In vitro fertilization exacerbates stroke size and neurological disability in wildtype mice.

BACKGROUND AND PURPOSE: Assisted reproductive technologies (ART) induce premature vascular aging in human offspring. The related alterations are well-established risk factors for stroke and predictors of adverse stroke outcome. However, given the young age of the human ART population there is no information on the incidence and outcome of cerebrovascular complications in humans. In mice, ART alters the cardiovascular phenotype similarly to humans, thereby offering the possibility to study this problem. METHODS: We investigated the morphological and clinical outcome after ischemia/reperfusion brain injury induced by transient (45 min) middle cerebral artery occlusion in ART and control mice. RESULTS: We found that stroke volumes were almost 3-fold larger in ART than in control mice (P < 0.001). In line with these morphological differences, neurological performance assessed by the Bederson and RotaRod tests 24 and 48 h after artery occlusion was significantly worse in ART compared with control mice. Plasma levels of TNF-alpha, were also significantly increased in ART vs. control mice after stroke (P < 0.05). As potential underlying mechanisms, we identified increased blood-brain barrier permeability evidenced by increased IgG extravasation associated with decreased tight junctional protein claudin-5 and occludin expression, increased oxidative stress and decreased NO-bioactivity in ART compared with control mice. CONCLUSIONS: In wildtype mice, ART predisposes to significantly worse morphological and functional stroke outcomes, related at least in part to altered blood-brain barrier permeability. These findings demonstrate that ART, by inducing premature vascular aging, not only is a likely risk factor for stroke-occurrence, but also a mediator of adverse stroke-outcome. TRANSLATIONAL PERSPECTIVE: This study highlights that ART not only is a likely risk factor for stroke-occurrence, but also a mediator of adverse stroke-outcome. The findings should raise awareness in the ever-growing human ART population in whom these techniques cause similar alterations of the cardiovascular phenotype and encourage early preventive and diagnostic efforts.

Tumour Necrosis Factor-α Inhibition Improves Stroke Outcome in a Mouse Model of Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) is a chronic inflammatory disorder where incidence and severity of myocardial infarction are increased. Data on the incidence and outcome of stroke are conflicting. Thus, we investigated outcome after Ischemia/Reperfusion (I/R) brain injury in a mouse model of RA and assessed for the role of the tumour necrosis factor-α (TNF-α) inhibitor Infliximab herein. We used a TNF-α reliant mouse model of RA. RA and wildtype (WT) animals were treated with vehicle (RA/WT) or Infliximab (RA Infliximab) for 4 weeks, before undergoing I/R brain injury. RA-animals displayed larger strokes and poorer neurological performance. Immunohistochemistry on brain sections revealed increased numbers of resident and peripheral innate immune cells (microglia and macrophages); increased Blood-Brain-Barrier (BBB)-disruption; decreased levels of the tight junction proteins (TJPs) claudin-5 and occludin; increased expression of matrix-metalloproteinases (MMP)-3 and -9 and enhanced lipid peroxidation. Treatment with Infliximab corrected these alterations. We show that RA associates to worse stroke-outcome via exacerbated BBB degradation by decrease of the TJPs claudin-5 and occludin. We identified MMPs-3 and -9 and increased oxidative stress as potential mediators thereof. Increased numbers of resident and peripheral innate immune cells (microglia and macrophages) may in turn contribute to all these effects. Infliximab-treatment restored the phenotype of RA-mice to baseline. Our data provide evidence clearly linking RA to adverse stroke-outcome in mice and indicate an approved TNF-α inhibitor as a potential strategy to reduce stroke-burden in this setting.

Serum levels of osteopontin predict diabetes remission after bariatric surgery.

AIM: Bariatric surgery has been shown to effectively improve glycaemic control in morbidly obese subjects. However, the molecular bases of this association are still elusive and may act independently of weight loss. Here, our retrospective study has investigated the inflammatory molecule osteopontin (OPN) as a potential predictor of type 2 diabetes mellitus (T2DM) remission. METHODS: Baseline serum levels of OPN were analyzed in 41 T2DM patients who underwent bariatric surgery. Anthropometric measures and biochemical variables, including insulin sensitivity indices (HOMA2), were assessed at baseline and at 1 and 3 years after surgery. RESULTS: At baseline, patients who experienced T2DM remission had increased waist circumference, body weight and BMI, and higher serum OPN, compared with non-remitters. Patients with and without T2DM remission improved their lipid and glucose profiles, although insulin resistance indices were only improved in the T2DM remission group. In the overall cohort of both T2DM remission and non-remission patients, baseline circulating levels of OPN significantly correlated with reductions of body weight and BMI over time, and insulin sensitivity improved as well. However, only the HOMA2-%S remained independently associated with serum OPN on multivariate linear regression analysis (B: 0.227, 95% CI: 0.067-0.387, ß = 0.831; P = 0.010). Baseline values of OPN predicted 3-year T2DM remission independently of body weight loss, lower BMI and duration of diabetes (OR: 1.046, 95% CI: 1.004-1.090; P = 0.033). CONCLUSION: Although larger studies are still needed to confirm our preliminary results, pre-operative OPN serum levels might be useful for predicting 3-year T2DM remission independently of weight loss in patients undergoing bariatric surgery.

