Late Effects of Disturbed IGF Signaling in Congenital Diseases.

The biologic effects of insulin-like growth factor-1 (IGF-1) are mediated by specific cell surface receptors. IGF-1 binding to the extracellular -subunits activates the tyrosine kinase intrinsic to the cytoplasmic portion of the IGF-1 receptor, leading to autophosphorylation of specific tyrosine residues in the receptor -subunit. One early molecular event that links the receptor kinase to the biologic actions of IGF-1 is tyrosine phosphorylation of the insulin receptor substrate family (IRS-1 to -4). IRS acts as a multisite ‘docking’ protein by binding to downstream signal-transducing molecules. Phosphorylation of multiple tyrosine residues results in the association of IRS-1 with the Src homology 2 (SH2) domains of other cytoplasmic signaling proteins, including phosphatidylinositol 3 kinase, Syp, Grb2 and Nck. By binding to Grb2, IRS proteins couple the IGF-1 receptor to the Ras/mitogenactivated protein kinase pathway. This pathway regulates cell growth, differentiation and proliferation. Severe pre- and postnatal growth retardation may arise from abnormalities of IGF-1 signaling such as IGF-1-binding alterations and IGF-1 receptor mutations. Knockout studies have shown severe growth impairment in mice lacking IRS family components or Akt. Finally, in human placentas from pregnancies complicated by intrauterine growth retardation, multiple alterations of IGF-1-signaling molecules have recently been described

Adiponectin levels are reduced in children born small for gestational age and are inversely related to postnatal catch-up growth

Adiponectin is an adipocytokine with insulin-sensitizing and antiatherogenic properties. Reduced concentrations of adiponectin precede the onset of type 2 diabetes and the development of atherosclerosis. Our aim was to quantify adiponectin concentrations in small for gestational age (SGA) children. Fifty-one SGA children, 24 obese, and 17 short-normal children with birth weight appropriate for gestational age (short-AGA) were studied. The statures of the SGA children were corrected for their midparental height and subdivided into two groups according to their corrected height: catch-up growth group, children with corrected height of 0 z-score or greater (n = 17); and noncatch-up growth group, subjects with corrected height less than 0 z-score (n = 34). SGA children showed adiponectin levels significantly lower than short-normal children (35.2 +/- 3.5 vs. 80.4 +/- 26.6 mug/ml; P < 0.0001) and obese children (77.5 +/- 39.4 μg/ml; P < 0.0001). Catch-up growth children showed adiponectin levels significantly lower than noncatch-up growth subjects (29.4 +/- 10.3 vs. 38.1 +/- 11.5 mug/ml; P = 0.01). Adiponectin concentrations were inversely related to height z-score, corrected stature, weight, and body mass index and were positively related to birth weight. Our results suggest that adiponectin levels are reduced in SGA children and are even lower in those with postnatal catch-up growth. Whether this finding implies a higher risk of developing type 2 diabetes and atherosclerosis remains to be established

Models of radon exhalation from building structures: General and case-specific solutions.

Assessing the radon activity that exhales from building structures is crucial to identify the best strategies to prevent radon from entering a building or reducing its concentration in the inhabited spaces. The direct measurement is extremely difficult, so the common approach has consisted in developing models describing the radon migration and exhalation phenomena for building porous materials. However, due to the mathematical complexity of comprehensively modelling the radon transport phenomenon in buildings, simplified equations have been mostly adopted until now to assess the radon exhalation. A systematic analysis of the models applicable to radon transport has been carried out and it has resulted in four models differing in the migration mechanisms – only diffusive or diffusive and advective – and the presence of inner radon generation. The general solutions have been obtained for all the models. Moreover, three case-specific sets of boundary conditions have been formulated to account for all the actual scenarios occurring in buildings: both perimetral and partition walls and building structures in direct contact with soil or embankments. The corresponding case-specific solutions obtained serve as a key practical tool to improve the accuracy in assessing the contribution of building materials to indoor radon concentration according to the site-specific installation conditions in addition to the material inner properties

Histological Features and Biocompatibility of Bone and Soft Tissue Substitutes in the Atrophic Alveolar Ridge Reconstruction

The reconstruction of the atrophic alveolar ridges for implant placement is today a common procedure in dentistry daily practice. The surgical reconstruction provides for the optimization of the supporting bone for the implants and a restoration of the amount of keratinized gingiva for esthetic and functional reasons. In the past, tissue regeneration has been performed with autogenous bone and free gingival or connective tissue grafts. Nowadays, bone substitutes and specific collagen matrix allow for a complete restoration of the atrophic ridge without invasive harvesting procedures. A maxillary reconstruction of an atrophic ridge by means of tissue substitutes and its histological features are then presented

