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Objective The objective of this study was to report midterm clinical outcomes with a self-expandable sutureless aortic valve. Methods Between 2010 and 2013, 658 patients at 25 European institutions received the Perceval sutureless valve (LivaNova Plc, London, United Kingdom). Mean follow-up was 3.8 years; late cumulative follow-up was 2325.2 patient-years. Results The mean age of the population was 78.3 ± 5.6 years and 40.0% (n = 263) were 80 years of age or older; mean Society of Thoracic Surgeons-Predicted Risk of Mortality score was 7.2 ± 7.4. Concomitant procedures were performed in 31.5% (n = 207) of patients. Overall duration of cardiopulmonary bypass time was 64.8 ± 25.2 minutes and aortic cross-clamping time was 40.7 ± 18.1 minutes. Thirty-day all-cause mortality was 3.7% (23 patients), with an observed:expected ratio of 0.51. Overall survival was 91.6% at 1 year, 88.5% at 2 years, and 72.7% at 5 years. Peak and mean gradients remained stable during follow-up, and were 17.8 ± 11.3 mm Hg and 9.0 ± 6.3 mm Hg, respectively, at 5 years. Preoperatively, 33.4% of those who received the Perceval valve (n = 210) were in New York Heart Association functional class I or II versus 93.1% (n = 242) at 5 years. Conclusions This series, representing, to our knowledge, the longest follow-up with sutureless technology in a prospective, multicenter study, shows that aortic replacement using sutureless valves is associated with low mortality and morbidity and good hemodynamic performance.

Introduction: Changing patterns of migration hasrequired states andgovernments to respond to the specific medical and legal needs of asylum seekers. Based on medical assessments undertaken at the University Institute of Legal Medicine, the present study aims to describe the cases of asylum applicants who have suffered from physical violence, including torture, and the variables involved. Methods: Over a 10-year period, 225 survivors were examined by clinical forensic professionals from the University Institute of Legal Medicine. Results:85% of asylum applicants came from Africa, 87% were male, and the most common age group was 26-40 years old. 46% of applicants fled their country for political reasons. Blunt force injuries were reported in 45% of cases, the trunk was the most affected area of the body (40%), and applicants presented with an average of two different mechanisms of lesions and an average of four lesions each. Discussion/conclusion:Assessment of physical violence on asylum seekers requires the cooperation of professionals with different skillsets and training.

Age estimation is a relevant field of application in archaeology, which is often limited by the fragmentation of recovered skeletal remains. There is therefore an urgent need for the development of novel methods. A potentially useful bone district is the sella turcica. The aim of this study was to evaluate the metrical standards of three different measurements of the sella turcica (length, depth and diameter) in 177 lateral cephalometric radiograms belonging to male and female individuals aged between 7 and 13 years, in order to find standards useful for age estimation. The results were evaluated by two-way ANOVA. There was no significant interaction between sex and age in any variable. The linear regression model fitted to the age and diameter measurements yielded the following equation: age (years) = 4.14*diameter (cm) + 5.76. Slope and intercept 95% CIs were, respectively, 4.64–7.61 years per centimetre and 2.34–5.28 years. The relevant coefficient of determination was R2 = 0.15, while the root mean square error was 1.74 years. The present results provide a novel method that is useful for the age estimation of skeletal remains recovered in archaeological contexts: further studies are needed in order to improve the method on a larger sample.

When estimating post-mortem interval (PMI) in forensic anthropology, the only method able to give an unambiguous result is the analysis of C-14, although the procedure is expensive. Other methods, such as luminol tests and histological analysis, can be performed as preliminary investigations and may allow the operators to gain a preliminary indication concerning PMI, but they lack scientific verification, although luminol testing has been somewhat more accredited in the past few years. Such methods in fact may provide some help as they are inexpensive and can give a fast response, especially in the phase of preliminary investigations. In this study, 20 court cases of human skeletonized remains were dated by the C-14 method. For two cases, results were chronologically set after the 1950s; for one case, the analysis was not possible technically. The remaining 17 cases showed an archaeological or historical collocation. The same bone samples were also screened with histological examination and with the luminol test. Results showed that only four cases gave a positivity to luminol and a high Oxford Histology Index (OHI) score at the same time: among these, two cases were dated as recent by the radiocarbon analysis. Thus, only two false-positive results were given by the combination of these methods and no false negatives. Thus, the combination of two qualitative methods (luminol test and microscopic analysis) may represent a promising solution to cases where many fragments need to be quickly tested.

