Comparative effects of plateletderived growth factor-BB and insulin-like growth factor-I, individually and in combination, on periodontal regeneration in Macaca fascicularis

Platelet-derived growth factor (PDGF) and insulin-like growth factor I (IGF-I) in combination have previously been shown to enhance periodontal regeneration. The objective of this study was to further characterize the biological effects of this combination of growth factors in non-human primates and compare the effects to those of each growth factor individually. Ligature-induced periodontitis was initiated in 10 cynomolgus monkeys. After periodontal lesions were established, surgery was performed, and either a methylcellulose gel vehicle or vehicle containing 10 μg each of either PDGF-BB, IGF-I or both PDGF-BB and IGF-I was applied to exposed root surfaces. Biopsies were taken 4 and 12 wk after treatment and the extent of periodontal regeneration was assessed by histomorphometry. At both 4 and 12 wk vehicle-treated lesions generally revealed minimal osseous defect fill (ODF) (8.5±2.1% and 14.5±5.7%, respectively) and new attachment (NA) (34.1±5.2% and 26.6±10.5%, respectively). IGF-I treatment did not significantly alter healing compared to vehicle in any parameter at both 4 and 12 wk. PDGFBB-treated sites exhibited significant (p<0.05) regeneration of NA (69.6±12.0%) at 12 wk; trends for PDGF-BB treatment effect were also observed in other parameters at 4 and 12 wk. although these increases were not statistically significant. Treatment with PDGF-BB/IGF-I resulted in 21.6±5.1 % and 42.5±8.3% ODF at 4 and 12 wk, respectively, and 64.1±7.7% and 74.6±7.4% NA at 4 and 12 wk, respectively (all significantly greater than vehicle, p<0.05). The results from this study demonstrated that: 1) IGF-1 alone at the dose tested did not significantly alter periodontal wound healing; 2) PDGF-BB alone significantly stimulated NA, with trends of effect on other parameters; and 3) the PDGF-BB/IGF-I combination resulted in significant increases in NA and ODF above vehicle at both 4 and 12 wk.     

Hyperprolactinemia as a marker of neurotransmitter imbalance in uremic population

Serum prolactin (PRL) levels are elevated in patients with chronic renal failure (CRF) but the mechanisms responsible for these abnormalities are not fully understood. PRL secretion is undoubtedly influenced by many substances, which can be variously altered in uremia: monoamines, endogenous opiates and PTH. Our data suggest that in early renal failure PRL levels are already significantly high and the 24-h pattern of PRL secretion is significantly different from that in controls. PRL derangements could be due in mild renal failure, to unknown factors (GABA?); in severe CRF, to a major change in dopaminergic activity; in hemodialysis (HD), to a low turnover of monoamines, and in peritoneal dialysis (PD) to increased activity of serotoninergic and dopaminergic systems.     

Verapamil inhibits interleukin-6 and vascular endothelial growth factor production in primary cultures of keloid fibroblasts.

An increased secretion of cytokines and growth factors has been hypothesised to play a role in the abnormal growth of keloid fibroblasts. The aim of this study was to evaluate the effect of the calcium antagonist verapamil on the interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion, as well as on cellular growth, in primary cultures of fibroblasts derived from the central part of keloid lesions. These cells grew faster than peripheral keloid and nonkeloid fibroblasts, and, in long-term cultures, became stratified assuming a three-dimensional structure. Compared with peripheral and nonkeloid fibroblasts, central keloid fibroblasts presented an increased production of both IL-6 and VEGF (P<0.03 and P<0.005, respectively). Verapamil (100 microM) decreased IL-6 and VEGF production (P<0.03 and P<0.005, respectively) in central keloid fibroblasts cultures at 72 h. Moreover, verapamil decreased cellular proliferation by 29% and increased apoptosis to an absolute value of 8%. The results of this study demonstrate that in primary cultures of central keloid fibroblasts verapamil reduces the sustained basal IL-6 and VEGF production and inhibits cell growth; these data may offer the link with the beneficial effect of calcium antagonists on keloid scars in vivo.     

High affinity neurotrophin receptors in the human pre-term newborn, infant, and adult cerebellum

The immunohistochemical occurrence of the high affinity neurotrophin (NT) receptors trkA, trkB, and trkC is shown in the pre-term newborn, infant, and adult human post-mortem cerebellum. Immunoreactive neuronal perikarya and processes were observed in all specimens examined, where they appeared unevenly distributed in the cerebellar cortical layers and deep nuclei, and showed regional differences among cerebellar lobules and folia. The trk receptor-antibodies, tested by Western blot on human cerebellum homogenates, revealed multiple immunoreactive bands for trkA and single bands for trkB and trkC. The results obtained show the tissue localization of the trk receptor-like immunoreactivity in the human cerebellum from prenatal to adult age. The analysis for codistribution of the receptors with the relevant ligand and among the receptors in discrete cortical and deep nuclei tissue fields shows a wide variety of conditions, from a good similarity in terms of type and density of labeled structures, to a lack of correspondence, and suggests the possibility of colocalization of trk receptors with the relevant neurotrophin and among them in the cerebellar cortex. These results sustain the concept that the neurotrophin trophic system participates in the development, differentiation, and maintenance of the human cerebellar connectivity and support the possibility of a multifactorial trophic support for the neurotrophins through target-derived and local mechanisms.     

Prognostic relevance of histological grade and its components in node-negative breast cancer patients.

Available results highlight the lack of good level of evidence studies on the pure prognostic value of histological grade. In the present study, the prognostic relevance of histological grade and of its three components, tubule formation, nuclear pleomorphism and mitotic count, was analyzed in a series of 372 patients with node-negative breast cancer treated with locoregional therapy alone until early relapse. Histological grade was determined blindly by two observers and discordance between evaluations was resolved after joint review using a multihead microscope. No relation was observed between histological grade and any of its three components and disease-free survival. Conversely, a significant relation was observed between histological grade and distant metastasis-free survival (at 6 years, 94, 86 and 76% for grades 1, 2 and 3, respectively, P=0.013) as well as overall survival (98, 90 and 86%, P=0.001). A breakdown analysis as a function of the three components showed that neither tubule formation nor nuclear pleomorphism was associated with prognosis, and only mitotic count strongly influenced both distant metastasis-free survival (91, 82 and 74%, P=0.014) and overall survival (97, 87 and 85%, P=0.011). Histological grade suffers from a much higher subjectivity than any other microscopic evaluation of biomarkers as it is the sum of three different morphological features. Within the Italian Network for Quality Assessment of Tumor Biomarkers program we observed that histological grade is an independent prognostic variable, but also that this role is ascribable only to the number of mitotic figures. In conclusion, due to the ever smaller size of diagnosed breast cancers, resulting in less cancer tissue for biofunctional and molecular analysis, mitotic count evaluated under strict quality control conditions seems to be an accurate and feasible prognostic variable.     

Platelet alpha granule secretion in cerebral ischemia: effect of short and long term low dose aspirin treatment

The effect of short and long-term therapy with aspirin (50 mg/day) on platelet alpha granule secretion was studied in 11 healthy controls and 57 patients suffering from transient cerebral ischemic attacks (TIA) with and without accompanying diabetes and hypertension. Plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF 4) were measured as indicators of platelet alpha granule secretion. beta-TG and PF 4 levels were increased following cerebral ischemia. Aspirin treatment failed to suppress plasma levels of both proteins when measured a month and then a year after initiation of treatment. Therefore, these proteins may be poor indicators of platelet inhibition by aspirin.