A Logical Modeling of Severe Ignorance.

In the logical context, ignorance is traditionally defined recurring to epistemic logic. In particular, ignorance is essentially interpreted as "lack of knowledge". This received view has - as we point out - some problems, in particular we will highlight how it does not allow to express a type of content-theoretic ignorance, i.e. an ignorance of φ that stems from an unfamiliarity with its meaning. Contrarily to this trend, in this paper, we introduce and investigate a modal logic having a primitive epistemic operator I, modeling ignorance. Our modal logic is essentially constructed on the modal logics based on weak Kleene three-valued logic introduced by Segerberg (Theoria, 33(1):53-71, 1997). Such non-classical propositional basis allows to define a Kripke-style semantics with the following, very intuitive, interpretation: a formula φ is ignored by an agent if φ is neither true nor false in every world accessible to the agent. As a consequence of this choice, we obtain a type of content-theoretic notion of ignorance, which is essentially different from the traditional approach. We dub it severe ignorance. We axiomatize, prove completeness and decidability for the logic of reflexive (three-valued) Kripke frames, which we find the most suitable candidate for our novel proposal and, finally, compare our approach with the most traditional one.

Synergistic use of bioactive agents for the management of different skin conditions: an overview of biological activities.

Recently, many plant-derived bioactive agents have been included in dermo-cosmetics formulations. This leads to an extensive portfolio of innovative products with an expanded range of benefits, including anti-aging, antioxidant, hydrating and depigmenting. Although different technologies drawing on science and nature are used to create these high-performing molecules, there remains some debate about the mechanism of action of the natural bioactive ingredients within dermo-cosmetics. This review recapitulates the main biological mechanisms underlying the activity of natural active ingredients, with a specific focus on their synergistic use for the management of common, yet quite specific, skin conditions. A total of 28 plant-derived bioactives were selected from the Givaudan Active Beauty (Argenteuil, France) portfolio, a multinational company specializing in innovative natural actives research. An extensive literature review about their biological activity was conducted by a PubMed search using different keywords. No language or publication date restrictions were used. Givaudan Active Beauty data on file were also considered. The bioactive ingredients were described according to the pathogenetic mechanisms underlying 10 common skin conditions that dermo-cosmetics may address. Literature data have shown that plant-derived bioactives are involved in a wide range of biological mechanisms showing anti-inflammatory, antioxidant, and moisturizing properties, along with skin barrier protection and collagen synthesis activities. As a result, different combinations of bioactives within dermo-cosmetics can be defined to counteract simultaneously the different pathogenetic mechanisms underlying different skin conditions. Available literature supports the synergistic use of plant-derived bioactive agents within dermo-cosmetics as a viable and safe option for managing the most common skin conditions.

MR Micro-Neurography and a Segmentation Protocol Applied to Diabetic Neuropathy.

The aim of this study was to assess with MRI morphometric ultrastructural changes in nerves affected by diabetic peripheral neuropathy (DPN). We used an MR micro-neurography imaging protocol and a semiautomated technique of tissue segmentation to visualize and measure the volume of internal nerve components, such as the epineurium and nerve fascicles. The tibial nerves of 16 patients affected by DPN and of 15 healthy volunteers were imaged. Nerves volume (NV), fascicles volume (FV), fascicles to nerve ratio (FNR), and nerves cross-sectional areas (CSA) were obtained. In patients with DPN the NV was increased and the FNR was decreased, as a result of an increase of the epineurium (FNR in diabetic neuropathy 0,665; in controls 0,699, p = 0,040). CSA was increased in subjects with DPN (12,84 mm2 versus 10,22 mm2, p = 0,003). The FV was increased in patients with moderate to severe DPN. We have demonstrated structural changes occurring in nerves affected by DPN, which otherwise are assessable only with an invasive biopsy. MR micro-neurography appears to be suitable for the study of microscopic changes in tibial nerves of diabetic patients.