High baseline C-reactive protein levels predict partial type 2 diabetes mellitus remission after biliopancreatic diversion.

BACKGROUND AND AIMS: Several studies demonstrated that surgery can improve inflammation parameters, such as C-reactive protein (CRP). Few biomarkers have been investigated to potentially predict type 2 diabetes mellitus (T2DM) remission. We aimed at determining whether pre-surgery serum CRP levels could predict T2DM remission after 3 years in patients undergoing bariatric surgery, especially biliopancreatic diversion (BPD). METHODS AND RESULTS: This study was conducted from 2007 to 2009 at the Surgical Department of the University of Genoa, Italy. Forty-four patients with T2DM undergoing BPD (n = 38) or Roux-en-Y gastric bypass (n = 6) were enrolled. The primary endpoint was to evaluate whether pre-surgery CRP levels could predict T2DM partial remission at 3-year follow-up. Secondary endpoints were to assess whether glycaemic, lipid, and inflammatory parameters modified during the follow-up. At baseline, patients with T2DM ranged from overweight to morbid obesity, had mild dyslipidaemia, and a low-grade inflammation. Bariatric surgery improved body weight, lipid and glycaemic profile both at 1- and 3-year follow-up. Pre-surgery CRP levels progressively decreased at 1- and 3-year follow-up. Among inflammatory pre-surgery parameters, only high CRP levels were shown to predict T2DM partial remission after 3 years. Multivariate analysis confirmed the predictive value of pre-surgery CRP levels independently of age, gender, type of surgery, and body mass index. CONCLUSION: Bariatric surgery, in particular BPD, improved both metabolic and inflammatory biomarkers at 1- and 3-year follow-up. Pre-surgery high CRP levels predicted 3-year T2DM partial remission, indicating a promising target population to be especially treated with BPD.

Gonadotropin levels in women with polycystic ovary syndrome: their relationship to body weight and insulin levels.

The purpose of this work was to investigate the relationship of gonadotropin levels to body weight and insulin levels in woman with polycystic ovary syndrome (PCOS). Specifically, we wished to test the hypothesis that circulating luteinizing hormone (LH) and insulin levels are different in obese and normal weight patients with PCOS. The basal plasma levels of gonadotropins, estrogens, androgens and sex hormone-binding globulin, the gonadotropin responses to gonadotropin releasing hormone (GnRH) and the insulin and C-peptide responses to a 3-hour oral glucose tolerance test (OGTT) were measured in 19 obese and 19 normal weight patients with PCOS and 7 obese and 8 normal weight ovulatory controls. Data of the patients were evaluated according to body weight (obese vs normal weight) and basal LH (high vs normal). There was no significant difference in basal LH and androgen levels and in the insulin response to oral glucose between obese and normal weight patients with PCOS. Compared to the weight matched controls, both obese and non obese patients showed significantly higher LH responses to GnRH and C-peptide responses to OGTT. When the high LH patients (no = 18) were compared those with normal LH (no = 20), the high LH subjects exhibited significantly higher androstenedione levels. Both obese (no = 10) and normal weight (no = 8) patients with high LH showed significantly greater C-peptide responses to OGTT than obese (no = 9) and non obese (no = 11) patients with normal LH. However, as compared with the weight matched controls, both the high LH and normal LH patients had significantly greater C-peptide responses to OGTT. We conclude that obese and non obese patients with PCOS do not seem to differ in the prevalence of elevated LH levels or in the LH secretory pattern. Insulin resistance, expressed by an enhanced pancreatic sensitivity to oral glucose, is present in both the high LH and the normal LH subjects, even though the PCOS patients with elevated LH tend to be more insulin resistant and hyperandrogenic than the normal LH patients.