Clinical impact and prognostic role of KRAS/BRAF/PIK3CA mutations in stage I colorectal cancer

Stage I colorectal carcinoma has excellent prognosis, with 5-year survival rate up to 95%. The occurrence of lymphovascular invasion, tumor budding, high number of PDC, or lymph node micrometastases is associated with tumor progression. The aim of this study was to evaluate the mutational status of 62 stage I colorectal carcinomas (CRC) (taken from 37 patients surviving more than five years since the initial diagnosis and from 25 patients who died of disease) and to correlate it with histopathological features and the clinical outcome. Mutations of KRAS, NRAS, BRAF, and PIK3CA genes were analyzed through Myriapod Colon Status Kit, using the high-throughput genotyping platform Sequenom MassARRAY System. Mutations in those genes were found in 31 cases (50%) and mainly in those with poor prognosis. The most frequent mutations occurred at codons 12 and 13 of the KRAS gene (40% of cases). We found concomitant PIK3CA mutations in 5 cases (8%). The presence of PIK3CA mutations was mainly observed in tumors with poor prognosis and with unfavorable histopathological prognostic features. High PDC grade (P = 0 0112), the presence of tumor budding (P = 0 0334), LVI (P &lt; 0 0001), KRAS mutations (P = 0 0228), PIK3CA mutations (P = 0 0214), multiple genetic mutations in KRAS and PIK3CA genes (P = 0 039), and nodal micrometastases (P &lt; 0 0001) were significant prognostic variables for CSS. The presence of LVI was the only independent and statistically significant prognostic variable for CSS in our cohort of pTNM stage I CRCs. The analysis of KRAS/PIK3CA mutational status may be used to identify patients with stage I CRC at high risk of bad outcome and who may need additional treatments, including biological therapies

Increased prevalence of expiratory flow limitation during exercise in children with bronchopulmonary dysplasia.

Evidence regarding the prevalence of expiratory flow limitation (EFL) during exercise and the ventilatory response to exercise in children born preterm is limited. This study aimed to determine the prevalence of EFL as well as contributing factors to EFL and the ventilatory response to exercise in preterm children with and without bronchopulmonary dysplasia (BPD). Preterm children (=32 weeks gestational age) aged 9-12 years with (n=64) and without (n=42) BPD and term controls (n=43), performed an incremental treadmill exercise test with exercise tidal flow-volume loops. More preterm children with BPD (53%) had EFL compared with preterm children without BPD (26%) or term controls (28%) (p&lt;0.05). The presence of EFL was independently associated with decreased forced expiratory volume in 1 s/forced vital capacity z-score and lower gestational age (p&lt;0.05). There was no difference in peak oxygen uptake between preterm children with BPD and term controls (48.0 versus 48.4 mL·kg-1·min-1; p=0.063); however, children with BPD had a lower tidal volume at peak exercise (mean difference -27 mL·kg-1, 95% CI -49-?-5; p&lt;0.05). Children born preterm without BPD had ventilatory responses to exercise similar to term controls. Expiratory flow limitation is more prevalent in children born preterm with BPD and is associated with airway obstruction and a lower gestational age