First case of combined robot-assisted thymectomy and transaxillary thyroidectomy: technique and robot-docking optimization.

Robot-assisted thymectomy and total transaxillary thyroidectomy represent two excellent therapeutic options for functional and oncological diseases of these two organs. We report the first case in literature of combined robot-assisted resection. The patient was positioned in supine position with the left arm raised cranially 90°-120° to expose the axillary area. After completing the thymectomy we rotated 30° counter-clockwise the robot for the second surgical time. This led to an optimization of disposable instruments and a gain in terms of hospitalization and postoperative recovery for the patient. To perform these two procedures it was enough to rotate 30° the robot.

Improvement and automation of a real-time PCR assay for vaginal fluids.

The identification of vaginal fluids is crucial in forensic science. Several molecular protocols based on PCR amplification of mfDNA (microflora DNA) specific for vaginal bacteria are now available. Unfortunately mfDNA extraction and PCR reactions require manual optimization of several steps. The aim of present study was the verification of a partial automatization of vaginal fluids identification through two instruments widely diffused in forensic laboratories: EZ1 Advanced robot and Rotor Gene Q 5Plex HRM. Moreover, taking advantage of 5-plex thermocycler technology, the ForFluid kit performances were improved by expanding the mfDNA characterization panel with a new bacterial target for vaginal fluids and with an internal positive control (IPC) to monitor PCR inhibition. Results underlined the feasibility of a semi-automated extraction of mfDNA using a BioRobot and demonstrated the analytical improvements of the kit.

New and Common Haplotypes Shape Genetic Diversity in Asian Tiger Mosquito Populations from Costa Rica and Panamá.

The Asian tiger mosquito, Aedes albopictus (Skuse) (Diptera: Culicidae), is a vector of several human pathogens. Ae. albopictus is also an invasive species that, over recent years, has expanded its range out of its native Asia. Ae. albopictus was suspected to be present in Central America since the 1990s, and its presence was confirmed by most Central American nations by 2010. Recently, this species has been regularly found, yet in low numbers, in limited areas of Panamá and Costa Rica (CR). Here, we report that short sequences (∼558 bp) of the mitochondrial cytochrome oxidase subunit 1 (COI) and NADH dehydrogenase subunit 5 genes of Ae. albopictus, had no haplotype diversity. Instead, there was a common haplotype for each gene in both CR and Panamá. In contrast, a long COI sequence (∼1,390 bp) revealed that haplotype diversity (±SD) was relatively high in CR (0.72±0.04) when compared with Panamá (0.33±0.13), below the global estimate for reported samples (0.89±0.01). The long COI sequence allowed us to identify seven (five new) haplotypes in CR and two (one new) in Panamá. A haplotype network for the long COI gene sequence showed that samples from CR and Panamá belong to a single large group. The long COI gene sequences suggest that haplotypes in Panamá and CR, although similar to each other, had a significant geographic differentiation (Kst=1.33; P<0.001). Thus, most of our results suggest a recent range expansion in CR and Panamá.

Liver transplantation in defects of cholesterol biosynthesis: the case of lathosterolosis.

We report the outcome of liver transplantation (LT) in the only surviving patient with lathosterolosis, a defect of cholesterol biosynthesis characterized by high lathosterol levels associated with progressive cholestasis, multiple congenital anomalies and mental retardation. From her diagnosis at age 2 she had shown autistic behavior, was unable to walk unaided and her sight was impaired by cataracts. By age 7 she developed end-stage liver disease. After a soul-searching discussion within the transplantation team, she was treated with LT as this represented her only lifesaving option. At 1-year follow-up, her lathosterol levels had returned to normal (0.61 mg/dL from 13.04 ± 2.65) and her nutrition improved. She began exploring her environment and walking by holding onto an adult's hand and then independently. Her brain magnetic resonance imaging (MRI) had shown a normal picture at age 1, whereas a volume reduction of white matter with ex vacuo ventricular dilatation and defective myelinization were observed before transplant. At 5-year follow-up, a complete biochemical recovery, an arrest of mental deterioration and a stable MRI picture were achieved, with a return to her every day life albeit with limitations. Timely liver transplant in defects of cholesterol biosynthesis might arrest the progression of neurological damage.

