PAPP-A activity is increased in cerebrospinal fluid from patients with diabetic polyneuropathy and correlates with peripheral nerve impairment.

OBJECTIVE: Insulin-like growth factors (IGFs) have neuroprotective effects. IGF activity is partly controlled by pregnancy-associated plasma protein-A (PAPP-A), an enzyme which enhances IGF-action by cleavage of IGF-binding protein-4 (IGFBP-4). To study the role of PAPP-A and the IGF system in diabetic polyneuropathy (DPN), we measured immunoreactive (total) concentrations of IGF-I and IGF-II, bioactive IGF by cell-based bioassay, PAPP-A, as well as intact and PAPP-A-cleaved IGFBP-4 in cerebrospinal fluid (CSF) and serum from patients with type 2 diabetes (T2D) with and without DPN. DESIGN: Twenty-three patients with T2D were included. Based on clinical examination, vibratory perception thresholds and nerve conduction studies, patients were diagnosed with (n = 9) or without (n = 14) DPN. RESULTS: In CSF, PAPP-A activity, as estimated by IGFBP-4 fragment levels, was higher in patients with than without DPN (34.57 vs 13.79 µg/L, p = .003) and concentrations correlated with peripheral nerve impairment measures (r = 0.73, p < .01). Furthermore, serum bioactive IGF was lower in patients with than without DPN (0.8 vs 1.3 µg/L, p = .006) and correlated inversely to the severity of DPN (r = -0.67, p < .01). CONCLUSIONS: In both CSF and serum, members of the IGF system correlated with measures of peripheral nerve impairment in patients with T2D. This supports a relationship between the IGF system and the development of DPN. Further studies are needed to clarify if these changes are causally linked to the pathogenesis of DPN.

The influence of blood pressure management on neurological outcome in endovascular therapy for acute ischaemic stroke.

BACKGROUND: Observational studies have suggested that low blood pressure and blood pressure variability may partially explain adverse neurological outcome after endovascular therapy with general anaesthesia (GA) for acute ischaemic stroke. The aim of this study was to further examine whether blood pressure related parameters during endovascular therapy are associated with neurological outcome. METHODS: The GOLIATH trial randomised 128 patients to either GA or conscious sedation for endovascular therapy in acute ischaemic stroke. The primary outcome was 90 day modified Rankin Score. The haemodynamic protocol aimed at keeping the systolic blood pressure >140 mm Hg and mean blood pressure >70 mm Hg during the procedure. Blood pressure related parameters of interest included 20% reduction in mean blood pressure; mean blood pressure <70 mm Hg, <80 mm Hg, and <90 mm Hg, respectively; time with systolic blood pressure <140 mm Hg; procedural minimum and maximum mean and systolic blood pressure; mean blood pressure at the time of groin puncture; postreperfusion mean blood pressure; blood pressure variability; and use of vasopressors. Sensitivity analyses were performed in the subgroup of reperfused patients. RESULTS: Procedural average mean and systolic blood pressures were higher in the conscious sedation group (P<0.001). The number of patients with mean blood pressure <70-90 mm Hg and systolic blood pressure <140 mm Hg, blood pressure variability, and use of vasopressors were all higher in the GA group (P<0.001). There was no statistically significant association between any of the examined blood pressure related parameters and the modified Rankin Score in the overall patient population, and in the subgroup of patients with full reperfusion. CONCLUSION: We found no statistically significant association between blood pressure related parameters during endovascular therapy and neurological outcome. CLINICAL TRIAL REGISTRATION: NCT 02317237.

Insulin-like growth factor binding protein 2 is a marker for antiestrogen resistant human breast cancer cell lines but is not a major growth regulator.

Antiestrogens target the estrogen receptor and counteract the growth stimulatory action of estrogen on human breast cancer. However, acquired resistance to antiestrogens is a major clinical problem in endocrine treatment of breast cancer patients. To mimic acquired resistance, we have used a model system with the antiestrogen sensitive human breast cancer cell line MCF-7 and several antiestrogen resistant cell lines derived from the parental MCF-7 cell line. This model system was used to study the expression and possible involvement in resistant cell growth of insulin-like growth factor binding protein 2 (IGFBP-2). By an oligonucleotide based microarray, we compared the expression of mRNAs encoding insulin-like growth factor binding protein 1,2,3,4,5 and 6 (IGFBP-1 to -6) in the parental MCF-7 cell line to three human breast cancer cell lines, resistant to the antiestrogen ICI 182,780 (Faslodex/Fulvestrant). Only IGFBP-2 mRNA was overexpressed in all three resistant cell lines. Thus, we compared the IGFBP-2 protein expression in MCF-7 cells to nine antiestrogen resistant breast cancer cell lines, resistant to either ICI 182,780 or tamoxifen or RU 58,668 and found that IGFBP-2 was overexpressed in all nine resistant cell lines. Three of the resistant cell lines, resistant to different antiestrogens, were selected for further studies and IGFBP-2 overexpression was demonstrated at the mRNA level as well as the intra- and extracellular protein level. The objective of this study was to examine if IGFBP-2 is involved in growth of antiestrogen resistant human breast cancer cells. Therefore, IGFBP-2 expression was inhibited by antisense oligonucletides and siRNA. Specific inhibition of IGFBP-2 protein expression was achieved in MCF-7 and the three selected antiestrogen resistant cell lines, but no effect on resistant cell growth was observed. Thus, we were able to establish IGFBP-2 as a marker for antiestrogen resistant breast cancer cell lines, although IGFBP-2 was not a major contributor to the resistant cell growth.