Metal-free materials for fixed prosthodontic restorations

ackground Fixed prosthodontic treatment (crowns, fixed dental prostheses (FDPs), complete arch prostheses) involves the use of several different materials to replace missing tooth structure. Traditionally full metal or metal frameworks veneered with ceramic (metal-ceramic (MC)) have been used. In recent years several different metal-free systems have become available to clinicians and patients. In general, metal-free restorations should allow practitioners to better reproduce natural tooth colour, avoiding shortcomings of MC restorations. The comparative in service clinical performance of fixed prosthodontic treatments of different materials is unclear. Objectives To assess the effects of metal-free materials for prosthodontic restorations compared to metal-ceramic or other conventional all-metal materials. Search methods Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (searched 3 May 2017), Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 4) in the Cochrane Library (searched 3 May 2017), MEDLINE Ovid (1946 to 3 May 2017), and Embase Ovid (1980 to 3 May 2017). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials (searched 3 May 2017). No restrictions were placed on the language or date of publication when searching the electronic databases. Selection criteria Randomised controlled trials (RCTs) in which the clinical performance of metal-free fixed prosthodontic restorations was compared with metal-ceramic (MC) or other conventional restorations in adult patients requiring prosthodontic treatment. RCTs in which the clinical performance of different kinds of metal-free systems were compared among themselves were also considered. Data collection and analysis We used standard methodological procedures expected by Cochrane. Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted independently and in duplicate. Trial authors were contacted for missing information. Available results for the outcomes of interest of the systematic review of the studies included were tabulated as they could not be included in a formal meta-analysis. Main results Nine trials involving a total of 448 participants were included. We judged two trials to be at unclear risk of bias and seven to be at high risk of bias. The majority of items of risk of bias were evaluated to be at unclear or high risk level in more than 50% of the included trials. Each trial except two was addressing a different type of intervention. All evidence was rated as being of very low quality due to problems with risk of bias and imprecision of results, the latter being due to very small sample sizes, low event rates, 95% confidence intervals including the possibility of benefit for both the test and control groups, or combinations of these problems. This means that we are very uncertain about all of the results presented in this review. One trial compared metal-free single crowns (full contour zirconia) to cast gold single crowns in 224 participants and found insufficient evidence of a difference in failure rate after one year, but after five years there was some evidence of a benefit for the gold crowns. There was insufficient evidence of a difference for crown complications at either time of assessment. One trial compared three-unit metal-free FDPs (lithium disilicate) to three-unit metal-ceramic FDPs in 37 participants. There was insufficient evidence of a difference in bridge failure at one and six years, but some evidence of a benefit for the lithium disilicate group in terms of bridge complications at six years. One trial compared zirconia-ceramic FDPs to metal-ceramic FDPs in 34 participants but found insufficient evidence of a difference in bridge failures (i.e. no failures in either treatment group), bridge complications or patients' aesthetic evaluation at any time of assessment up to three years. One trial comparedmetal-free cantilevered FDPs tometal-ceramic cantilevered FDPs in 21 participants. There was insufficient evidence of a difference for any primary outcome: bridge failures (i.e. no failures in either treatment group), bridge complications, or patients' aesthetic evaluation at any time of assessment up to three years. One trial compared metal-free implant-supported screw retained single crowns (zirconia veneered with feldspathic ceramic) to metal-ceramic implant-supported screw-retained single crowns in 20 participants. There was insufficient evidence of a difference for any primary outcome: crown failures (i.e. no failures in either treatment group), crown complications, or satisfaction/aesthetic evaluation at any time of assessment up to two years. Two trials compared metal-free implant abutments (zirconia) to metal implant abutments both supporting single crowns in 50 participants. There was insufficient evidence of a difference in abutment failure at one year. One trial compared metal-free implant-supported FDPs made of two different types of zirconia ceramic in 18 participants. There was insufficient evidence of a difference in failures at any time of assessment up to 10 years (i.e. no failures in either treatment group). There was some evidence of a benefit for the zirconia-toughened alumina group in terms of complications (chipping). One trial compared metal-free tooth-supported FDPs made with two different veneering techniques (pressed versus layered) in 40 participants. There was insufficient evidence of a difference for failures (i.e. no failures in either treatment group) or complications at any time of assessment up to three years. Authors' conclusions There is insufficient evidence to support or refute the effectiveness of metal-free materials for fixed prosthodontic treatment over metal-ceramic or other type of standard restorations. The overall quality of existing evidence was very low, therefore great caution should be exercised when generalising the results of the included trials. Until more evidence becomes available clinicians should continue to base decisions on which material to use for fixed prosthodontic treatment on their own clinical experience, whilst taking into consideration the individual circumstances and preferences of their patients. There is urgent need of properly designed RCTs

Type 3 hypersensitivity in COVID-19 vasculitis

Coronavirus Disease 2019 (COVID-19) is an ongoing public health emergency and new knowledge about its immunopathogenic mechanisms is deemed necessary in the attempt to reduce the death burden, globally. For the first time in worldwide literature, we provide scientific evidence that in COVID-19 vasculitis a life-threatening escalation from type 2 T-helper immune response (humoral immunity) to type 3 hypersensitivity (immune complex disease) takes place. The subsequent deposition of immune complexes inside the vascular walls is supposed to induce a severe inflammatory state and a cytokine release syndrome, whose interleukin-6 is the key myokine, from the smooth muscle cells of blood vessels

Guillain-Barr&#233; syndrome : report of two rare clinical cases occurring after allergenic bone grafting in oral maxillofacial surgery

Guillaine-Barr\ue9 Syndrome (GBS), also known as post-infectious polyneuropathy or acute idiopathic polyneuritis, is an infrequent disorder of the peripheral nervous system. The cause of GBS is unknown. It has been associated in the past with microbial infections, vaccinations, surgical procedures and debilitation of the patient. The classic signs of GBS occurring in the two patients being reported here are muscle weakness, motor and sensory impairment and ascending paralysis with respiratory involvement. The documented cases involved GBS syndrome following oral and maxillofacial surgery in which allogeneic-banked freeze-dried bone have been utilized along with autogenous grafting. There were no incidents of viral infection, vaccination or the other prodromal incidents involved in these cases. It is believed that the description of these two cases would be of interest in that it may stimulate the reporting of similar anecdotal occurrences by other surgeons. Both patients fully recovered from the GBS and are presently alive and well