Intratesticular testosterone is increased in men with Klinefelter syndrome and may not be released into the bloodstream owing to altered testicular vascularization­ a preliminary report.

Klinefelter syndrome (KS, 47,XXY) is associated with low serum testosterone (T), long thought to arise from disturbed steroidogenesis in Leydig cells. However, intratesticular testosterone (ITT) concentrations were recently found to be normal in a KS mouse model(41,XXY*). So far, nothing was known about ITT concentrations in human patients with KS. Therefore, ITT, sex hormone-binding globulin (SHBG) and histological parameters were measured in human testicular biopsies of 11 KS patients, 30 azoospermic patients with Sertoli-cell-only syndrome and nine men with normal spermatogenesis as controls. ITT concentrations showed an overall pronounced excess over intratesticular SHBG in molar terms and were significantly increased in men with KS despite of reduced serum T levels. While the ratio of ITT/serum T was markedly increased in KS, the ITT/LH-ratio was comparable between all groups. After finding significantly increased ITT levels in men with KS, a finding even more striking than in the 41,XXY* KS mouse model, we set out to find a possible 'vascular' explanation for the lack of T release into the testicular blood stream. In testis biopsies from patients,reliable analysis of the vessels is, however, not possible because of the bias resulting from the dissection technique requiring avoidance of larger blood vessels to prevent bleeding. Consequently, the blood vessel constitution was evaluated in whole testis sections from adult male 41,XXY* and 40,XY*mice (n=5, each). Indeed, the blood vessel/testes surface ratio correcting for the smaller testes of XXY*mice was significantly lower in these mice compared with XY*controls. In conclusion, testicular T production does not seem to be impaired in men with KS. On the contrary, ITT concentrations are increased, but not because of increased SHBG activity. The data from the mouse model let us speculate that a reduced vascular bed might be involved in lower release of T into the blood stream.

Effect of repeated preheating cycles on flexural strength of resin composites.

The aim of this study was to assess the flexural strengths of three resin composites prepared at room temperature or cured after 20 or 40 cycles of preheating to a temperature of 45°C. Three resin composites were evaluated: Enamel Plus HFO (Micerium) (HFO), Enamel Plus HRi (Micerium) (HRi), Opallis + (FGM) (OPA). One group of specimens for each composite was fabricated under ambient laboratory conditions, whereas in the other groups, the composites were cured after 20 or 40 preheating cycles to a temperature of 45°C in a preheating device. Ten specimens were prepared for each group. A three-point bending test was performed using a universal testing machine at a crosshead speed of 0.5 mm/min. Data were analyzed with a two-way analysis of variance (ANOVA) test and a Games-Howell test (α = 0.05). The two-way ANOVA showed that both the material and the number of heating cycles were significant factors, able to influence the flexural strength values (p<0.05). However, there was not a statistically significant interaction (p>0.05). For all three composites flexural strengths were not affected after 20 preheating cycles in comparison with the control groups (0 preheating cycles) but were, however, significantly decreased when 40 prewarming cycles were conducted. The HRi and OPA groups had the highest flexural strengths, with no statistically significant differences among them. HFO presented significantly lower flexural strengths in comparison with HRi.

ASN540SER mutation is associated with a mild form of hypochondroplasia: a 7 years follow-up in an Italian boy.