One of the main issues in forensic anthropology consists of the identification of signs of trauma in skeletal remains, including sharp-force injuries. So far, several studies have been performed to assess differences between injuries caused by different instruments, not, however, through light microscopy.In this study, 152 sharp-force injuries were performed by 5 different tools through 2 different orientations on 2 humeral diaphyses and were analyzed by stereo and light microscopy to assess possible morphological differences.This study showed that although W-shaped injuries are frequently reported in cases of wood-cutting saws, other shapes are often observed; lesions due to metal-cutting saws are almost always U shaped, whereas injuries caused by knives are V shaped. Although cut marks may represent a variable range of features, the present study was able to highlight typical profiles that may be of some help for the diagnosis of weapon and the intentionality of the action.

The morphological assessment of skin injuries is a stronghold of forensic pathology and relies upon standard “rules” for a correct interpretation. But are these parameters reliable? When is the interpretation dangerously difficult? This study aims at quantifying the difficulties in the assessment of stab wounds, gunshot wounds and ligature marks by the observation of photographs in three questionnaires given to 11 experts (forensic pathologists) and 11 non-experts (trainees in forensic pathology). For stab wounds the overall percentage of correct answers was 47.5%, 56.9% for type of blade and 64.2% for type of edge. Gunshot wounds were correctly assessed only in 41.3% of cases. Finally, only in 47.1% of the cases a correct match ligature mark/object of constraint was found. The results show that wounds on the skin can frequently be misinterpreted if classification is strictly based on only morphological parameters; the judgment should therefore be based on an overall evaluation of all evidences, including also those provided by more advanced technological analyses (for example, SEM-EDS for the search of residues, radiological analyses, etc.)

OBJECTIVE—Perforin plays a key role in cell-mediated cytotoxicity. Mutations of its gene, PRF1, cause familial hemophagocytic lymphohistiocytosis but have also been associated with lymphomas and the autoimmune/lymphoproliferative syndrome. The aim of this work was to investigate the role of PRF1 variations in type 1 diabetes. RESEARCH DESIGN AND METHODS—We typed for the N252S and A91V variations in an initial population of 352 type 1 diabetic patients and 816 control subjects and a second population of 365 patients and 964 control subjects. Moreover, we sequenced the coding sequence and intron-exons boundaries in 200 patients and 300 control subjects. RESULTS—In both cohorts, allelic frequency of N252S was significantly higher in patients than in control subjects (combined cohorts: 1.5 vs. 0.4%; odds ratio 6.68 [95% CI 1.83–7.48]). Sequencing of the entire coding region detected one novel mutation in one patient, causing a P477A amino acid change not detected in 199 patients and 300 control subjects. Typing for HLA-DQA1 and DQB1 alleles showed that type 1 diabetes–predisposing DQα/DQβ heterodimers were less frequent in patients carrying N252S or P477A than in those carrying wild-type PRF1. We previously found that natural killer (NK) activity is not decreased in most N252S heterozygotes, but we detected one whose NK activity was normal at the age of 12 but strikingly low in early childhood. Here, we discovered that NK function was low in three heterozygotes in early childhood, one homozygous adult, and in the subject carrying P477A. CONCLUSIONS—These data suggest that N252S and possibly other PRF1 variations are susceptibility factors for type 1 diabetes development.

The term “ponticulus posticus” refers to a partial or complete bony arch over the vertebral artery as it crosses the superolateral surface of the posterior arch of the atlas. This anatomical modification is linked to different symptoms, ranging from neckache to headache and migraine. This bony arch may also be incorrectly assessed during orthopaedic surgery for fixation of C1–C2, with consequent risk of damaging the vertebral artery. Its frequency in the general population has been widely analysed by literature in different geographic contexts, but an analysis of the prevalence of such feature in the Italian population is still missing. A Northern Italian orthodontic sample was analysed to assess the prevalence of ponticulus posticus. Lateral teleradiographies of 221 patients were examined. All the patients underwent lateral cephalometry for odontoiatric purposes and none of them was affected by congenital diseases or skeletal deformities. In the analysed sample, ponticulus posticus had a prevalence of 7.7 % for the complete form, and 9.0 % for the incomplete form. Complete and partial forms were observed, respectively, in 8.8 and 11.0 % of males, and in 6.9 and 7.7 % of females, without statistically significant differences. The current investigation provided the first data concerning the frequency of ponticulus posticus in Italy: further studies are needed to widen the sample, verify possible regional variations and improve the analysis by more advanced radiological examinations such as CT and cone beam CT scans.

