Serum concentration-guided intravenous magnesium sulfate administration for neuroprotection in patients with aneurysmal subarachnoid hemorrhage: a retrospective evaluation of a 12-year single-center experience.

Delayed cerebral infarction (DCI) is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). The benefits of magnesium sulfate as an alternative treatment are controversial, and most previous studies examined its benefits only as adjunctive treatment to traditional nimodipine. We retrospectively analyzed aSAH patients records with magnesium sulfate between 2010 and 2021. We aimed for a serum magnesium concentration of 2-2.5 mmol/l between post-hemorrhage days 3 and 12. The patients were separated in three groups based on average serum magnesium concentration (magnesium >2 mmol/l, reduced magnesium 1.1-1.9 mmol/l, and no magnesium). Additionally, we assessed delayed cerebral infarction (DCI) and clinical outcome at follow-up, using the modified Rankin Scale (mRS), categorized in favorable (0-3) and unfavorable outcome (4-5). In this analysis, 548 patients were included. Hereof, radiological evidence of DCI could be found in 23.0% (n = 126) of patients. DCI rates were lower if patients' average serum magnesium was higher than 2 mmol/l (magnesium 18.8%, n = 85; reduced magnesium 38.3%, n = 23; no magnesium 51.4%, n = 18; p < 0.001). Also, at the last follow-up, patients in the group with a higher serum magnesium concentration had better outcome (favorable outcome: magnesium 64.7%, n = 293; reduced magnesium 50.0%, n = 30; no magnesium 34.3%, n = 12; p < 0.001). This 12-year study reveals the value of serum concentration-guided magnesium administration in aSAH patients. Our findings demonstrate the safety and efficacy when titrated to a serum concentration of 2-2.5 mmol/l. We observed higher rates of delayed cerebral infarction and unfavorable outcomes in patients with serum concentrations below 2 mmol/l.

Peripubertal estrogen levels and physical activity affect femur geometry in young adult women.

UNLABELLED: The growing skeleton is particularly responsive to exercise around the time of puberty, suggesting a possible role for estrogen in mechanical adaptation in young women. We assessed femoral neck strength index at age 17 in young women with varying adolescent physical activity levels and E2 levels in the first 3 years after menarche. The results indicate that both E2 levels in the first year after menarche and adolescent physical activity are positively associated with bone strength in young adulthood, such that hormone levels may modify human osteogenic responses to exercise. INTRODUCTION: It is well established that physical activity contributes to bone strength in young females, but less is known about how peripubertal estrogen affects skeletal responses to exercise. METHODS: We used data from 84 participants in the Penn State Young Women's Health Study to test the prediction that young women who (1) had higher E2 levels during the first year after menarche or (2) were more physically active in adolescence will have greater bone strength at the end of adolescence. Subjects were divided into tertiles of physical activity and of E2 level in the first, second, and third postmenarchal years, and femoral strength was calculated from dual-energy X-ray absorptiometry scans of the proximal femur using hip structure analysis. RESULTS: At age 17, subjects with the highest E2 levels in year 1 after menarche had 5-14% greater strength in the narrow neck and intertrochanteric region, and the most active subjects had 10-11% greater strength in the femoral narrow neck vs. less active girls. CONCLUSIONS: This study suggests that both physical activity and peripubertal estrogen have important influences on young adult bone strength and that hormone levels may be mediators of human osteogenic responses to exercise.

The role of the urokinase-type plasminogen activator (uPA) and its receptor (CD87) in lipodermatosclerosis.

BACKGROUND: Lipodermatosclerosis refers to a sclerosing panniculitis and dermopathy of the lower extremities sometimes seen in association with venous ulceration. Matrix metalloproteinases are implicated in the pathogenesis of venous leg ulcers and the in vitro activation of recombinant MMP-2 is controlled by the plasminogen activation system. To better understand the role of plasminogen activation in the pathogenesis of venous leg ulcers we investigated fibrinolytic factors and their inhibitors in tissue samples of lipodermatolsclerosis. METHODS: The expression and the functional state of the urokinase-type plasminogen activator (uPA), the tissue-type plasminogen activator (tPA), the urokinase receptor (CD87), the plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) were assayed using reverse transcription polymerase chain reaction, Western blot, fibrin zymography and immunohistochemistry analyses in tissue samples of lipodermatosclerosis. RESULTS: Our results provide direct evidence of elevated expression of uPA (p<0.01) and CD87 (p<0.01) mRNA and protein level in lipodermatosclerosis in comparison with healthy skin. By immunohistochemistry, elevated expression of uPA and CD87 could be detected. Fibrin zymography showed significantly elevated endogenous uPA activity (p<0.01) in liposclerotic lesions compared to healthy controls. CONCLUSION: Our findings indicate that elevated plasminogen activation in lipodermatosclerotic tissue may play a crucial role in the pathogenesis of venous leg ulceration.