Skeletal dysplasias (SKD) are genetic disorders that result in the abnormal development of part or all of the skeleton and are commonly associated with short stature. The most common SKDs that typically result in short stature include achondroplasia/hypochondroplasia (HCH) both caused by different mutations in the same gene. HCH diagnosis is based on the clinical appearance during development and conventional X-ray findings. In about 70% of patients, missense mutations in the gene coding for the fibroblast Growth Factor Receptor 3 (FGFR3) affects the amino acid at position 540, mostly resulting in the amino acid exchange N540K.Subjects with HCH, heterozygous for the N540K substitution are significantly more disproportionate than individuals without this mutation. We report the clinical and radiographic features of an Italian family with HCH with an unusual N540S mutation, inside the common mutation hot spot of this condition. This is the first case reported in Italy and the third in the literature. During a 7-years-follow-up, the boy started the puberty at the age of 11.3 years and the growth spurt was observed between 13.7 and 14.9 years (+ 9.1 cm.).During pubertal development the sitting height (SDS) improved from - 1.5 to - 0.6 and the subischial leg length (SDS) progressed from - 2.6 to - 3.3.At the age of 16.7 year the standing height was 157.6 cm ( - 2.4 SDS), testicular volume was 15 ml and bone age 16.5 year. The present study and the other two cases reported in the literature stress the important role of the asn 540 site in the tyrosine kinase I domain in the pathogenesis of HCH and underline the importance that, in patients with HCH who do not have the common N540K mutation, sequence analysis of the tyrosine kinase I domain of FGFR3 should be performed to exclude other changes in that region.

Conservative restorations of endodontically compromised anterior teeth in paediatric patients: physical and mechanical considerations.

AIM: Objective of this in vitro study was to evaluate the influence of fiber post placement on fracture resistance of pulpless anterior teeth restored with standardised Class III and Class IV resin composite fillings. MATERIALS AND METHODS: One hundred and five human maxillary central incisors were selected and randomly divided into 7 (n=15) experimental groups (endodontic therapy/ endodontic therapy and one Class III resin composite filling/ endodontic therapy and one Class IV resin composite filling/ endodontic therapy and two Class III resin composite fillings/ endodontic therapy, fiber post and one Class III resin composite filling/ endodontic therapy, fiber post and one Class IV resin composite filling/ endodontic therapy, fiber post and two Class III resin composite fillings). Specimens underwent fracture strength test. Means (N) were calculated and data were analysed using 1-way ANOVA and Tukey multiple comparisons tests (p=0.05). RESULTS: Concerning teeth with two Class III, fiber post placement significantly increased fracture strength values from 603.59 to 864.24 N. Specimens restored with one Class III (795.21 N without post, 936.68 N with post) showed higher fracture strength values if compared with specimens with two Class III, with significant differences just concerning specimens without a fiber post. Fracture strength was not significantly influenced by fiber post placement in Class IV groups (720.71 N without post, 799.69 N with post). CONCLUSION: Data suggest that fiber post placement may significantly improve anterior teeth fracture strength when at least two Class III composite fillings are associated to the endodontic treatment. No significant effect of fiber post placement could be recorded when just one Class III or one Class IV composite filling were present.

Histomorphologic alterations of human enamel after repeated applications of a bleaching agent.

The objective of the study was to analyse the histomorphology of enamel after repeated applications of a professional bleaching regimen. Enamel specimens were obtained from buccal surfaces of 20 extracted human incisors. Two specimens were obtained for each tooth. Half of each tooth was maintained in distilled water and served as control; the other part was treated with a 38 percent hydrogen peroxide professional bleaching agent. The treated specimens were divided in four groups: in group 1, the professional bleaching protocol suggested by the manufacturer was applied once; in group 2, the same protocol was repeated twice; in group 3, three times; in group 4, four times. Between bleaching applications and before SEM evaluation, enamel specimens were maintained in artificial saliva for 1 week. Enamel specimens for each group were submitted to a qualitative scanning electron microscopy (SEM) analysis (200X, 500X, 1000X, 3000X), comparing the treated specimens with the related control enamel. Results of the SEM analysis showed no relevant alteration on the enamel surfaces, when the bleaching protocol was applied once or twice. However, significant changes of enamel surface morphology were SEM observed in groups 3 and 4, suggesting a predominance of depressions when bleaching procedure was repeated three or four times. From the results of this in vitro study, it is possible to state that bleaching procedures should not be carried out indiscriminately. SEM analysis showed important alterations of the prismatic structure of the enamel when the bleaching protocol was applied three and four times.