Extrapolating type of blade from a bone lesion has always been a challenge for forensic anthropologists: literature has mainly focused on the morphological characteristics of sharp force lesions, whereas scarce indications are available concerning the metrical assessment of cut marks and their correlation with the size of blade. The present study aims at verifying whether it is possible to reconstruct the metrical characteristics of the blade from the measurements taken from the lesion. Eleven blades with different thickness, height and shape were used for this study. A metallic structure was built, in order to simulate incised wounds and reiterate hits with the same energy. Perpendicular and angled tests were performed on fragments of pig femurs, in order to produce 110 lesions (10 for each blade). Depth, height and angle were measured and compared with metrical characteristics of each blade. Results showed a wide superimposition of metrical characteristics of width and angle of lesions regardless the type and the orientation of blade: for symmetric blades a high correlation index was observed between the depth of the lesion and the angle of the blade in perpendicular tests (0.89) and between the angle of lesion and the height of the blade in angled tests (−0.76); for asymmetric blades in both the tests a high correlation was observed between the angle of the blade and angle and width of the lesion (respectively 0.90 and 0.76 for perpendicular tests, and 0.80 and 0.90 for angled ones). This study provides interesting data concerning the interpretation of cutmarks on bone and suggests caution in assessing the size of weapons from the metrical measurements of lesions.

This study aims at verifying the potential of a recent radiological technology, cone beam CT (CBCT), for the reproduction of digital 3D models which may allow the user to verify the inner morphology of sharp force wounds within the bone tissue. Several sharp force wounds were produced by both single and double cutting edge weapons on cancellous and cortical bone, and then acquired by cone beam CT scan. The lesions were analysed by different software (a DICOM file viewer and reverse engineering software). Results verified the limited performances of such technology for lesions made on cortical bone, whereas on cancellous bone reliable models were obtained, and the precise morphology within the bone tissues was visible. On the basis of such results, a method for differential diagnosis between cutmarks by sharp tools with a single and two cutting edges can be proposed. On the other hand, the metrical computerised analysis of lesions highlights a clear increase of error range for measurements under 3 mm. Metric data taken by different operators shows a strong dispersion (% relative standard deviation). This pilot study shows that the use of CBCT technology can improve the investigation of morphological stab wounds on cancellous bone. Conversely metric analysis of the lesions as well as morphological analysis of wound dimension under 3 mm do not seem to be reliable.

Objective Hereditary periodic fever syndromes (HPFs) develop as a result of uncontrolled activation of the inflammatory response, with a substantial contribution from interleukin-1β or tumor necrosis factor α (TNFα). The HPFs include familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), TNF receptor–associated syndrome (TRAPS), and cryopyrinopathies, which are attributable to mutations of the MEFV, MVK, TNFRSF1A, and CIAS1 genes, respectively. However, in many patients, the mutated gene has not been determined; therefore, the condition in these patients with an HPF-like clinical picture is referred to as idiopathic periodic fever (IPF). The aim of this study was to assess involvement of X-linked inhibitor of apoptosis (XIAP), which plays a role in caspase inhibition and NF-κB signaling, both of which are processes that influence the development of inflammatory cells. Methods The XIAP gene (X-linked) was sequenced in 87 patients with IPF, 46 patients with HPF (13 with HIDS, 17 with TRAPS, and 16 with FMF), and 182 healthy control subjects. The expression of different alleles was evaluated by sequencing XIAP-specific complementary DNA mini-libraries and by real-time polymerase chain reaction and Western blot analyses. The functional effect of XIAP on caspase 9 activity was assessed by a fluorimetric assay, and cytokine secretion was evaluated by enzyme-linked immunosorbent assay. Results Sequencing disclosed a 1268A>C variation that caused a Q423P amino acid substitution. The frequency of 423Q-homozygous female patients and 423Q-hemizygous male patients was significantly higher in the IPF group than in the control group (69% versus 51%; odds ratio 2.17, 95% confidence interval 1.23–3.87, P = 0.007), whereas no significant difference was detected in the HPF group (59%) compared with controls. In primary lymphocytes and transfected cell lines, 423Q, as compared with 423P, was associated with higher XIAP protein and messenger RNA expression and lower caspase 9 activation. In lipopolysaccharide-activated monocytes, 423Q was associated with higher secretion of TNFα. Conclusion These results suggest that 423Q is a predisposing factor for IPF development, possibly through its influence on monocyte function.

