolished the effect of Dimethyl fumarate on ICAM-1 and Casein kinase 2. Dimethyl fumarate preserved pNrf2 and MAFG expression in the nuclear lysate after ICH and the effect of Dimethyl fumarate was abolished by Casein kinase 2 inhibitor TBCA and MAFG siRNA. Dimethyl fumarate reduced microglia activation in peri-hematoma areas after ICH. The protective effect of Dimethyl fumarate on brain edema and neurological function was repeated in a blood injection mouse model.
Conclusion
Dimethyl fumarate ameliorated inflammation, reduced blood barrier permeability, and improved neurological outcomes by Casein kinase 2 and Nrf2 signaling pathways after experimental ICH in mice.
Purpose: Although snake bites occur frequently in Benin City, the prevalence has not been documented. This study was therefore done to determine the prevalence, morbidity, mortality, and the orthodox treatment of victims. Results: Males were twice more often bitten than females, and teenagers and youths in their early twenties constituted the peak age range of victims. Most victims (59.5%) were bitten in the bush or farm. The limbs were the commonest sites of bite with the feet (73.5%) and arms (20.9%) more frequently bitten; both the upper and lower right limbs were also more frequently bitten than the corresponding left limbs. All patients who showed symptoms of envenomation (68.3%) received polyvalent antivenom, 67.4% received antibiotics while over 90% of patients received antitetanus prophylaxis. Some of the patients (61.5 %) were treated with analgesics, while 17.2% and 82.3% received diazepam and intravenous fluids, respectively. Although there was a high degree of morbidity as shown by the long stay of many patients in the hospital (mean duration of stay by patients in hospital is 5.7±5.1 days; range <1-23 days), mortality was not recorded. Conclusion: It is concluded that there is a high prevalence of snake bites with high morbidity especially among the very active youthful segment of the Benin City population.
In order to evaluate whether amlodipine or hydrochlorothiazide would be preferable to initiate therapy, 90 untreated hypertensive Nigerians of both genders aged 31-86 years with blood pressure >160/90 and ≤180/120 mm Hg were recruited into a randomized 48-week study. Patients, 30 each in amlodipine, hydrochlorothiazide, and amlodipine-hydrochlorothiazide groups, were treated, respectively, with amlodipine 5 mg for 6 weeks and the dose increased to 10 mg till week 12, after which hydrochlorothiazide 25 mg was added; hydrochlorothiazide 25 mg till week 6, after which amlodipine 5-10 mg was added; and amlodipine 5-10 mg + hydrochlorothiazide 25 mg. Body mass index, blood pressure, heart rate, and 24-hour urine volume were evaluated at baseline and at the end of weeks 1, 3, 6, 12, 24, 36, and 48. The primary efficacy variables were decreased in mean trough sitting diastolic and systolic blood pressure such that blood pressure < 140/90 mm Hg was regarded as normalized. At week 48 in the amlodipine group, 27 patients versus 25 patients in the hydrochlorothiazide group had diastolic blood pressure <90 mm Hg (90% vs. 83.3%; P <.03). In the amlodipine group, 23 patients versus 20 patients in the hydrochlorothiazide group had blood pressure < 140/90 mm Hg (76.7% vs. 66.7%; P <.01). In the amlodipine-hydrochlorothiazide group, 27 patients (90%) and 15 patients (50%) had diastolic blood pressure <90 mm Hg and blood pressure < 140/90 mm Hg, respectively. This study has demonstrated that a regimen of amlodipine to which hydrochlorothiazide is subsequently added provides superior efficacy on blood pressure control when compared with a regimen of hydrochlorothiazide to which amlodipine is subsequently added or with ab initio amlodipine-hydrochlorothiazide combination therapy.
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