Detection of chromosomal aneuploidies in fetal cells isolated from maternal blood using single-chromosome dual-probe FISH analysis.

Detection of chromosomal aneuploidies using fetal cells isolated from maternal blood, for prenatal non-invasive genetic investigation, has been a long-sought goal of clinical genetics to replace amniocentesis and chorionic villous sampling to avoid any risk to the fetus. The purpose of this study was to develop a sensitive and specific new assay for diagnosing aneuploidy with circulating fetal cells isolated from maternal blood as previously reported using two novel approaches: (i) simultaneous immunocytochemistry (ICC) evaluation using a monoclonal antibody for i-antigen, followed by fluorescence in situ hybridization (FISH); (ii) dual-probe FISH analysis of interphase nuclei using two differently labeled probes, specific for different loci of chromosomes 21 and 18; in addition, short tandem repeats (STR) analysis on single cells isolated by micromanipulation was applied to confirm the presence of fetal cells in the cell sample enriched from maternal blood. Blood samples were obtained from women carrying trisomic fetuses, and from non-pregnant women and men as controls. Using ICC-FISH approach, a large heterogeneity in immunostaining pattern was observed, which is a source of very subjective signal interpretation. Differently, dual-probe FISH analysis provided for a correct diagnosis of all pregnancies: the mean percentage of trisomic cells was 0.5% (range, 0.36-0.76%), while the mean percentage of trisomic cells in the control group (normal pregnancies or non-pregnant women) was ≤0.20%. The application of the dual-probe FISH protocol on fetal cells isolated from maternal blood enables accurate molecular detection of fetal aneuploidy, thus providing a foundation for development of non-invasive prenatal diagnostic testing.

Heavy metals in human amniotic fluid: a pilot study.

OBJECTIVE: Many heavy metals are essential nutrients for a healthy life. However, significant evidence supports prolonged prenatal exposure as a risk factor for several adverse health effects. The aim of this study is to evaluate the presence of heavy metals in human amniotic fluid (AF) to demonstrate that there is an early fetal in utero exposure. METHODS: The concentrations of a variety of heavy metals, including Be, Ag, Ba, Pb, U, Hg, Sr, Cu, Mn, V, Pd, Sn, Sb, Te, Pt, Sc, Tl, Ni, As, Co, Zn and Se, were measured in 25 AF samples obtained from amniocentesis between 15 and 18 weeks of gestational, after informed consent. RESULTS: Be, Ag, Ba, Pb, U, Cu, Sr, Mn, V, Sn, Te, Pt, As, Tl, Sb, Co, Se and Zn concentrations were detected in measurable amounts in second trimester AF. Mg levels are elevated in all samples. Pd, Ni, Sc and Hg concentrations are below the detection limits in all samples. CONCLUSION: This study demonstrates that heavy metals pass into and accumulate in AF from a very early stage of gestation. Other studies are needed to evaluate the long-term health effects of this early exposure.

Genotype, phenotype and hormonal levels correlation in non-classical congenital adrenal hyperplasia.

Non-classical congenital adrenal hyperplasia (NCAH) is a morbid condition sustained by the reduced function of one of the enzymes involved in the adrenal steroid biosynthesis pathway, mainly the 21-hydroxylase. Different degrees of enzyme activity impairment determine different clinical pictures, with childhood or post-pubertal onset. The aim of this study was to evaluate the relationship between genotype, phenotype, and adrenal hormonal levels in a group of 66 patients affected by NCAH attending outpatient pediatric or endocrinological Clinics. Our findings show that age at pubarche/menarche was significantly younger, height SD score) and Δ bone age-chronological age were significantly higher in patients with a more severe enzyme activity impairment, while cutaneous androgenization and menstrual irregularities in post-pubertal girls were not related to the grading of genotype.