KSR1 is a mitogen-activated protein (MAP) kinase scaffold that enhances the activation of the MAP kinase extracellular signal-regulated kinase (ERK). The function of KSR1 in NK cell function is not known. Here we show that KSR1 is required for efficient NK-mediated cytolysis and polarization of cytolytic granules. Single-cell analysis showed that ERK is activated in an all-or-none fashion in both wild-type and KSR1-deficient cells. In the absence of KSR1, however, the efficiency of ERK activation is attenuated. Imaging studies showed that KSR1 is recruited to the immunological synapse during T-cell activation and that membrane recruitment of KSR1 is required for recruitment of active ERK to the synapse.

Macrophage colony stimulating factor (MCSF) influences proliferation and survival of mononuclear phagocytes through the CSF-1 receptor. The DAP12 adaptor protein, which transduces signals emanating from various myeloid receptors, is critical for mononuclear phagocyte function. DAP12-mutant mice and humans show defects in osteoclasts and microglia and exhibit brain and bone abnormalities. Here, we demonstrated that DAP12 deficiency impairs MCSF-induced macrophage proliferation and survival in vitro. In addition, DAP12-deficient mice show fewer microglia in defined central nervous system areas, and DAP12-deficient progenitors regenerate myeloid cells inefficiently following BM transplantation. MCSF-CSF1-R signaling induced stabilization and nuclear translocation of β-catenin, which activates cell cycle genes. DAP12 was essential for phosphorylation and nuclear accumulation of β-catenin. These results outline a mechanistic explanation for the multiple defects in DAP12-deficient mononuclear phagocytes.

6 páginas, 2 figuras, 3 tablas -- PAGS nros. 193-198, Human ICOS is a T cell costimulatory molecule supporting IL10 secretion. A pilot study investigating variations of the ICOS gene 3'UTR detected 8 polymorphisms forming three haplotypes (A, B, C). Haplotype-A and -C displayed the highest difference. Activated T cells from healthy AA homozygotes expressed significantly less ICOS and secreted more IL10 than AC heterozygotes, whereas AB heterozygotes displayed intermediate levels. Analysis of 441 multiple sclerosis patients and 793 controls showed that frequency of AA homozygosity was significantly lower in MS patients with relapsing–remitting onset (N = 416) than in controls (OR = 0.70). Moreover, AA patients with relapsing–remitting onset had lower relapse rate and multiple sclerosis severity score than non-AA patients, This work was partially supported by Telethon grant E1170 (Rome), FISM grant 2005/R/10 (Genoa), AIRC (Milan), PRIN Project (MIUR, Rome), Fondazione Cariplo (Milan), Compagnia di San Paolo (Turin), Fondazione Cassa di Risparmio di Cuneo (Cuneo), Regione Piemonte (Turin), and Associazione “Amici di Jean” (Turin)

Mutations decreasing function of the Fas death receptor cause the autoimmune lymphoproliferative syndrome (ALPS) with autoimmune manifestations, spleen/lymph node enlargement, and expansion of CD4/CD8-negative T cells. Dianzani Autoimmune Lymphoproliferative Disease (DALD) is a variant lacking this expansion. Perforin is involved in cell-mediated cytotoxicity and its biallelic mutations cause familial hemophagocytic lymphohistiocytosis (HLH). We previously described an ALPS patient carrying heterozygous mutations of the Fas and perforin genes and suggested that they concurred in ALPS. This work extends the analysis to 14 ALPS, 28 DALD, and 816 controls, and detects an N252S amino acid substitution in 2 ALPS, and an A91V amino acid substitution in 6 DALD. N252S conferred an OR = 62.7 (P = .0016) for ALPS and A91V conferred an OR = 3 (P = .016) for DALD. Copresence of A91V and variations of the osteopontin gene previously associated with DALD conferred an OR = 17 (P = .0007) for DALD. In one N252S patient, NK activity was strikingly defective in early childhood, but became normal in late childhood. A91V patients displayed lower NK activity than controls. These data suggest that perforin variations are a susceptibility factor for ALPS/DALD development in subjects with defective Fas function and may influence disease expression.