Autologous platelet-derived wound healing factor promotes angiogenesis via alphavbeta3-integrin expression in chronic wounds.

Healing of venous leg ulcers depends on the adhesive interaction and formation of new vascular cells. Angiogenesis on the surface of angiogenic blood vessels requires the vascular integrin alphavbeta3 also known as the vitronectin receptor. Autologous platelet-derived wound healing factor (autologous PDWHF) has been described to regulate the wound healing process by forming granulation tissue in the early healing phase. Here we analysed the influence of autologous PDWHF on the expression of the alphavbeta3 integrin in tissue specimen of venous leg ulcers in comparison with placebo treated controls by using reverse transcriptase-polymerase chain reaction and immunohistochemistry. Our investigations provide evidence that mRNA and protein expression of alphavbeta3 were significantly increased in healing venous leg ulcers after 96 h treatment (p<0.05), whereas the total amount of alphavbeta3 mRNA and protein was not altered in placebo treated patients. In healing leg ulcers the alphavbeta3 integrin was predominantly localized around capillary vessels preferentially at sites of newly formed granulation tissue. Placebo controlled patients displayed no altered expression of the alphavbeta3 integrin in biopsy specimen. These findings suggest that topical autologous platelet-derived wound healing factor influences the process of angiogenesis/revascularization via alphavbeta3 integrin-expression hereby promoting granulation tissue formation in healing leg ulcers.

Lipodermatosclerosis is characterized by elevated expression and activation of matrix metalloproteinases: implications for venous ulcer formation.

Lipodermatosclerosis refers to skin induration of the lower extremities and is associated with patients preceding venous ulcerations. To better understand the pathogenesis of ulcer formation we investigated the expression of matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) in lipodermatosclerosis. By preparing biopsies from healthy skin and liposclerotic lesions, MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were analyzed by using reverse transcriptase-polymerase chain reaction, western blot, zymography, hydrolysis of [3H]labeled collagens, and immunohistochemistry. Our investigations provide evidence that mRNA and protein expression of MMP-1, MMP-2, and TIMP-1 were significantly increased in lipodermatosclerosis, whereas the total amount of MMP-9 and TIMP-2 mRNA and protein was not altered. Western blot of liposclerotic lesions revealed an inactive proMMP-1-TIMP-1 complex, whereas MMP-2 was prominent as an active 66 kDa band. Increased proteolytic activity of MMP-2 could be proven in lesional in comparison with healthy skin by zymography and [3H] collagen degradation. Increased diffuse staining was found for MMP-1 in the epidermis and dermis in comparison with controls. In lipodermatosclerosis, MMP-2 was predominantly localized in the basal and suprabasal layers of the epidermis, in perivascular regions, and in the reticular part of the dermis. Furthermore, MMP-2 was imbalanced by locally reduced expression of TIMP-2 in the basement membrane zone of lesional skin. Our findings indicate lipodermatosclerosis to be characterized by elevated matrix turnover.

Modulation of human monocyte superoxide production by recombinant interleukin-3.

We have examined the generation of superoxide by human monocytes isolated from peripheral blood cultured in the presence of recombinant human interleukin-3 in comparison to tumor necrosis factor-alpha and interferon-gamma. The rate of superoxide production of unstimulated and stimulated monocytes [by formyl-methionyl-leucyl-phenylalanine (0.1 microM) and by phorbol-myristate-acetate (2 ng/ml and 200 ng/ml)] decreased during the culture period in the absence of interleukin-3, whereas cells treated with interleukin-3 maintained or surpassed their initial superoxide-producing capacity. An increase of phorbol-myristate-acetate- and formyl-methionyl-leucyl-phenylalanine-stimulated superoxide production of monocytes cultured with interleukin-3 compared to control cells was detected first after 24 h of monocyte culture. It was maximal after 96 h of monocyte culture. At this time the stimulated superoxide production of monocytes cultured in the presence of interleukin-3 surpassed that of interferon-gamma and tumor necrosis factor-alpha treated cells. Suboptimal concentrations of the stimulus phorbol-myristate-acetate (2 ng/ml) resulted in higher priming than 200 ng/ml phorbol-myristate-acetate. A dose dependence of the effect of interleukin-3 on the superoxide production was observed. Our results demonstrate that interleukin-3 primes cultured human peripheral blood monocytes for enhanced stimulated respiratory burst activity to a higher extent than interferon-gamma and tumor necrosis factor-alpha.