Long-standing mild hypertransaminasaemia caused by congenital disorder of glycosylation (CDG) type IIx.

A 32 year-old asymptomatic male came to our attention with a 21-year history, documented elsewhere, of puzzling increases in his serum transaminase level. At first, very low serum ceruloplasmin level suggested Wilson disease. Two liver biopsies showed mild portal inflammation, steatosis and mild fibrosis. Further investigation revealed low levels of the glycoproteins AT III and clotting factor XI, leading to a diagnosis of congenital disorder of glycosylation (CDG) type II. Further studies as to the cause of this 'apparently new' CDG, are ongoing. On the basis of our data and a literature review, we suggest that subjects with asymptomatic hypertransaminasaemia be screened for CDG.

A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children.

OBJECTIVE: To identify a set of clinical parameters that can predict the probability of carrying mutations in one of the genes associated with hereditary autoinflammatory syndromes. METHODS: A total of 228 consecutive patients with a clinical history of periodic fever were screened for mutations in the MVK, TNFRSF1A, and MEFV genes, and detailed clinical information was collected. A diagnostic score was formulated based on univariate and multivariate analyses in genetically positive and negative patients (training set). The diagnostic score was validated in an independent set of 77 patients (validation set). RESULTS: Young age at onset (odds ratio [OR] 0.94, P = 0.003), positive family history of periodic fever (OR 4.1, P = 0.039), thoracic pain (OR 4.6, P = 0.05), abdominal pain (OR 33.1, P < 0.001), diarrhea (OR 3.3, P = 0.028), and oral aphthosis (OR 0.2, P = 0.007) were found to be independently correlated with a positive genetic test result. These variables were combined in a linear score whose ability to predict a positive result on genetic testing was validated in an independent data set. In this latter set, the diagnostic score revealed high sensitivity (82%) and specificity (72%) for discriminating patients who were genetically positive from those who were negative. In patients with a high probability of having a positive result on genetic testing, a regression tree analysis provided the most reasonable order in which the genes should be screened. CONCLUSION: The proposed approach in patients with periodic fever will increase the probability of obtaining positive results on genetic testing, with good specificity and sensitivity. Our results further help to optimize the molecular analysis by suggesting the order in which the genes should be screened.

Changes in awakening cortisol response and midnight salivary cortisol are sensitive markers of strenuous training-induced fatigue.

The aim of the study was to examine the effects of strenuous training on the hypothalamic- pituitary-adrenal axis activity. Exercise tests and saliva collections for analysis of awakening cortisol response (ACR) and midnight cortisol were performed before and after a 7-day period of intensified training in a group of 15 soccer players. Intensified training resulted in a performance decrement as shown by the pre-post-training changes in maximal values of counter movement jump (CMJ) height (p=0.008). Cortisol assessment during the first 30 min after awakening showed significant increases both before and after the 7-day period and post-training ACR higher than pre-training ACR (p<0.001). Midnight cortisol also significantly increased after training (mean+/-SD, before: 3.0+/-0.7 nmol/l vs after: 5.9+/-3.3 nmol/l; p=0.017). The analysis of individual data showed an important inter-individual variability in the pre-post-training changes: several subjects increased post-awakening peak of cortisol, rate of cortisol increase from awakening to peak, and area under the curve (AUC) values, whereas other subjects showed no training-related increases. Significant correlations were observed between pre-post-training change in CMJ and in the following variables: awakening cortisol (r=0.74), post-awakening peak of cortisol (r=0.81), rate of cortisol increase (r=0.75), and AUC (r=0.79). Briefly, the lower the performance decrease, the higher the training-associated ACR increase. These data could indicate that a dysregulated adaptation to exercise occurred in athletes who experienced a higher performance decrease after training and lower (or absent) hormonal changes. Future studies are needed to elucidate the physiological determinants which underlie the exercise-elicited changes in ACR and in midnight cortisol levels and their value in predicting impaired adaptations to exercise.